Immune Response Ebook

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

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The Immunity Crisis in America

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

Immunity Crisis Summary

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Author: Nicholas St Jon
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The HLA system and the immune response to HIV

CD8 T cells recognize their antigen (peptide) in context with HLA class I molecules on antigen-presenting cells, whereas CD4 T cells require the presentation of antigenic peptides in context with HLA class II molecules. The generation of an HIV-specific immune response is therefore dependent on the individual HLA pattern. In vitro studies in HLA B57-positive patients demonstrate that these patients display HLA B57-restricted CTL directed against HIV-1 peptides. However, it is possible that the identification of protective HLA alleles or HLA-restricted peptides in HIV-1-infected patients with a benign course of disease does not necessarily indicate that the same alleles or peptides are crucial for the design of a protective vaccine. Kaul and co-workers were able to show that CD8 T cells from HIV-1-exposed but uninfected African women recognize different epitopes than CD8 T cells from HIV-1-infected African women (62). This suggests that the epitopes, that the immune system is directed...

The Th1Th2 immune response

Depending on the secretion pattern of cytokines, CD4 T cells may be differentiated into TH1 and TH2 cells. TH1 CD4 T cells primarily produce interleukin-2 (IL-2) and IFNy, which represent the cytokines that support the effector functions of the immune system (CTL, NK-cells, macrophages). TH2 cells predominantly produce IL-4, IL-10, IL-5 and IL-6, which represent the cytokines that favor the development of a humoral immune response. Since TH1 cytokines are critical for the generation of CTLs, an HIV-1-specific TH1 response is regarded as being a protective immune response. Studies on HIV-exposed but non-infected individuals have shown, that following in vitro stimulation with HIV-1 env antigens (gp120 gp160) and peptides, T cells from these individuals secrete IL-2 in contrast to non-exposed control persons (79). Similar studies were undertaken in healthcare workers after needle-stick injuries and in newborns from HIV-infected mothers. Although these observations may indicate that a...

HIV1 specific humoral immune responses

The association between an HIV-1-specific humoral immune response and the course of disease is less well characterized. In a SIV model, injection of an antibody cocktail consisting of various neutralizing antibodies is able to prevent SIV infection after a mucosal virus challenge (80), indicating that primary protection is mainly dependent on a broad humoral immune response. In contrast, B cell depletion by a monoclonal antibody directed against B cells in monkeys with already established SIV infection, does not affect the course of plasma viremia (81). Long-term non-progressors with HIV tend to have a broad neutralizing activity towards a range of primary isolates and show persistence of neutralizing antibodies against autologous virus. At present, it is unclear whether the presence of neutralizing antibodies in LTNP represents part of the protection or whether it merely reflects the integrity of a relatively intact immune system. Individuals that have a substantial risk for HIV-1...

Interleukin2 Immunotherapy

Clinical trials using l-carnitine (1 g day orally) found that it may be used successfully to prevent cardiac complications during IL-2 immunotherapy in cancer patients with clinically relevant cardiac disorders (Lissoni et al 1993). Thus a beneficial interaction is possible under professional supervision.

Recognition in the Context of a Humoral Immune Response

An understanding of the parameters governing the HIV-1 receptor interactions would be incomplete without an understanding of the context in which this recognition occurs. While all recognitions pit specific versus non-specific interactions, HIV-1 receptor recognition occurs in the context of a persistent infection. In order to bind to receptor while simultaneously eluding neutralization by the humoral immune system, gp120 has evolved sophisticated strategies of evasion (Fig. 3) 17,22,27 . Carbohydrate masking involves covering exposed protein surfaces with a dense array of N-linked glycans. Because these glycans are derived from host biochemical pathways, they are interpreted as self by the immune system and do not elicit antibodies. In addition, the carbohydrate sterically inhibits access to the underlying protein surfaces. Epitopes protected by carbohydrate masking are thus immunologically silent. In terms of the potentially vulnerable receptor binding surfaces, the virus must...

Influence of Age Related Decline in Immune Function and Influence on Intestinal Bifidobacteria Microbiota

Immunosenescence is defined as the state of deregulated immune function that contributes to the increased susceptibility of the elderly to infection and, possibly, to autoimmune diseases and cancer (49,50). When immunosenescence appears, the functional capacity of the immune system of the host gradually declines with age. The most dramatic changes in immune function with age occur within the T cells compartment, the arm of the immune system that protects against pathogens and tumors (51-54). The fact that T lymphocytes are more severely affected than B cells or antigen-presenting cells is mainly due to the involution of the thymus, which is almost complete at the age of 60. The host is then dependent on the T cells of various specificities, which eventually leads to changes in the T cell repertoire. CD45RA + native cells are replaced by CD45RA memory cells, and a T cell receptor oligoclonality develops. At the same time, T cells with signal transduction defects accumulate. Age-related...

Within Hostimmune System Models

The compartmental differential equation models described earlier are also adaptable to the study of the dynamics of the immune system in response to infection. Such models can provide novel and useful insights into the observed time course of quantitative clinical measures of infection within the human host and how these might relate to the probable course which may be taken by the infection by providing explanations for observed dynamical changes in such measures they also offer the prospect of illuminating some of the reasons why response to infection appears to differ between hosts. Useful examples of such work may be found in work on HIV by Nowak and Bangham (1996) and Nowak et al. (1997), and on viral hepatitis by Bocharov et al. (2004).

Brief Review Of Immune Responses Innate Immunity

Cells responsible for the innate immunity provide the first line of host defense monocytes macrophages, dendritic cells (DC), natural killer cells (NK), and neutrophils. These are the body's sentinels, able to detect danger and signal it to other cells, by the synthesis of molecules, such as NO (nitric oxide) which displays antibacterial activity, cytokines, and chemokines, which are small peptides acting by means of specific receptors expressed at the surface of targeted cells. Some of them have pro-inflammatory properties, and increase expression of surface markers on some cells allowing migration into neighboring lymphoid organs. DCs and macrophages are able to display a phagocytic activity, and by production of inflammatory chemokines and cytokines, to modulate other cells such as neutrophils, polymorphonuclear cells and eosinophils in the case of hypersensitivity, which increase the inflammatory action, and ultimately B and T cells, which will set up an acquired immune response...

The Intestinal Immune System

The IIS is a particular immune system anatomically and functionally distinct from that present at the peripheral level (30-32). It is in contact with an enormous quantity of Ags, food proteins and intestinal bacteria, and does not mount an inflammatory response against them. At the same time, it has to protect against enteric pathogens and toxins. Three lines of defense are present (i) natural defenses stomach acidity, bile salts, mucus, motility, permeability, (ii) innate immune responses Ag capture, cytokine secretion, TLRs, and (iii) acquired immune responses namely oral tolerance (OT) and secretory IgA (sIgA) response. All of them interact together.

Modulation of Specific Immune Responses The IgA Anti Rotavirus Response

Little information is available regarding the role of intestinal microbiota composition on the modulation of the specific sIgA Ab response against enteropathogens. Indeed, it can be assumed that, according to the composition of the digestive microbiota and the presence, or not, of some bacteria in the dominant microbiota, the specific immune responses might be different. This fact is of particular importance in babies where the poorly diversified intestinal microbiota is strongly influenced by the type of milk. Indeed, it is well known that breastfed babies are more resistant to enteric infections than formula-fed babies (69,70). Human breast milk contains abundant bioactive components that may provide direct protective effects to infants against enteric pathogens (71), but breast-feeding also influences the intestinal microbiota composition enhancing Bifidobacterium development. To test the influence of the intestinal microbiota on the modulation of a specific intestinal sIgA-Ab...

Activation of the Immune System

Innate immunity plays a very important role in the activation of the immune system and the ability to develop specific acquired immune responses. Through their Ag-presenting activity and the synthesis of numerous pro-inflammatory chemokines and cytokines (IL-8, IL-1, IL-6, TNF-a, and IL-12), macrophages, and DCs play a key role in the regulation of immune responses. They are the gatekeepers of the host, generating innate resistance to pathogens, and specific immune responses by the stimulation of T-cell-acquired immunity and regulation of the TH1 Th2 balance.

Adenoassociated Virus For Immunotherapy

The potential of AAV vectors for cancer immunotherapy is evident from recent studies using cytokine gene transfer and in vivo immunization approaches (108-110). Active immunization with tumor cells transduced with rAAV encoding cytokines either by a plasmid based-delivery system or by a recombinant virus-mediated infection has resulted in regression of tumor growth upon further challenge. In a separate study, high-level IFN-y and elevated major histocompatibility complex (MHC) class I expression was observed following transfer of D122 gene-modified murine lung cancer cells that significantly delayed tumor development (111). Similar findings of antitumor immunity following transfer of cytokine-encoding AAV DNA in a rat prostatic tumor model (112) were reported. Enhancements in antitumor T-cell response was observed in vitro by AAV-mediated transduction of B7.1 and B7.2 genes in a human multiple myeloma cell line (113). In a vaccination scheme, Liu et al. have recently shown that...

Trial design for testing immunotherapy in tuberculosis

In view of the increasingly widely accepted need for immunotherapy as the only real hope for the improvement of treatment under realistic field conditions, the failure of the Durban trial to yield interpretable data raises important questions about future exploitation of immunotherapy, whether immunological or endocrinological. Is it possible to devise a trial in patients with drug-resistant disease that would conform to regulatory requirements The sporadic distribution of these patients and their lack of uniformity has frustrated attempts to devise such trials in the past. Secondly, and more importantly, would it be possible to design a study that could be performed under realistic field conditions that would satisfy regulatory bodies Until these dilemmas are resolved, it may not be possible to test immunotherapy for tuberculosis in a meaningful way.

Immunotherapy for HCC

To improve the prognosis of progressive HCC and the recurrence-free survival rate after topical treatment, we need to develop whole-liver treatment based on a new point of view. It is in this context that there are high expectations for immunotherapy to treat HCC (Butterfield, 2004 Palmer et al., 2005 Avila et al., 2006). Immunotherapy for cancer has been developing from nonspecific to specific, from those using unknown mechanisms to those where the mechanism has been clarified. To holistically activate immune responses in vivo, immunomodulating therapy using bacterial compounds has been replaced by cytokine therapy. Adoptive immunotherapy using lymphokine-activated killer cells (LAK) has been replaced by therapy using tumor-infiltrating lymphocytes (TIL) that are tumor-specific, and nonspecific immunostimulation has been replaced by specific treatment using DC or tumor-specific antigens. In addition, conventional approaches have been reevaluated from an up-to-date point of view...

Hspapc Interactions Initiation Of Immune Responses

Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601 Abstract The immunogenicity of HSPs is exquisitely dependent on its interaction with professional antigen presenting cells. The interaction is specific and occurs through surface receptors on the APC such as CD91. Other molecules such as CD40, LOX-1, CD36, Toll-like receptor-2 & 4, SR-A and SREC-I have also been proposed to be HSP receptors and are discussed. The physiological situations where the HSP-APC interaction is necessary such as cross-priming of antigens and maturation of the APCs and the implication of these events for the priming of immune responses against infectious agents and tumors and for maintenance of tolerance against self antigens are deliberated

Immunotherapy of experimental tumors with haptenmodified vaccines

There is considerable evidence that the failure of immunotherapy to eradicate cancers, whether spontaneous human cancers or experimental transplantable tumors, is a result of immunological tolerance. The most striking illustration of this hypothesis remains the work of Mullen et al. (25). They produced two variants of the fibrosarcoma 1591 a regressor tumor that was highly immunogenic and always rejected by normal mice and a progressor tumor that had become nonimmunogenic as a result of losing a tumor-rejection antigen. Surprisingly, animals that had been implanted with the progressor tumor were unable to reject even a small challenge of the regressor tumor. These progressor tumor-bearing mice were not generally immunosuppressed, since they generated normal immune response to alloantigens, allogeneic tumors, and certain other syngeneic tumors. Their immunological tolerance was tumor-specific. Fujiwara et al. (32) took a somewhat different approach. They found that a fairly large (8-mm...

Exosomes and their potential application in immunotherapy

Active immunotherapy with mature DCs is being extensively tested for treatment of malignancies. DC-based immunotherapy, however, remains difficult to handle for scale up, definition of quality control parameters, and long-term storage. Indeed, many investigators have shown that one leukopheresis enables up to 4-10 DC injections, whereas there is evidence that a larger number of injections, perhaps spanning over a year or more, appear to be required for long-lasting antitumor protections. Maturation of DCs has been shown to be necessary for efficient DC migration and Tc1 differentiation in lymph nodes. However, GMP cytokine cocktails, required for efficient maturation of DCs need to be, more broadly defined. Finally, regulatory authorities' criteria for the development of therapeutics require biochemical or functional characterization of off-the-shelf products that cannot be readily achieved.

Early studies of adoptive immunotherapy of tumors

Two of the fundamental concepts that underlie tumor immunotherapy, namely that cellular elements could confer immunity upon na ve recipients and that unique tumor antigens were the relevant targets, were established empirically long before T lymphocytes were defined or the nature of antigen recognition was understood at a molecular level. Billingham observed that immunity to skin grafts could be transferred to na ve recipients by lymph node (LN) cells and introduced the term adoptive immunity to describe this phenomenon (3). This concept was soon extended to transplantable tumors by Mitchison (1). In his pioneering study, Mitchison documented the efficacy of TDLN cells rather than distant LNs or peripheral blood, the requirement for viable lymphoid cells, the dependence on a sufficient cell dose for protection, and the development of a memory response. Klein demonstrated that primary hosts rendered surgically free of carcinogen-induced tumors and subsequently immunized with irradiated...

Critical developments for adoptive immunotherapy using autologous t cells

Clinical applications of adoptive immunotherapy will likely be most effective and least toxic if they use an autologous source of tumor-reactive T cells. T cells recognize tumor antigens in the form of peptide fragments of proteins presented by MHC molecules. Thus, each tumor antigen that is targeted must be matched for the relevant MHC molecule. Additionally, humans have a large number of alleles in the HLA gene complex and a mismatch of donor and recipient at either class I or class II loci leads to rapid rejection of transferred effector cells or alternatively risk of graft vs host disease. The source of autologous T cells is important because successful adoptive immunotherapy is dependent on the dose of tumor-reactive T cells. The effector cell number is the product of the precursor frequency in the sample multiplied by the total number of cells generated. Therefore, identification of sources of T cells that are already considerably enriched for tumor-reactive precursors is...

Subversion of the immune system

However, it is clear that once infection has occurred, HHV-6 is able to establish latency and remain quiescent for prolonged periods of time unless the immune system is otherwise immunocompromised. One of the mechanisms by which viruses establish long-lived infections and subvert the immune system is by directly infecting immune cells thereby impairing surveillance. The original report of the isolation of HHV-6 by Salahuddin et al. (1986) described an isolate from patients with a B-cell lymphoproliferative disorder, although these lymphomas frequently contain T lymphocytes that were the likely source of the virus (G. Krueger, personal communication). Horvat et al. (1993) reported that HHV-6 inhibited the lymphoproliferative responses of human peripheral blood monocytes in vitro. Kondo et al. (2002) identified monocytes macrophages as target cells during acute infection. According to Lusso et al. (1991, 1993, 1995), HHV-6 is able to productively infect...

Enhanced Immune Response

Immune system modulation and the prevention of gastrointestinal tract colonisation by a variety of pathogens are perhaps the most important actions of probiotics. Probiotics bind to intestinal epithelial cells and inhibit the binding of pathogenic bacteria to the gut wall by production of inhibitory substances such as bacteriocins, lactic acid and toxic oxygen metabolites. Of the toxic oxygen metabolites, hydrogen peroxide is of major importance as it exerts a bactericidal effect on many pathogens (Kaur et al 2002). The ability to produce bacteriocins, hydrogen peroxide and other antimicrobial compounds is strain-dependent and requires the presence of folic acid and riboflavin in the case of lactobacilli. Binding to the gut wall also initiates signalling events that result in the synthesis of cytokines (Vanderhoof & Young 2003) Studies in germ-free mice have proven that intestinal bacteria are essential for a healthy systemic immune system (Falk et al 1998).

Effect of Glycosylation Changes on the Interaction of Viral Envelope Glycoproteins With the Immune System

Carbohydrates are generally regarded as poorly immunogenic because (1) identical glycan epitopes are also found on host cell glycoproteins, thus are recognized as self by the immune system, (2) glycoproteins display considerable microheterogeneity, and (3) carbohydrates are extensive structures that may mask potential protein-based epitopes (22). Indeed the glycosylation of HIV gp120 is thought to act as an evolving glycan shield, whereby changes in N-glycosylation acceptor sites due to escape mutations in gp120 enable HIV to evade the host immune response by shielding underlying epitopes with variable glycosylation (23,24). Similarly, the acquisition of N-glycosylation sequons in the influenza H3 HA1 glycoprotein is also thought to protect from the binding of neutralizing antibodies (25). Recent studies of antibodies, produced in monkeys inoculated with SIV gp120 glycosylation mutants, indicate that N-linked glycosylation influences immunogenicity in addition to antigenicity (15).

Hsp60 And The Innate Immune System

Many of the reported pro-inflammatory effects that result from exposure of cells to HSP60 are actually mediated through LPS or other microbial compounds contaminating the HSP60 (Gao and Tsan 2003 Tsan and Gao 2004). In spite of the controversy surrounding the involvement of TLRs in the effects of HSP60 on the immune system, it became clear that HSP60 could play an important role in controlling adaptive immune responses through its effects on APCs and function as a powerful accessory signal in the induction of Th1-like responses (Flohe et al. 2003).

The Essential Role of the Adaptive Immune Response in HCV Clearance

In the absence of high levels of immunosuppression, HCV is a non-cytopathic virus. In the absence of an ongoing immune response, it infects and persists in target cells, predominantly hepatocytes, without inducing inflammation and damage. This has been demonstrated in both experimental chimpanzee models (Thimme et al., 2002) and in drug users or humans who were accidentally infected with contaminated needles during health care practice (Thimme et al., 2001 Timm et al., 2004). In these studies, increases in viremia were not associated with parallel increases in serum transaminase levels, thus reflecting an absence of hepatocyte damage. Furthermore, following liver transplantation, infection does not lead to liver damage for a 3-week period despite high levels of virus. The only cytopathic lesion that has been directly ascribed to HCV is the association of Genotype 3 infection with steatosis, the accumulation of lipids in hepatocytes (Pawlotsky, 2004). Although non-cytopathic, gene...

Role of the Innate Immune System During HCV Infection

The innate immune response represents the first line of defense against pathogens and is maintained by complement, natural killer (NK), natural killer T cells (NKT) cells, and macrophages. It is widely accepted that this arm of the immune system is effective in removing most pathogens that infect the body. The innate immune response also plays an important role in activating and amplifying the adaptive immune system (Trobonjaca et al., 2001 Chan et al., 2006). Viruses produce viral pathogen-associated molecular patterns (PAMPs) that are able to initiate a cascade Several reports in both chimpanzee and humans indicate that the virus activates the innate immune response before and during acute infection by inducing secretion of endogenous type I interferon (IFN-a and - ) and by activating NK cells. Analysis of gene microarray experiments from experimentally infected chimpanzee liver biopsies has revealed the induction of a broad range of IFN-a inducible genes (ISGs) (Bigger et al.,...

Immune Function Assessment

Phenotypes of genetically altered mice can be validated and enhanced by conducting basic immune function assays. These assays provide information to distinguish whether phenotypic characteristics are associated with secondary changes and ill health, or are the direct or indirect result of genetic manipulation. Basic immune analyses provide further evidence of the validity of these observations. In addition, novel phenotypes can be identified for understanding molecules and pathways involved in immunocyte development and immune function, including immunodeficiency, cancer, autoimmunity, biology of aging, and resistance to infectious diseases. The identification of lineage-specific developmental defects in mutant mice is also possible.

Interfering With the Immune Response Against the Virus

For the viral antitumor effect to succeed, viral replication must out-compete tumor proliferation. However, the fact that oncolytic viruses are attenuated in their replication and that they also provoke an intense immunogenic response may hinder efficient tumor spread and lysis. Therefore, one strategy to improve biologic efficacy may involve interfering with the immune response. The immune response of the body to adenoviruses and HSVs follows a similar pattern consisting of an immediate innate response and a slower adaptive response. The nonspecific early occurring immune response contributes the largest effect to elimination of the viruses (44). This innate response includes the activation of the complement cascade (45) and the recruitment and activation of macrophages, neutrophils, and natural killer cells which kill the infected cells either directly, or indirectly by secreting antiviral cytokines and chemokines (46,47). In addition, the recruitment and activation of...

Active specific immunotherapy

Active nonspecific immunotherapy, utilizing agents such as BCG, IL-2, levamisole, and diptheria toxoid, has been used to stimulate a systemic or generalized immune response not directed against any particular tumor antigen (2). Nonspecific immuno-therapy relies on the existence of immune effector cells (T and B cells) that have already recognized and processed the tumor as foreign. Then, by enhancing the overall immune response, the hope is to enhance the tumor-specific elements to create an effective anticancer response. Poor, nonreproducible results have led clinical researchers to move toward active specific immunotherapy (ASI) approaches. In this approach, the goal is to immunize the patient against his her own cancer specifically, via induction of a tumor-specific immune response able to kill tumor cells (3). Whole-cell autologous vaccine preparations require a fresh sample of the patient's own tumor, either primary or derived from an established tissue culture. Primary tumor is...

Essential Metals And The Immune System

The elements zinc, iron, copper, selenium, chromium, and cobalt are essential metals for the human body and the immune system. There is ample evidence that Fe deficiency comprises humoral immunity in both humans (Feng et al., 1994 MacDougall and Jacobs, 1978) and animals (Kochanowski and Sherman, 1985), possibly because of the need for iron in early events associated with cell activation, including generation of second messengers (Kuvibi-dila et al., 1999). In contrast, excess iron suppresses innate and cell-mediated immunity (Bowlus, 2003). Zn deficiency and the following increased corticos-teroid levels cause apoptotic loss of precursor B and T cells in mice, leading to thymic atrophy and lym-phopenia (Fraker and King, 2004). Zn deficiency also seems to be of clinical relevance in humans (Black, 2003). Excess of Zn has resulted in divergent effects on the immune function, including some reports of immunostimulation in humans. Copper deficiency is immunosuppressive and reduces IL-2...

Immune Response Considerations

The administration of medicinal recombinant proteins raises the potential that the human immune system will recognize these proteins as foreign (1). A number of factors have been shown to either encourage or discourage immune assault. Oral or intravenous administration illicits weak immune responses, whereas subcutaneous or repeated administration strengthens the response (2,3). The immune response is sometimes exaggerated in patients with autoimmune disease and in patients with cancer or those treated with immunosuppressive therapies (4). The presence of extraneous proteins acquired during the industrial manufacturing may act as immune adjuvants, resulting in a heightened immune reaction (5). Simple proteins, proteins with tertiary and quarternary structures similar to other self proteins, and proteins that are soluble tend to be either nonimmunogenic or less immunogenic than those that are complex, degraded, aggregated, or denatured (3,6). Glycosylation prevents exposure of the...

Nonspecific active immunotherapy

Although the purpose of this chapter is to describe the results for vaccines in the treatment of lung cancer, it is important to consider that nonspecific inflammatory mediators have demonstrated activity in lung cancer and although experimentally, they are giving way to the more specific tumor vaccines, they may be combined with vaccines in the future. Initial studies utilizing the bacille Calmette-Guerin (BCG) strain of Mycobacterium tuberculosis, bovis BCG, administered by the intrapleural, intratumoral, intradermal, or aerosolized routes demonstrated positive results, although two randomized trials failed to show any effect (48,49). Other attempts at nonspecific immunotherapy in lung cancer have included Nocardia rubra cell wall skeleton, Corynebacterium parvum, transfer factor (TF), Krestin (PSK), the streptococcal preparation OK-432 (50), and more recently, SRL172, a suspension of heat killed Mycobacterium vaccae, which is currently in a pilot study for SCLC (51). Patients with...

Therapies Targeting the Immune System

The incidence of autoimmune disorders is increased in some MDS populations (Saif et al. 2002). Autologous cy-totoxic T-lymphocytes have been observed to exert an inhibitory effect on MDS myelopoiesis in vitro. The clinical features of subsets of MDS overlap with aplastic anemia (AA) and large granular lymphocyte (LGL) lym-phoproliferative disorders, two diseases thought to be related to dysregulation of the immune system (Barrett et al. 2000). Clinical studies have shown activity of the immunosuppressives antithymocyte globulin and cy-closporine in the treatment of select groups of MDS patients.

Stimulating the Immune System

Different gene therapy approaches have been put forward to stimulate the immune system. The basic principle underlying immunotherapy in cancer is that tumors have Stimulating the immune system. Transfer of suicide genes. Replacement of tumor suppressor genes. Inhibition of oncogenes. Inhibition of angiogenesis. Induction of apoptosis. antigens that are capable of provoking weak humoral or cellular reactions. By activating this immune response against tumor cells through gene transfer it is hoped that tumors can be eradicated either by the transferred gene product or activation of the patient's own immune system. In animal models, the administration of cytokines such as inter-leukin (IL)-2, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor (TNF)-a, interferons and granulocyte macrophage colony-stimulating factor (GM-CSF) have resulted in tumor regression (8). The systemic administration of cytokines in human trials though has been limited by the severe toxicity of these cytokines. Gene...

Innate And Adaptive Immunity

The fundamental purpose of the immune system is to distinguish between self and non-self. Foreign antigens are eliminated in a variety of ways by both the so-called innate and adaptive components of the immune system. The innate immune system deals with foreign invaders through rapid, albeit fairly nonspecific, responses. Moreover, there is no recall or memory within the innate immune system. By contrast, the adaptive immune system takes a bit longer to respond, but retains memory for the specific antigen, and is able to respond in an accelerated fashion in the event of re-encounter with the same antigen. Indeed, it is this ability to ''learn'' and remember specific antigens that is the basis for vaccination. The two major types of lymphocytes that comprise the adaptive immune system are B cells and T cells. Both are derived from hematopoetic stem cells in the bone marrow, but they function in entirely different ways. B cells produce soluble proteins known as antibodies, which can...

Immune Surveillance And Susceptibility To Infection

Respiratory infections are recognized as the fifth leading cause of death for individuals over age 65 (National Vital Statistics, 2001). There are many factors that make the elderly more susceptible to lung infections. These include declining immune function, impaired oral and mucociliary clearance, neurologic disorders, malnutrition, chronic organ dysfunction syndromes, and the presence of parenchymal lung disease (Meyer, 2004). Although various aspects of systemic immunity decline with advancing age, there is considerable variation among individuals. Fairly robust immune responses can be identified in centenarians (Franceschi et al., 1995), and many other factors such as the presence of a swallowing disorder and aspiration can cause pneumonia in the elderly despite intact immune responses. Both T and B lymphocyte responses tend to gradually wane with advancing age, and antibody responses to vaccines are less robust in the elderly than in younger individuals (Meyer, 2001). Although...

Immune Function And Maintenance Of Epithelial Surfaces

Vitamin A maintains the health of epithelial cells in the body, which form an important barrier to infection, and immune system function. More specifically, studies in animal models and cell lines show that vitamin A and related retinoids play a major role in immunity, including expression of mucins and keratins, lymphopoiesis, production of antibodies, and the function of neutrophils, NK cells, macrophages, T-lymphocytes and B-lymphocytes (Semba 1999). It has also been shown to potentiate antibody responses and lymphocyte proliferation in response to antigens and restore the integrity and function of mucosal surfaces (Semba 1994).

In Vitro Measures of Functional Antigen Specific Immune Responses

In addition to phenotypic assays, in vitro assays of T-cell function play an important role in detecting and quantitating antigen-specific immune responses. Functional assays measure a T-cell activity in response to a specific antigenic stimulus, include proliferation, cytokine secretion, and cytolytic function. These assays can be performed on specimens stimulated in vitro with antigen and cytokines, or on PBMC samples, without any preceding in vitro stimulation. The proliferation assay has been in use for a long time and it has frequently been used in clinical trials to compare T-cell responses before and after immunization (6,7,38-41). Depending on the immunization strategy, a small percentage (38,39) to as many as half (40) or all (41) patients have been found to respond by proliferation assays. Its major advantage is the ability to perform the assay directly on peripheral blood samples, giving a picture of the T-cell activity present in vivo (although the long in vitro culture...

Vertebrate Immune Responses

All vertebrates have what is traditionally termed an innate immune response, a rather generic, nonspecific system. Gnathostomes (jawed vertebrates) also have an adaptive response, that learns via antigen-antibody reactions to combat specific pathogens. Innate immunity does not improve with subsequent exposures to a pathogen. Adaptive immunity is specific and has memory in that the adaptive response to a pathogen improves with each subsequent exposure during an individual's life, but this knowledge is not transmitted to the next generation. This does not mean that jawed vertebrates have a more effective immune system in general agnathic vertebrates are still around, and their rarity relative to gnathostomes is generally attributable to their having been outcompeted by jawed vertebrates, not pathogen attack. However, it certainly raises the question as to what forces led to the evolution of the complex adaptive system (see below). Innate vertebrate immune Responses ical barriers such as...

HSP Immune Responses and Lack of Self Tolerance

Besides their immunodominance as microbial antigens, under various circumstances HSP do elicit immune responses also when (over-)expressed as self antigens by cells or tissues. And this seems to be a peculiar feature of HSP, especially because in many cases immune responses to this self antigen are not associated with pathogenic autoimmunity. Evidently, healthy individuals have a broad repertoire of T and B cells with specificity for mammalian or self HSP. Self HSP specific immunity has been seen to exist in mice, rats, humans and other species studied so far. Apparently, thymic selection ensures the selection of a repertoire of cells with cognate receptors that can recognize such proteins, despite the fact that they are omni-present in almost every cell of our body. Whatever the mechanisms behind this lack of tolerance may be, it needs to be compensated efficiently by immune regulation in the periphery in order to control self HSP specific immunity. And indeed, as we will discuss...

Adaptive Vs Innate Immune Systems

The immune system is an organization of cells and molecules with specialized roles in defending against infection. There are two fundamentally different types of responses to invading microbes. Innate (natural) responses occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) responses improve on repeated exposure to a given infection. The innate responses use phagocytic cells (neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (basophils, mast cells, and eosinophils), and natural killer cells. The molecular components of innate responses include complement, acute-phase proteins, and cytokines. Acquired responses involve the proliferation of antigen-specific B and T cells, which occurs when the antigen receptors of these cells bind to antigen (Delves and Roitt 2000).

And the Skin Immune System

Hidradenitis Suppurativa Immune System

The involvement of the immune system in HS remains controversial. Immunological investigations of some patients with HS suggested no abnormalities of the immune system 15 . In contrast, other authors showed increased peripheral suppressor T cell activity 48 , suggestive of a precipitating cell-mediated immune response. This is further supported by the presence of activated, HLA-DR-positive lymphocytes 8 . Although in lower numbers and preferentially located in the direct perivascular compartment, Leu-8-positive immunoregula-tory lymphocytes were also present in lesions, suggestive of a loss of Leu-8 cellular antigen in lymphocytes during further migration into the dermal tissue 8 . These results indicate that the lymphocytic infiltrate is definitely the result of in vivo activation of lymphoid cells. Indeed, the significant fall of the T-helper suppressor ratio over time after the initiation 8 supports the existence of a precipitating cell-mediated immune response with only a short...

Immune System

The immune system, which has the job of making the body immune to infection and disease, consists of the bone marrow, thymus gland, spleen, lymph nodes, and tonsils. Lymphocytes, or white blood cells, are produced in the bone marrow. Some of these cells travel to the thymus, mature into T cells, and are then sent into the bloodstream to become killer or helper T cells. Killer T cells reject foreign tissue and destroy viruses, fungi, and parasites, whereas helper T cells assist another group of white cells known as B cells. B cells are lymphocytes that have traveled from the bone marrow to mature in the spleen or lymph nodes. At maturity, B cells enter the bloodstream, where they produce antibodies to resist bacteria. In addition to the two types of lymphocytes, two other types of cells that contribute to immunity are monocytes and leukocytes. The effectiveness of white blood cells, and hence the efficiency with which the body is able to eliminate foreign substances, decreases with...

Immunotherapy

Immunotherapy with crude extracts of M. tuberculosis is not possible, and it causes necrosis and disease exacerbation (Anderson 1891, Koch 1891). In contrast to the necrotic skin test responses to the antigens of tuberculosis itself, tuberculosis patients have defective skin-test responses to the common antigens (Kardjito et al 1986), so injection of these antigens, or of environmental saprophytes that contain them, causes trivial local reactions. These antigens can be protective when they evoke an exclusively Th1 response (Fig. 2), and they are safe to administer. These points, together with the Th2-to-Th1 switching properties of the M. vaccae-derived preparation SRL172, justify its investigation as a potential immunotherapeutic in tuberculosis. It has been shown to be effective in mice (without any chemotherapy Rook & Hernandez-Pando 1996) and in pilot studies in humans (Corlan et al 1997). bacterial clearance, weight gain or ESR at eight weeks. These results may indicate that in...

Cell Surface Antigenantibody AgAb Cytotoxicity Type Ii Reactions

Signs and symptoms include hemoglobinuria and kernicterus (jaundice). C. Prevention. Sensitization of the mother can be prevented by injecting the Rh-negative mother with anti-Rh antibody (i.e., RhoGAM) within 1-2 days of delivery. This antibody neutralizes the fetal Rh-positive antigens entering the mother's circulation during the removal of the placenta, thereby preventing stimulation of the maternal immune system and injury to future Rh-positive newborns.

Overview

The immune system is a complex system composed of several types of sessile and mobile cells that interact in lymphoid tissue dispersed throughout the body. This system is stimulated by the introduction of foreign material (antigen) into the host its function is the elimination of this material.

Cancer Immunology

Cancer antigens. Cancer cells arise from normal cells. In order for the immune system to attack cancer cells, the cancer cells need to be distinguished from self (i.e., they need to possess antigens). (1) Virus-induced TSA are cross-reactive (i.e., the genome of a particular virus synthesizes the same viral antigens in whatever cell that virus infects). Consequently, immunotherapy should be applicable to all individuals infected by the same virus. 2. Immune response to cancer antigens 3. Cancer cell evasion of the immune system. Cancer cells can evade the immune system in multiple ways. Examples include the following. a. The relatively weak immune response may be overwhelmed by rapid tumor growth. IV. CANCER IMMUNOTHERAPY

Michael A Morse MD Timothy M Clay PhD and H Kim Lyerly MD

How Cellular Effectors Recognize Tumors Components of the Immune System Involved in Tumor Interest in activating the immune system to control tumors dates to more than 100 yr ago and is often attributed to William B. Coley who used the inflammatory response to bacterial products as a form of immunotherapy (1). This initiated the era of attempts to nonspecifically activate the immune system with the hope that tumors would be targeted as part of the overall, predominantly inflammatory, response. Following the abandonment of the crude bacterial products in Coley's toxin, other bacteria or their cell wall products such as bacille Calmette-Guein (BCG), Corynebacterium parvum, nocardia rubra, OK-432, and others have been tested. In some circumstances, these inflammatory activators have had success as antitumor agents. For example, BCG has activity in superficial bladder cancer in situ (2). Later, cytokines such as interleukin (IL)-2 that could activate T and natural killer (NK) cells were...

From Primary Cultures to the Aging Organism Lessons from Human T Lymphocytes

One of the prominent clinical features of human aging is the dramatic increase in morbidity and mortality due to infections. Aging is also the most significant risk factor for developing cancer. Both phenomena are related to the age-associated decline in immune function, particularly within the T cell compartment, the part of the immune system that patrols the body for cells that appear foreign, which would indicate they are infected or cancerous. Development of long-term cell culture protocols for analyzing the effect of chronic antigenic stimulation on primary T cells from young adult donors has led to the identification of multiple characteristics of the terminal stage of replicative senescence in this cell type. These include inability to divide, altered cytokine patterns, resistance to apoptosis, shortened telomeres, reduced antiviral cytolytic function, and loss of expression of a major signaling molecule, CD28. Many elderly persons have high proportions of T cells with similar...

Telomerase And T Cells

A major difference between mice and humans with respect to this important facet of cell biology. In terms of the aging immune system as well, the life-long exposure to pathogens also differentiates elderly humans from aged mice housed in barrier facilities, further underscoring the value of using a human cell culture model for analysis of the role of T cell replicative senescence in human aging. Results of these experiments showed significant effects of hTERT on proliferative and functional aspects of the T cells. Briefly, we observed that hTERT trans-duction led to telomere length stabilization and reduced expression of the p16INK4A and p21WAF1 cyclin-dependent kinase inhibitors, implicating both of these proteins in the senescence program (Dagarag et al., 2004). Indeed, the transduced cultures showed indefinite proliferation, with no signs of change in growth characteristics or of karyotypic abnormalities. In terms of protective immune function, the telomerized HIV-specific CD8+ T...

Alzheimers Disease And Atherosclerosis

There is some evidence that chronic activation of T cells, leading to increased proliferation and telomere shortening, may be involved in other age-related diseases as well. The etiology of Alzheimer's disease (AD) is not known, but our recent studies suggest a possible involvement of T cells. We observed that the telomere length of T cells, but not of B cells or monocytes, correlates with mental function tests in AD patients (Panossian et al., 2002). Those patients with lower Mini Mental Status Examination (MMSE) scores, which is a marker of disease status, had T cells with shorter telomeres than those persons with higher MMSE scores. These findings suggest that the immune system of AD patients is perturbed in some way and may not necessarily respond normally to therapeutic vaccines aimed at retarding AD disease progression. Interestingly, one such therapeutic vaccine trial was recently interrupted due to unanticipated brain inflammation in some participants (Nicoll et al., 2003).

Senescent T Cells And Mortality

The ultimate effect of T cells on aging is with respect to mortality itself. Early work suggested a connection, based on correlative data, between T cell proliferative responses in cell culture and mortality over the subsequent few years (Wikby et al., 1998). More recently, telomere analysis of total lymphocytes in a group of 60 year olds was shown to be predictive of mortality many years later (Cawthon et al., 2003). In these studies, it was shown that the individuals who had telomeres in the lowest quartile were 7-8 times more likely to die from infections compared with those with the longest telomeres. Longitudinal studies of elderly Swedes over several decades confirm the link between immune parameters and lifespan. These data show that early mortality is associated with a so-called immune risk phenotype, which includes a cluster of T cell parameters, including high proportions of senescent CD8+ T cells (Nilsson et al., 2003). Interestingly, the presence of these risk factors is...

Dermatomyositis Polymyositis

A variety of specific autoantibodies may be present in some patients with DM or PM, implicating the immune system in their pathogenesis. In DM, humoral immune mechanisms may be particularly important, given the predilection for inflammatory cellular infiltration in nonnecrotic muscle fibers and around blood vessels. Vasculopathy can be a particularly prominent feature of childhood disease, with deposition of immunoglobulins and complement components in blood vessels sometimes making skin biopsy specimens indistinguishable from those found in SLE patients. In PM, cell-mediated antigen-specific cytotoxicity appears to be more in pathogenesis, since increased expression of major histocompatibility class I molecules and increased numbers of T cells are found in the muscle in this disorder.

Release Of Heat Shock Proteins Passive Versus Active Release Mechanisms

Abstract There is now no doubt that heat shock proteins have a profound immunoregulatory effect on the host's immune system. This knowledge has successfully been harnessed to generate a number of important clinical trails. However, one intriguing question that remains to be answered is how heat shock proteins (HSP) which do not have peptide leader sequence targeting secretion can gain access to the extracellular milieu. This chapter will discuss the most recent findings in the area of HSP release and attempts to broadly categorize these findings into two basic mechanisms the passive and active mechanisms

Answers To Patients Frequently Asked Questions

Astragalus appears to have numerous biological effects, such as digestive and immune system stimulation and heart muscle stimulation. Early research suggests that it may have a role in the treatment of asthma, memory deficits, elevated cholesterol levels and as an adjunct to chemotherapy treatment for cancer. When will it start working

Chemical Components

Beta-carotene comes in natural and synthetic forms, with the natural form being derived mainly from algal sources and consisting of roughly equal amount of 9-c s and all-trans isomers, with small amounts of the 13-c s isomer. Synthetic beta-carotene is primarily composed of the all-trans isomer with small residues of the 13-c s isomer (PDRHealth 2005). Although all-trans beta-carotene is converted into vitamin A, which plays an essential role in vision, growth, reproduction, immune function and maintenance of the skin and mucous membranes (see Vitamin A monograph), the 9-c s isomer is not converted into vitamin A but does act as an antioxidant (Ben-Amotz & Levy 1996).

Anticarcinogenic Activity

Whether beta-carotene has anticancer properties in humans is unclear. It has been suggested any such effects could be mediated through multiple mechanisms that may include antioxidant activity preventing oxidative damage to DNA and inhibition of lipid peroxidation, stimulation of gap junction communication, effects on cell transformation and differentiation, inhibition of cell proliferation and oncogene expression, effects on immune function and inhibition of endogenous formation of It has further been suggested that beta-carotene may increase lung cancer risk in smokers because of its ability to improve lung function. Thus smokers supplemented with beta-carotene may have increased lung capacity, resulting in deeper breathing of carcinogens and other oxidants. It is also suggested that beta-carotene may improve smokers' immune responses and thus reduce the number of days they suffered from upper respiratory tract infections and enabling them to smoke more (Bendich 2004).

Prospects for prevention and control

For the epidemic diseases, other challenges remain. The caliciviruses pose the greatest epidemic threats, and investigation often identifies a breach of sanitation with faecal contamination of water or food (either at its source or by a food-handler) that can be corrected. At the same time, the virus can be transmitted by person-to-person contact or perhaps by aerosols, and therefore much disease is not easily prevented (Becker et al 2000). Control of calicivirus disease outbreaks is currently directed at halting those outbreaks where problems of contamination of food or water can be easily corrected. This approach leaves many outbreaks to run their course despite the best public health interventions and intent. Efforts to develop vaccines against the caliciviruses are being pursued with the hope that even mimicking the short-term natural immunity of infection would be a useful preventive measure for travellers and soldiers, provided that the vaccine contained the proper broad mix of...

The structure of HIV1

Using electron microscopy, HIV-1 and HIV-2 resemble each other strikingly. However, they differ with regard to the molecular weight of their proteins, as well as having differences in their accessory genes. HIV-2 is genetically more closely related to the SIV found in sootey mangabeys (SIVsm) rather than HIV-1 and it is likely that it was introduced into the human population by monkeys. Both HIV-1 and HIV-2 replicate in CD4 T cells and are regarded as pathogenic in infected persons, although the actual immune deficiency may be less severe in HIV-2-infected individuals.

Nk Cells And Tumor Cell Killing

Apart from their intracellular chaperoning functions, HSP have been found to play key roles in tumor immunity. Most immunotherapeutic approaches exploit the carrier function of HSP for tumor-derived peptides. Following cross-presentation of HSP-chaperoned peptides on MHC class I molecules (Arnold-Schild et al., 1999 Basu et al., 2001 Binder et al., 2000 Binder et al., 2004 Sondermann et al., 2000) an antigen-specific CD8+ T cell response is thus initiated (Binder et al., 2001 Doody et al., 2004 Schild et al., 1999 Srivastava et al., 1998). However, even in the absence of immunogenic peptides, HSP serve as danger signals for the host's immune system (Asea et al., 2000). Exosomes have recently been described as export vehicles for Hsp70 from the endosomal compartment into the extracellular milieu (Bausero et al., 2005 Gastpar et al., 2005 Lancaster and Febbraio, 2005). NK cells comprising 5-20 of peripheral blood lymphocytes (PBL) are important players of the innate immune system that...

Molecular Mechanisms of DC Dysfunction in Cancer

Cell differentiation is a complex process, which involves multiple genes controlled by multiple transcription factors. One of the transcription factors, NF-kB, is especially important for DC biology. NF-kB regulates the transcription of many genes involved in immune responses (reviewed in refs. 121 and 122). NF-kB is composed of 50- and 65-kDa subunits (p50, p52, p65 RelA , cRel, and RelB), which are bound to a 10-bp motif in the promoter of responsive genes. These subunits form both homo- and heterodimeric complexes and differentially regulate gene expression (123). NF-kB is present as an inactive complex in the cytoplasm of many cells bound to members of the IkB family of inhibitory proteins. Activation of NF-kB involves serine phosphorylation, dissociation, and degradation of IkB followed by release and nuclear translocation of NF-kB. Several studies have demonstrated that RelB, a component of NF-kB, is required for the development of DCs (124-126). Block of NF-kB with dominant...

Chemokine receptors as coreceptors for HIV entry

CXCR4 is mainly expressed on naive T cells, whereas CCR5 is present on activated and effector memory T cells. During the early course of HIV-1 infection, predominantly M-tropic HIV-1 isolates are detected. Interestingly, M-tropic HIV-1 isolates are preferentially transmitted regardless of whether or not the donor predominantly harbors T-tropic isolates. At present, it remains unclear whether this in vivo preference of M-tropic HIV-1 isolates is determined by selected transportation of M-tropic isolates by sub-mucosally located dendritic cells or whether the local cytokine chemokine milieu favors the replication of M-tropic viruses. Recent intriguing studies by Cheng Meyer et. al. suggest that M-tropic HIV-1 viruses are able to 'hide' more easily from the immune system by replicating in macrophages, in comparison to T-tropic viruses, thus giving them a survival advantage in the infected individual.

Proposal 6 Rescue Of An Immunedeficient System Via Gene Therapy

It is well known that immune deficiency, such as HIV, is the disease of greatest concern to the public at the present time. Many important proteins, such as the CD families, have been discovered to play a significant role in the deficient immune system. In order to increase the immune capabilities of patients, gene therapy has been established. Due to the great public interest in this type of therapy, research funding is virtually unlimited. Therefore, one may switch to this new research avenue that involves several collaborators. In view of recent advances in molecular biology, a proposal regarding gene therapy will be a very good approach. Specifically, one may transfect human cells such as bone marrow stem cells with overexpression of sense cDNA constructs. Stably transfected cells that constitu-tively express proteins (e.g., CD4) can be directly injected into the immune system of the patient. An alternative is to overexpress and purify a large amount of the proteins in bacteria or...

Overview of the tgfpsignaling pathway

TGF-P is a member of a superfamily of dimeric polypeptide growth factors that includes bone morphogenetic proteins, activins, and inhibins. All of these growth factors share a cluster of conserved cysteine residues that participate in intramolecular disulfide bonds and form a common cysteine knot structure (1). Virtually every cell in the body produces at least one isoform of TGF-P, has receptors for TGF-P on their cell surface, and responds to TGF-P stimulation in some fashion. In addition to its role in regulating the immune system as detailed below, TGF-P has many additional physiological roles including regulating cellular proliferation, differentiation, and apoptosis in a diverse array of cell types, as well as regulating complex processes such as development, wound healing, and angiogenesis. The vital role of the TGF-P-signaling pathway in these cellular processes has been demonstrated by targeted deletion of the genes encoding members of the pathway in mice as has been reviewed...

From Bench To Bedside

As mentioned earlier, screening of primary human tumors and metastases derived there of revealed that Hsp70 is frequently expressed on the cell surface of malignant cell types. In contrast, the corresponding normal tissues were always found to be Hsp70 membrane-negative. Therefore, we hypothesized that membrane-bound Hsp70 might act as a tumor-specific recognition structure for the immune system. Since we observed that the cytolytic activity of NK cells in vitro could be further enhanced by incubation with IL-2 plus Hsp70 peptide TKD, we asked the question as to whether these NK cells might be superior in the eradication of tumors compared to NK cells that had been stimulated with IL-2 alone. In two independent xenograft tumor mouse models we studied the immunological effects of ex vivo IL-2 TKDactivated NK cells (Moser et al., 2002). A single intravenous (i.v.) injection of IL-2 TKD-activated NK cells resulted in a significant regression of colon tumors in SCID beige mice. In the...

Lymphatic tissue as the site of viral replication

After entry of HIV-1 into a quiescent CD4 T cell and after completion of reverse transcription, the viral genome is represented by proviral unintegrated HIV DNA. The activation of CD4 T cells is necessary for the integration of the HIV DNA into the host cell genome and is therefore a prerequisite for the synthesis of new virions. In this regard, the micromilieu of the lymphoid tissue represents the optimal environment for viral replication. The close cell-cell contact between CD4+ T cells and antigen-presenting cells, the presence of infectious virions on the surface of the FDC, and an abundant production of pro-inflammatory cytokines such as IL-1, IL-6 or TNFa, promotes the induction of viral replication in infected cells and augments viral replication in cells already producing the virus. It should be noted that both IL-1 and TNFa induce NF-kP which binds to the HIV-1 LTR to promote proviral transcription. The importance of an antigen-induced activation of CD4 T cells is underlined...

Active tumormediated immunosuppression mechanisms of tgfP action

As discussed above, secretion of TGF-P by tumors and the surrounding stroma cells is perhaps the most widely used method by which tumors actively suppress the immune system. The immunosuppressive effects of TGF-P have been demonstrated in vitro and in vivo, with exogenous TGF-P 1 producing immunosuppression in animal models (14). How does TGF-P mediate its immunosuppressive effects Although TGF-P has diverse effects on virtually every cell type in the immune system, for the purposes of this review, the focus will be on its immunosuppressive effects on cells involved in tumor immunology, i.e., T cells and antigen-presenting cells (APCs). The effects of TGF-P on other aspects of the immune system have been recently reviewed (15).

Experimental evidence supporting a role of tgfP in active tumormediated immunosuppression

The evidence presented above supporting TGF-P as a major mechanism for tumormediated immunosuppression is primarily circumstantial. If TGF-P is the major mechanism for tumor-mediated immunosuppression, one would predict that blocking the TGF-P-signaling pathway would result in more effective tumor vaccines, and conversely, that increased TGF-P signaling would allow tumors to escape the immune system. These predictions have been experimentally verified. In terms of increasing TGF-P signaling, expression of TGF-P 1 in the highly immunogenic CH-3 cell line (to increase the level of TGF-P 1 in vivo) allows this cell line to escape immune surveillance and form tumors in mice, whereas the non-TGF-P 1-expressing cell line cannot (27). Importantly, there is no downregulation of MHC class I molecules or tumor-specific antigens in this model. In addition, overexpression of TGF-P 1 (by either Strategies to block the TGF-P-signaling pathway include decreasing expression of TGF-P ligand with...

Modes of IgSuperfold Interaction

Several IgSF molecules that act as cell-surface receptors or coreceptors in the immune system employ interaction modes similar to those used by immunoglobulins for antigen recognition. one obvious example is the T-cell receptor, an IgSF molecule that is discussed in detail elsewhere in this handbook (see Chapter 11). A second, closely related example is provided by the cytotoxic T-cell coreceptor CD8. Like the T-cell receptor, CD8 interacts with major histocompatibility complex (MHC) class I molecules. Both TCR and CD8 have an MHC class I binding surface composed of the two sets of CDR-like loops (BC, C'C, and FG) from a dimer of variable domains. The structure of the CD8aa-MHC class I complex (Fig. 2) for both human and murine molecules reveals CD8 binds one MHC class I molecule, interfacing with the MHC a2 and a3 domains as well as contacting P2-microglobulin 13,14 . The focal point of the interaction is the DE loop of the MHC class I a3 Ig-like domain, which is clamped between the...

Host Response To Vaccinia

Vaccinia virus has mechanisms to avoid detection and clearance by the immune system. The vaccinia has evolved expression of immunosuppressive proteins (38). Viral surface proteins act as complement inhibitors and the extracellular envelope is known to be almost completely resistant to antibody neutralization (39). Understanding vaccinia's immune evasion strategies may help optimize the virus as a vector for clinical use. The virus is effective in suppressing both innate immunity and the development of T-helper cells. Vaccinia virus has adopted genes whose product can block the function of the interferon family members interferon- (IFN) a p,y or that can inhibit chemokines, which are some of the earliest substances produced during the initiation of a viral host immune response (42-47) (Table 1). Gene Products which Inhibit the Immune Response Gene Products which Inhibit the Immune Response

Bone Cartilage and Ligaments

Lateral Meniscus Popliteus

Fibroblasts are the most abundant cells found in ligaments. These cells manufacture and secrete protein subunits to form collagen-rich extracellular fibers. Fibroblasts also secrete hyaluronic acid, a substance that gives tissue matrix its syrupy consistence. Also present are a number of immune system cells and stem cells that respond to local injury by dividing to produce additional cells for self-repair.

The Tau Hypothesis And Tau Pathology

Promoter (Oddo et al., 2003a Oddo et al., 2003b). The APP and tau genes both incorporate at the same locus, greatly simplifying the breeding by ensuring that they are co-inherited. These animals develop synaptic dysfunction before plaques or tangles appear, and the deficits in LTP correlate with the accumulation of intraneuronal A . The patterns and relative timing of A and tau deposition, which are distinct, closely resemble those in AD brain. While closer to AD-like tangle morphology, the tau deposits have not been definitively characterized as NFTs. Interestingly, A immunotherapy in these animals results in the clearance of amyloid plaques and of early, but not established, tau pathology (Oddo et al., 2004).

Vaccinia As A Cancer Vaccine

Recently, a phase I clinical trial of vaccinia expressing prostate specific antigen (PSA) in prostate cancer patients was published. In this trial the Wyeth strain virus was delivered intradermally every 4 wk for three doses without producing significant systemic toxicities. A cutaneous reaction, consistent with viral replication was seen in all patients treated with the virus at a dose of 2.65 x 107 pfu. Several patients developed T-cell immune responses to PSA associated with prolonged periods before disease progression (55). Another phase II clinical trial by the NCI examines the potential of three strains of recombinant vaccinia virus expressing either PSA, B7.1, or of the fowlpox virus expressing PSA. Vaccinia expressing the tumor antigen carcino embryonic antigen (CEA) has been studied clinically as a priming vaccine followed by a boost with avipox expressing CEA. This regimen consisted of 1 x 107 pfu Wyeth strain vaccinia injected intradermally. Although specific T-cell immune...

Immunological Approaches In Rat Brain Tumor Models

The tolerance of the central nervous system (CNS) for activated host immune reactions indicates that the effects of immunotherapy might be decreased for brain tumors. Iwadate et al., 35 developed an interleukin-2 producing 9L rat gliosarcoma and assessed the effect of secretion of interleukin-2 on the growth and immunological responses to the tumor implanted subcutaneously and intracranially. The Fischer 344 rats rejected the 9L IL-2 tumors when implanted subcutaneously however, the same tumors cells implanted intracranially grew tumors albeit with a slower growth rate than with the parental 9L cells. Lefranc et al., 36 carried out similar studies with 9L gliosarcoma cells transfected to produce GM-CSF and demonstrated that implantation of these cells prevented tumor growth. Local delivery of carmus-tine (BCNU) from biodegradable polymers prolongs survival in rats bearing intracranial 9L gliosarcoma 37 . Interleukin-2 can also produce a potent antitumor immune response and improve the...

Robert E Antosia md mph

The medical consequences of drought include an increased incidence of malnutrition and infectious diseases. The resultant lack of nutrition can ultimately lead to the classic conditions of marasmus (the lack of caloric intake) and kwashiorkor (lack of protein intake). Collectively, the states of inanition are referred to as protein-energy malnutrition (PEM). PEM results in impaired immune system function and increased mortality.

The Real World of Health Policy

WHEREAS The term dioxin refers to a group of chemicals that includes furans and biphenyl compounds (the most well-known dioxin being 2,3.7.8-TCDD), and dioxin is a potent human carcinogen and an endocrine-disrupting chemical affecting thyroid and steroid hormones, scientifically linked to endometriosis, immune system impairment, diabetes, neurotoxicity, birth defects, testicular atrophy and reproductive dysfunction and

Gene Expression Patterns In Normal And Diseased Tissues

Proteomic approaches towards identification of disease markers include comparison of protein expression in normal and diseased tissues, analysis of secreted proteins and direct patient serum profiling. In combination with mass spectrometry to identify the selected peptides and proteins, this becomes a powerful method for marker identification. One such approach has been used to detect tumor autoantibodies in the serum of patients with different cancer types 22,44 . This may ultimately be useful for cancer screening, diagnosis or in directed immunotherapy. Microarrays of proteins isolated from tumors have the potential to delineate the immune response to the tumor and to help discover tumor-specific antigens 45 .

Carbohydrate Structure and Diversity

The siglecs are a family of sialic acid binding lectins whose canonical CRD is a member of the immunoglobulin (Ig) superfamily. They are particularly important in the immune system, where they function in processes ranging from leukocyte adhesion to hemopoiesis 37 . Members of the family show specificity differences for a2,3- versus a2,6-linked sialic acids, as well as for sialic acids modified with respect to O-acetylation. The crystal structure of the CRD of siaload-hesin in complex with 3' sialylactose shows that interactions with the bound oligosaccharide are mediated primarily with the terminal sialic acid moiety 38 . Of particular interest are the roles played by cis interactions. CD22 (Siglec-2), for example, is a B-cell-specific receptor which, through interaction with a2,6-linked sialic acid containing glycoproteins on its own cell surface, inhibits B-cell receptor signaling. This stable inhibition can be broken by the addition of external competing saccharide and in vivo may...

Tolllike Receptor Impact on the Study of Innate Immunity

The biological defense mechanism of higher organisms, including humans, is generally divided into innate immunity and adaptive immunity (Dranoff, 2004). In the adaptive immune response, gene rearrangement by T cells and B cells enables the establishment of a defense mechanism of high specification against the molecular microstructure of a foreign substance, and this mechanism is immunologically memorized. However, as it takes a few days to induce adaptive immune responses, innate immunity works as an early defense mechanism. Innate immunity has existed as a biological defense mechanism from the earliest stages of evolution for example, insects have only innate immunity as a defense mechanism. Cells involved in innate immunity include macrophages, neutrophils, NK cells, NKT cells, and y T cells. Important humoral factors include complements, lectins, and interferons (IFNs) (Biron, 2001). Key notions in the paradigm of modern immunology are the presentation of the antigen by...

Experiences from Daily Practice

Even if the indication for HAART seems obvious, a conversation with the patient should clarify whether he or she is indeed prepared to start treatment. The problem is not the initiation of HAART, but its continuity, day after day, month after month. The decision to initiate treatment is often made prematurely. In some cases, patients put themselves under pressure unnecessarily, or let others do so. A single lower CD4 count value, a prolonged case of flu seeming to indicate a weakened immune system (I never had anything like that before), springtime lethargy, new study results, a promising new drug in the newspaper (I've heard so much about X), a partner who has started therapy - none of these are indications for initiation of treatment. We also tend to start HAART earlier in older patients (above 50 years). The regenerative capacity of the immune system in older patients is significantly reduced (Ledermann 2002, Grabar 2004). More importantly, the risk of developing opportunistic...

Models for the Study of Infection in Populations

This chapter provides an overview of the modeling of transmission dynamics of infectious diseases, with particular focus on the use of compartmental differential equation models, the most commonly used for such work. An introduction including a brief description of historical antecedents is followed by a section putting such modeling in its ecological context. The next section discusses some of the characteristics of infection in populations that are determinants of the observed population dynamics of infection. This is followed by a brief section considering the scope and limitations of dynamic models, followed by a section summarizing some of the key concepts relevant to this type of modeling work. Simple ordinary differential equation models are introduced in the next section. Demography and the relevance of population age structure to infection transmission dynamics, and partial differential equation models incorporating age structure and age-related processes of infection and...

The Ecological Context of Infection

Numerous strategies have evolved allowing infections to continue to reproduce and disseminate (Mims et al., 2001 Davies et al., 1999). Rapid reproduction facilitates dissemination before the host's immune system can suppress it alternatively a very slow rate of reproduction may allow the infection to establish and persist below the radar'' of the immune system. A highly virulent infection may kill the host before it has had the opportunity to disseminate (although in some cases consumption of the dead host by another potential host may be a potential route for further dissemination, as in hydatid disease) in some cases an infection may be highly virulent only when infecting a species not its usual host (e.g., arenaviruses causing hemorrhagic fevers or meningitis in humans, but little apparent disease in rodent reservoirs). Alternatively the infection may evolve with reduced virulence, providing a longer time window within which to spread to a new host. The duration of immunity evoked...

Target cells in vitro

The finding that both HHV-6 variants use the ubiquitous molecule CD46 as a membrane receptor is compatible with a broad cellular tropism. Productive infection, however, is limited to a small range of cells most likely by intracellular restriction factors acting beyond the viral entry step. Studies on the cellular tropism of HHV-6, and particularly of the A variant, have suggested that this virus is broadly 'immunotropic' as it infects several cells implicated in the generation of effective immune responses. Thereby, HHV-6 may affect, directly or indirectly, both the cellular and humoral arms of the immune system (see below). There is universal consensus that the primary target cells for HHV-6 infection both in vivo and in vitro are CD4+ T-Cells (Lusso et al., 1988 Takahashi et al., 1989). When activated mononuclear cells obtained from different sources (e.g. cord or peripheral blood, thymus, tonsils, lymph node) are exposed in vitro to HHV-6, the vast majority of the infected cells...

Consequences for the Further Course of Disease

Multiple factors influence the increase in CD4 cells duration of immunosuppres-sion, age, thymus size or extent of thymus degeneration (see chapter Goals and Principles of Therapy). Do these include baseline values at initiation of therapy Astonishingly, several cohorts found no association. (Yamashita 2001, Pezzotto 2001, Cozzi-Lepri 2001). However, these studies all showed that the rise in CD4 cells is similar, although levels remained lower if the CD4 count was initially low. In addition, it is our experience that immune reconstitution is rarely complete if values were initially low the more damaged the immune system, the less likely a complete recovery in the long run (Garcia 2004). In the Swiss Cohort, having a low CD4 cell count at baseline was a clear risk factor for not attaining 500 CD4 cells l after four years (Kaufmann 2002). There is also concern over the 10-15 of patients with a discordant response where HAART is virologically extremely successful, but CD4 cell count...

TF Tn and sTn Antigens

Mucins are major cell-surface antigens in a variety of epithelial cancers. They are primarily large extracellular molecules made up of multiple copies of serine- and threo-nine-rich tandem repeats (30-33). Though mucins (including carbohydrate and peptide epitopes) are also expressed on some normal tissues, they have proved to be excellent targets for anticancer attack for two reasons First, expression on normal tissues is largely restricted to the ductal border of secretory cells (31-33), a site largely inaccessible to the immune system. Cancer cells, on the other hand, have no patent ducts and so accumulate mucins over the entire cell surface. Second, peptide backbones of cancer mucins are not fully glycosylated and glycosylation that does occur is not complete. Glycosylation of cancer mucins with mono- or disaccharides such as Tn, sTn, or TF O-linked to serines or threonines is especially common. Thomsen-Friedenreich antigen (TF GalP 1-3GalNAca-O-serine threonine), Tn...

Physiology in Immunity

Since each variant of fungal sinusitis carries its own specific host response, further information regarding the role of nasal physiology in innate and adaptive immunity will be discussed with each of the different classifications of fungal sinusitis.

The role of immunity in cancer

The development of a number of cancers appears to be related to a depression of the individual's immune system, particularly in relation to cellular immunity, in a similar way (albeit on a different scale) to the effect of HIV infection. Studies have shown that the immune system is adversely influenced by On the other hand, a protective effect on the immune system is provided by

Heparinplatelet Interactions In The Pathogenesis Of

When complexed with GAG, PF4 exposes one or more neoantigens that stimulate formation of HIT antibodies (Amiral et al., 1992, 1995 Kelton et al., 1994 Newman and Chong, 1999). Recent evidence suggests that the neoantigen is formed by close approximation of two PF4 tetramers, which can happen when the positive charge of the PF4s is neutralized by GAGs (Greinacher et al., 2006). However, to be immunogenic, the PF4-GAG complexes presumably must be soluble and thereby accessible to the immune system. Perhaps this explains why PF4-GAG that is constitutively present on the endothelial surface is not immuno-genic, but soluble PF4-heparin complexes are.

And Kenneth A Foon MD

Active specific immunotherapy (ASI) is an attractive approach to cancer therapy, especially in an adjuvant setting. ASI is intended to boost or induce a host antitumor response, in contrast to passive immunotherapy, where large doses of preformed antitumor antibodies, or T cells with predetermined specificity, are infused. In classical ASI, patients are vaccinated with purified tumor-specific or tumor-associated antigens (TAAs). This approach has a number of major limitations. The tumor antigens are usually weakly immunogenic due to the induction of tolerance. This tolerance can be broken by presentation of the critical epitope in a different molecular environment (1). Secondly, it is difficult to obtain the purified antigen in sufficient quantities for vaccination. Although this limitation can be overcome by the synthesis of well-defined antigens by use of recombinant DNA technology, the recombinant molecule may not resemble the native structure of the protein. Moreover, mass...

Complementation of Homologous Targets

Immunosuppressants, such as cyclosporin and FK506, inhibit T cell activation and have made tissue and organ transplantation a reality. These drugs were first identified because of their antifungal activity, and their mechanism of immuno-suppression long remained a mystery. The mechanism of action of cyclosporin and FK506 was determined using S. cerevisiae 20 . Cyclosporin and FK506 bind proteins with peptidyl prolyl isomerase activity (called FK506 binding proteins and cyclosporin binding proteins) and forms a complex that inhibits the calcium-calmodulin phosphatase, calcineurin. The similarity between the activity of the immunosuppressants in T cells and yeast is shown in Fig. 4. In the presence of these immunosuppressants, yeast does not grow and divide after exposure to the yeast pheromone, a-factor. The mechanism of action of Rapamycin, another immunosuppressant, has been elucidated by studies in yeast 21 . The target of rapamycin is known to be TOR, which is involved in...

Causes and symptoms

Other researchers are also looking into the possibility that narcolepsy may be caused by some kind of autoimmune disorder. This theory suggests that the person's immune system accidentally turns against the specific area of the brain that controls alertness and sleep, injuring or destroying it.

Mechanisms of Selectively Targeting Tumor Cells The Interferon System

Indeed, it is now clear that the IFN-inducible genes are very important in preventing VSV-mediating cytolysis (50). The IFNs are a family of cytokines produced in response to infection, which act by inducing the expression of many cellular genes. The IFNs comprise two main families, referred to as type I (a p) and type II (y) (51). Type I IFNs, induced by most cell types, are clustered on the short arm of chromosome 9 and consist of several a genes and pseudogenes, and one P gene (50,52). In contrast, type II IFN consists of a single gene on chromosome 12 that is mainly secreted by Th-1 lymphocytes and natural killer (NK) cells. The IFNs can be induced by a number of stimuli, including viruses, dsRNA, growth factors and cytokines and are known to exert potent antitumor, antiviral, and immunomodulatory activities (53). PKR likely affords a first line of defense, to buy time for IFN to be induced (transcribed and translated). The importance of IFN in innate immunity to VSV infection has...

Structured Intermittent Treatment SIT at Fixed Intervals

In an NIH pilot study on SIT (structured intermittent treatment), 10 chronically infected patients with more than 300 CD4 cells l and a viral load below 50 copies ml were switched to a combination of d4T, 3TC, ritonavir and indinavir. This combination was administered as seven days of treatment and seven days interruption (7-on-7-off') for a period of at least 44 weeks. The result neither the viral load nor the proviral DNA increased. CD4 cells and HIV-specific immune responses remained unchanged, suggesting that the immune system is probably unaffected by such ultra-short breaks in treatment. A significant reduction in lipid levels did, however, occur (Dybul 2001). Some patients experienced several blips (temporary increases in viral load) to above 100 copies ml. The same group has recently reported successful use of the same strategy in eight patients using ddI, 3TC and efavirenz. Seven of eight patients have now been followed for more than 60-84 weeks (Dybul 2004). Nevertheless at...

VSV Recombinants and Stability

The ability of VSV to mutate was recently exploited in strategies designed to develop VSV vectors that were more attenuated in normal cells yet retained oncolytic activity. For example, variants of VSV (referred to as AV1 and AV2, with mutations in the M protein M51R and V221F S226R, respectively) were found to induce considerable amounts of IFN-a and thus replicate inefficiently in normal cells. However, these viruses remained highly lytic in 80 of human tumor cell lines tested and exerted oncolytic activity in immunocompetent animals harboring metastatic colon cancer (101,102). One of the many functions of the M protein involves its ability to block host mRNA export through association with nuclear pore proteins such as Nup 98, which are IFN-inducible. Following infection, VSV activates the IFN pathway. However, following induction, IFN mRNA needs to be exported out of the nucleus for translation, a requirement the M protein prevents. The AV variants do not potently inhibit host...

Cytotoxic T Cells and NKMediated Immunity

In cancer patients, evidence that anti-Id antibody can stimulate a CTL response was provided by immunization of melanoma patients with two different anti-Id antibodies mimicking high-molecular-weight proteoglycan antigen (73). Human leukocyte antigen (HLA)-A2-specific CTL responses were observed in 43 of the patients who appeared to express the HLA-A2 allele. Anti-Id antibody ACA 125, which mimics the ovarian tumor-associated antigen CA 125, also induced cellular immune responses that resulted in lysis of antigen-positive ovarian tumor cells (43). Although CTL assays in these two studies were performed with HLA-matched tumor cells, autologous tumor cells were not available and could not be used. Thus, other mechanisms of cytotoxicity could be involved in the lysis of the tumor cells. Durrant et al. (74) treated six patients with rectal cancer with the anti-Id antibody, 105AD7. PBMCs or lymph node cells from three of these patients caused significant killing of autologous tumor cells,...

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

Oncolytic studies indicated that wild type VSV exhibited considerable potential as an anticancer agent. However, the ability to modify VSV through genetic engineering obviously affords the prospect of creating new generations of custom-made VSV vectors that contain immunomodulatory and or suicide cassettes designed to increase their antitumor activity. In order to begin evaluating whether genetically engineered VSV carrying tumor-killing cassettes could be created and whether such viruses were more efficacious in tumor therapy than the wild-type VSV, we developed VSV vectors carrying, as models, the herpesvirus TK suicide cassette or the cytokine gene interleukin-4 (IL-4). The foreign genes were cloned as additional transcription units between the VSV G and L genes and all viruses were grown to exceptionally high titers (71,103). TK protein was synthesized to extremely high levels and was functional, being able to phosphorylate ganciclovirs (GCV). Recombinant viruses also retained...

Diagnostics and Virology

Rotavirus belongs to the family Reoviridae and is characterized by the presence of 11 segments of double stranded RNA that are encased by 3 shells, an inner core, an internal capsid and an outer coat. The outer coat is composed of 2 proteins that are seen by the child's immune system. These outer capsid proteins, called Viral Proteins 4 and 7 (VP4 and VP7) and also labeled the Protease-cleaved protein and the Glycoprotein respectively (P and G proteins) are the basis to characterize the diversity of this virus group and the targets to mount an immune response. Four or five strains of rotavirus ( P8 , G1 P8 , G3 P8 , G4 P8 , G9, and P4 , G2) predominate worldwide and these have become the prime targets for the vaccines in development. At the same time, in developing countries, many new strains arise although they rarely become the predominant strains over time.

Virus Encoded Proteins Are Developed through Targeted Evolution In Vivo

Large DNA viruses, in particular herpes- and poxviruses, have evolved a number of proteins that function as mimics of or as decoys for endogenous proteins of the host organism. Often the virus uses such proteins to evade key components of the immune system. The virus-encoded proteins are elegant examples of targeted evolution, where the virus has captured a gene from its host and through combinatorial chemistry varied its structure and thereby its function randomly through mutagenesis. Unlike biotech entrepreneurs, the virus has the advantage of being able to select the mutant protein with the optimal pharmacological property through in vivo screening in the intact organism. The virus with the most useful protein for example, the most potent or broad-spectrum antagonist will prevail. One example is the vMIP-II chemokine of human herpesvirus 8, which acts as an efficient blocker of a surprisingly large number of structurally different chemokine receptors. The chemokine system in...

MICA Expression in HCC and NKCell Sensitivity

The a1 and a2 domains and because their expression is not induced by IFN as they do not need association with (32 microglobulin to be expressed on the membrane (Bahram et al., 1994). In general, MHC class I molecules are constantly expressed in cells while MICA B are not expressed in normal cells, except in intestinal epithelial cells and some thymocytes. MICA B expression is known to be induced in stressed cells and transformed epithelial cells. The functions of MICA B have not been clarified since their discovery in 1994, although in 1999 they were found to be human ligands for NKG2D. Since then, their functional importance in the immune response has attracted attention (Jinushi et al., 2003a, 2003b). The characteristics of cancer cells from various organs can be examined from the perspective of MHC class I molecule expression. For example, with colon cancer cells, the decreased expression or the deficiency of HLA class I molecules is observed in many mechanisms (Miyagi et al.,...

Predictive Modeling Of Therapeutic Vulnerability Of Brain Tumors

Context 36 , inhibition of RAC1 leads to apoptosis induction in glioma cells and is found to be necessary for the migratory phenotype 37 . The hypothesis that migratory glioma cells are more resistant to apoptosis induction is supported by the finding that the anti-apoptotic PI3K pathway is activated in migratory glioma cells 38 . Based on these findings, the invasive transcriptome of malignant gliomas were studied by comparing the gene-expression profile of stationary and invasive glioma cells isolated by laser capture microdissection (LCM) from GBM biopsy specimens 39 . Gene candidates up-regulated with active invasion included adhesion molecules, transducers of extracellular and intracellular signaling as well as apoptosis resistance genes stationary glioma cells exhibited increased levels of cytoskeleton stabilizing elements as well as angiogenesis-related genes. Zagzag and coworkers in a similar approach reported down-regulation of MHC (major histocom-patibility) antigens in...

The Redundant Chemokine System Is an Optimal Target for Viral Exploitation

Of all subsets of leukocytes and play important roles in angio-genesis, organogenesis, and carcinogenesis 1 . Chemokines act through a large family of G-protein-coupled receptors, which are divided into subfamilies of CXC, CC, and CX3C receptors. This nomenclature refers to a fingerprint sequence in the ligands where the first two Cys residues are either neighbors (CC) or separated by one (CXC) or three (CX3C) residues. Although a few chemokine receptors are regulated by only a single chemokine protein, the system is generally characterized by a high degree of redundancy, in which a given chemokine receptor is activated by more than one ligand and a given chemokine acts through more than one receptor within a chemokine subfamily. Thus, the chemokine system is not only the key to the control of the immune system, but it is also an optimal target for viral exploitation, due to the redundancy among multiple endogenous proteins.