Immune System Boosters

How To Bolster Your Immune System

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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...

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...

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.

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).

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...

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 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.

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).

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.

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.,...

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...

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.

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...

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...

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...

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...

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...

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...

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...

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...

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...

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

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...

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...

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).

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.

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...

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...

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...

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...

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.

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.


With the exception of the HSV-tk ganciclovir gene therapy, viral vectors have been also extensively used to delivery immunomodulatory genes against HGG. Although a complete discussion of the rationale involving the use of immunotherapy is beyond the scope of this chapter, there is compelling data that local augmentation of the immune response may offer a potential benefit to brain tumor patients (50,51). As a result, several vectors have been used to deliver cytokines to brain tumors. This work, while still in preclinical stages, is likely to be evaluated in the context of a clinical trial in the nearby future. To date, the efficacy of several immunomodulatory genes has been examined in the context of HGG (Table 2). For instance, HSV has been used to deliver IL-4, IL-10, and IL-12 against experimental glioma (52-54). Miyatake et al. predicted that if an immune response plays a role in survival following intratumoral treatment of tumor-bearing animals with HSV, expression of IL-4...

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...

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.


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...

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...

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...

Bone Cartilage and Ligaments

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.

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...

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...

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...

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...

Sindbis virusderived vectors

SV and derived SV vectors have been extensively studied in the United States. The SV replicon system was the first of the three alphavirus replicon systems to be reported, in 1989 by Xiong et al. (3). As originally described, the engineered SV replicon RNA was packaged by tranfection of in vitro-transcribed RNA into BHK cells that were then infected with wild-type SV. As the replicon RNA contained the packaging signal, it was packaged in a small percentage of virions essentially competing with wild-type SV genomic RNA for encapsidation and assembly into infectious particles. The efficiency of producing particles containing replicon RNA encoding heterologous protein was estimated at approx 10 . A packaging system analogous to that described above for SFV replicons utilizing two in vitro-transcribed RNAs, one encoding the structural proteins and the other the engineered genomic RNA, was described in 1993 (76). However, this system still resulted in significant contamination of the...

Venezuelan equine encephalitis replicons

Alphavirus replicon vectors derived from VEE virus have also been recently applied to antitumor immunotherapy. The original report of the split helper RNA production system for VEE virus replicon particles (VRPs) was published in 1997 (1). In addition to the use of two separate nonoverlapping helper RNAs, the coding sequences for the various structural genes have incorporated previously described attenuating mutations (74,129). To some extent, the BL3 restriction has limited the number of groups investi- Immune Responses

Summary And Conclusions

Kindig T, Schorle H, Backman M, Hengartner H, Zinkernagel R, Morak I. Immune responses in IL-2 deficient mice. Science 1993 262 1059-1061 22. Voss SD, Hong R, Sondel PM. Sever combined immune deficiency, interleukin-2 and the IL-2 receptor. Experiments of nature continue to point the way. Blood 1994 83 626-635. 27. Rabinowich H, Vitolo D, Altarac S, Herberman RB, Whiteside TL. Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. J Immunol 1992 4 739-746 30. Figlin R, Gitlitz B, Franklin J, Dorey F, et al. Interleukin-2-based immunotherapy for the treatment of metastatic renal carcinoma an analysis of 203 consecutively treated patients. Cancer J Sci Am 1997 3 592-597

Continuation of treatment during pregnancy

As a rule, if pregnancy is diagnosed after the first trimester, the antiretroviral therapy (ART) should be continued. Interruption of treatment might give rise to an increase in viral load and a possible deterioration of immune function causing the danger of disease progression and, ultimately, of reduction of the immune status of mother and fetus. AZT should be administered as a component of a combination regimen starting at 32 weeks of gestation at the latest.

Mechanisms of dna vaccineinduced immunity

The ability to sneak in to an organism without inciting a strong immune response makes plasmid DNA unique among vaccines. In fact, complete adaptive immunity specific to plasmid DNA has not been reported. Importantly, although plasmid DNA is quickly deposited in myocytes and APCs (10), there is a several-hour time gap between injection of DNA vaccine and the appearance of encoded antigen. This might have major consequences for the ability of DNA vaccines to prime naive T cells. The amount of antigen produced in vivo after DNA inoculation is in the picogram to nanogram range (3). Equivalent amount of antigen introduced in vivo in the form of protein would probably be processed by macrophages without inducing an adaptive response, resulting in the impression that the antigen was either ignored or tolerized. These observations suggest that the plasmid itself may function as a powerful immunomodulator (Fig. 3). Receptor-mediated activation of monocytes is the most likely mechanism of...

Safety concerns and ethical issues

As much as gene therapy raises important ethical questions, they may not be directly applicable to DNA vaccination. By questioning DNA vaccines we might start questioning the whole concept of vaccination as well, since in many cases traditional vaccines contain microbial DNA. Routine immunizations have been remarkably successful in inducing resistance to infections with several common pathogens. This, however, may come at a price since some researchers have postulated that because of elimination of certain pathogens, the human population became more vulnerable to infections with newly evolving pathogens (148). If one considers the relationship between the evolution of the human immune system and the evolution of pathogenic microorganisms as a race for survival (149), there cannot be a winner. The mass-vaccination programs over the last 50 yr have likely shaped biological processes influencing natural selection in the human population. However, withholding vaccination in an effort to...

Characteristics of HIV infection in childhood

The HIV infection in childhood is different from the infection in adults with regard to transmission, the natural course of viral dynamics, maturity of the immune system and clinical manifestations. Several factors have to be considered when giving antiretroviral drugs to children children may already have been exposed to AZT and other drugs in utero, the pharmacokinetics of the drugs are age-dependent and children require special attention to help with adherence. In children, the higher viral load is associated with the somatic growth of the lymphatic system and the inability of the immature immune system in children to mount an HIV-specific response. When assessing the immune system in infants and children, it is very important to compare the child's CD4 count with the age-appropriate values (e.g. the mean CD4 count for a 6-month-old baby being 3.0 x 109 l). Lymphocyte counts are very high in infancy and decline to adult levels beyond 6 years of age...

Recombinant interleukin 2 adjunctive therapy in multidrugresistant tuberculosis

Multidrug-resistant tuberculosis patients respond poorly to antituberculosis therapy and therefore require new modalities of treatment to overcome the infection. Administration of low dose recombinant human interleukin 2 (rhuIL-2) in combination with chemotherapy to multidrug-resistant tuberculosis patients resulted in reduced or cleared sputum acid-fast bacilli in about 60 of the patients in association with enhanced activation of the immune system. Daily rhuIL-2 administration for 30 days induced increases in CD25+ and CD56+ cells in the blood. rhuIL-2 therapy also resulted in increased expression of y-interferon and IL-2 mRNA at the site of a delayed-type hypersensitivity (DTH) response to purified protein derivative of tuberculin. Differential display reverse transcriptase PCR revealed several genes expressed at the DTH skin test site that were up- or down-regulated during rhuIL-2 treatment. The differentially regulated genes included components of endocytic vacuoles,...

Conclusions and future directions

A few thousand papers have been published on the use of DNA vaccines across several species. Most of them support DNA as an excellent immunizing agent, particularly for priming immune responses. Plasmid DNA used as a part of a therapeutic cancer vaccine strategy certainly has the potential to induce tumor-specific immunity and possibly regression of disease in cancer patients. Challenges for the future will be (a) to identify more immunogenic and specific antigens, (b) to construct more efficient and tissue-specific promoters, (c) to improve methods of tissue-targeted DNA vaccine delivery, (d) to optimize processing and presentation of transgene-encoded antigens, (e) to design optimal combinations of DNA vaccine content corresponding to the individual needs of a patient. Current progress in the human genome sequencing and rapid advances in genomic expression profiling and functional proteomics are key factors that will allow creation of such smart vaccines. Identification of new...

Pathology Suggests An Autoimmune Etiology

MS tissue pathology suggests an immune-driven reaction to a myelin antigen. The pathology indicates a complex disorder that involves all arms of the immune system including cellular immunity, humoral immunity, and complement (8,9). Structures of the nervous system other than myelin, such as the axon and the oligodendrocyte cell body, may be lost or injured, thus making it difficult to identify the initial target. Even at very early stages, MS lesions demonstrate axonal as well as myelin damage (10). The pathology in MS appears to be heterogeneous (9), signifying variation in the innate immune response(s) and or the inciting event(s). MS patients have higher CCR5 mRNA expression by peripheral blood mononuclear cells than other forms of MS, but the surface protein expression of CCR5 on CD4+ T-cells from PBMC was similar in all MS subtypes and in controls (31). Both pro- inflammatory (IL-2, IFNy, TNFa and-) and anti- inflammatory (TGF-p, IL-4, IL-10) cytokines are expressed by...

Mechanisms of antitumor immunity

Because tumor cells arise endogenously, they are surveyed by the immune system in a noninflammatory environment. This is thought to result in immune tolerance, and the goal of gene-modified tumor vaccines is to overcome established mechanisms of immune tolerance by presenting relevant tumor antigens in an inflammatory context. Current approaches to tumor cell vaccine design are based on manipulating T cells or antigen-presenting cells (APCs) to recapitulate an inflammatory environment. T cells can be activated directly by either increasing the MHC peptide density presented by the vaccine, or genetically modifying the vaccinating tumor cells to express costimulatory molecules that provide a second activation signal to the T cell. This second signal, provided by cytokine gene transfer or the transfer of genes encoding costimulatory molecules, synergizes with the activation signal generated by engagement of the T-cell receptor (TCR)-MHC Ag complex. T cells can also be activated...

Oncogenic Capacity Of The Jakstat Signaling Pathway

Phenotype relies on unrestrained replicative potential, avoidance of immune surveillance, stimulation of angiogenesis, inappropriate tissue invasion, and metastasis. Coverage of all intracellular signaling pathways associated with oncogenesis is beyond the scope of this chapter, and we focus instead predominantly on the roles of the Jak-Stat pathway and selected members of the Src family protein tyrosine kinases as well as the SOCS proteins. The growth-suppressive and proapoptotic activities of Stat1 in response to cytokines such as IFN-y, TNF-a, and IL-6 are well documented. In the absence of Stat1, deficiencies occur in constitutive expression of caspases and IFN-y-induced expression of cas-pase 1 and the cyclin-dependent kinase inhibitor p21WAF1 CIP1 leading to an impairment of cell growth arrest and apoptosis (91-94). An important step in tumor development is evasion of the immune system, in which IFN-y plays an important role by upregulating expression of MHC proteins for antigen...

Reactivation and endogenous reinfection

Certain cytokines, as well as plant and food components (e.g. agglutinins, phorbol esters, aflatoxin) (Krueger et al., 1998). Reactivation per se does not cause disease unless the virus persists and replicates over longer periods of time secondary to immune deficiency, systemic autoimmune disorders or tumor growth. In essence, two main conditions support a pathogenic HHV-6 reactivation with reinfection of tissues continued abnormal stimulation of cells carrying viral genomes and defective host control of virus replication and spread. Pathologic persistent activity of reactivated HHV-6 under such conditions coincides with a number of diseases in various organs.

Response To Immunosuppressive Therapies Suggests An Autoimmune Etiology

Immunomodulating and immunosuppressive therapies constitute the cornerstones of therapy for MS and will be discussed in detail in later chapters of this book. These agents include glucocorticoids, immunosuppressive agents such as mitoxantrone, immunomodulators such as interferon-p, and glatiramer acetate. All of these agents are partially effective and are thought to act by modulating the immune response. Glucocorticoids are useful for hastening recovery of acute relapses. Glucocorticoids have a multitude of inhibitory effects on the immune system. They decrease expression of pro-inflammatory cytokines such as TNFa, IL-2, and IFN-y (117,118). In most studies, they have been shown to increase expression of anti-inflammatory cytokines such as IL-10 and TGFp-1 (119,120). Glucocorticoids also decrease MHC I and MHC II expression (121), induce T-cell apoptosis (122), inhibit nitric oxide synthesis (123), decrease expression of the adhesion molecules E selectin and ICAM-1 (124), decrease...

Attenuation And Safety

Additional mutations in the viral genome allow the host to respond more vigorously to viral infection. The V47 gene normally functions to down-regulate MHC class I peptides on the surface of virally infected cells. This cloaks an infected cell from the host's immune system. A mutation in the V47 gene enables major histocompatability complex (MHC) class I peptide expression, allowing antigen presentation to CD8+ cells. This interaction improves the hosts ability to identify and destroy infected cells and limits the ability of virus to generate new progeny (Table 1) (11).

Antibodyhapten Interactions

Specific, rapid, and high-affinity recognition of antigens by antibodies is essential for the host's immune system to respond to invasion by foreign cells and pathogens. Pecht and Lancet1 have presented a cogent analysis of antibody interactions with haptens, and the interested reader will find their examination of the kinetics and thermodynamics to be particularly lucid. Briefly, for the simple one-step binding scheme,

In Situ Cytokine Gene Therapy

The prostate and bladder are easily accessible for direct intratumoral gene therapy using routine techniques, such as transrectal ultrasound guided needle biopsy of the prostate or cystoscopy and intravesicular instillations of the bladder. Adaptation of these methods to deliver gene therapy vectors has been relatively straightforward, although there have been some difficulties overcoming the efficient gene transfer in the bladder (11). Concerns related to systemic toxicity and cancer cell specificity are generally reduced in local gene therapy applications. In addition to local anti-tumor effects, cytokine genes delivered locally to prostate cancer lesions may induce systemic responses that have therapeutic impact on disseminated cancer cells. This systemic immunotherapy using local cytokine gene therapy is termed in situ cytokine gene therapy or active vaccine therapy.

Related to Testes Specific Vespid and Pathogenesis Protein RTVP1

Lated that RTVP-1 was a secretary protein and might play a role in human immune system (69). Comparison between the deduced protein sequence of mRTVP-1 with known protein sequences revealed that this gene had 68 identity and 75 homology to the human RTVP-1 (hRTVP-1) protein (65). The mRTVP-lprotein contains two short inframe deletions of two amino acids (PH) at positions 86-87 and a 9-amino acid deletion (KVSGFDALS) from amino acid 158-166 relative to hRTVP-1. Both mouse and human proteins contain extracellular protein signature motifs (sig-1 and sig-2), a transmembrane domain, a putative N-linked glycosylation site, and a hydrophobic region near the carboxyl terminus. Interestingly, both proteins also contain a putative N-terminal signal peptide which suggests that both proteins are located on the cell membrane or secreted. Multiple lines of evidence support the concept that the RTVP-1 gene should be considered a tumor suppressor gene. Its regulation by p53, induction of apoptosis,...

Cell Mediated Delivery Of Cytokine Genes

Specific protocols have been developed to allow modification of APCs via direct loading with antigen(s) or by gene modification to generate cells that have increased capacity for antigen uptake and presentation to effector immune cells including T-cells. To the extent that these modified cells are introduced systemically and depending on the cell type used there is targeting capacity associated with antigen gene modified cell-based systemic immunotherapy. Cells that have been developed for gene-modification based immunotherapy vehicles include tumor cells, APCs (macrophages and DCs) and more recently adult stem cells. Modification of these cells with cytokine genes is particularly attractive for prostate cancer therapy.

Cytokine Modified Dendritic Cells

DCs are extremely efficient APCs that are widely dispersed in tissues and peripheral blood. Because they can be manipulated ex vivo and are perhaps the most specialized APCs they have been considered the prime candidates for cell mediated cancer therapy. A number of clinical trials using DC have been performed for prostate cancer (109-116) as well as other cancers (see ref. 117 for a review of the first 1000 trials). Although melanoma is the most commonly treated cancer using DC immunotherapy, GU cancers, notably, renal and prostate, are also being evaluated (118). Most of these studies involve DC primed with specific polypeptides that will bind MHC Class I or II molecules or with tumor lysates. Tumor derived mRNA transfected into DCs is being used to circumvent the challenge of lack of identity of TAAs. In current clinical trials DCs are most often injected intradermally or subcutaneously and less commonly intravenously or into a lymph node (118). A challenge with current clinical...

Chaperone protein interactions with professional antigenpresenting cells receptors for hsps

Our perspective so far has been from the inside of the cell, where chaperone proteins associate with intracellular peptides, to the outside of the cell, whereupon chaperone proteins obtained from the intracellular environment by extraction and purification may be utilized as multivalent, peptide-laden vaccines once removed from the cell. The next step is to return the vaccine to host cells, specifically, to those of the immune system involved in antigen presentation. Therefore, we will examine what is known mechanistically about the specific interactions of chaperone proteins with APCs that lead to immune effector cell responses.

Chaperone protein interactions with professional antigenpresenting cells phenotypic effects on apcs

Although the specific receptor(s) for chaperone proteins await clarification, the phe-notypic effects of exogenous chaperones on APCs are legitimately recognizable, if not entirely uniform. Professional APCs such as macrophage cells and DCs upregulate expression of MHC class I and II molecules, costimulatory molecules CD80 86 (B7-1 and B7-2), and CD40 (78,88,89) when these APCs are exposed to exogenous chaperone proteins, whether those chaperones are tumor derived or have been isolated from normal tissues, i.e., devoid of tumor-peptide antigen (90). Such stimulated APCs will also secrete a plethora of pro-inflammatory cytokines, including TNF-a, IL-10, IL-6, and IL-12, presumably triggered via NF-KB-promoted pathways (78,89). It appears that exogenous chaperone proteins are at the crux of both adaptive and innate immune responses in that they are capable of supplying peptide antigens in an extraordinarily effective manner whereas their mere presence primes the immune system for action...

Clinical Evidence for Deficiencies of TCell Mediated Immunity in the Neonate

In contrast, infection in utero can have dramatic, damaging effects on an otherwise healthy fetus (Brown and Abernathy, 1998 Gandhi and Khanna, 2004). Although the majority of infected infants are asymptomatic, 5-10 will suffer severe neurologic damage including microcephaly, seizures, deafness, and retardation. Additional infants will appear asymptomatic at birth but will progress to have significant hearing loss. Infection acquired after birth is usually asymptomatic, but interestingly both congenital infection and post-natal infection through the pre-school years result in prolonged shedding of the virus, while in adults such continuous shedding after primary CMV infection is limited to approximately 6 months after acquisition. This indicates an inability of the neonatal and infant immune system to control the virus compared to the immunocompetent adult (Stagno, 1983). and flow cytometry, they showed that CMV-specific CD8+ T cells could be detected pre-natally and early after...

Bacterial Extracts in Cancer Vaccines

It is now known that host recognition of microbial components occurs through the recently described TLRs. This family of receptors and their associated intracellular messengers evolved to recognize and respond to conserved microbial components. The response manifests in an immediate activation of cells of the innate immune system resulting in the secretion of inflammatory cytokines, reactive oxygen intermediates, and defensins. In addition to providing immediate nonspecific protection, this inflammatory response induces and regulates the initiation of the antigen-specific adaptive immune responses, controlling dendritic cell (DC) maturation and differentiation of T helper (Th) cells (reviewed in ref. 17).

Future Bbbd Directions

In the pre-clinical setting, we have studied the BR96 mAb which binds to a LewisY-related antigen expressed in lung, breast, ovarian, and colon cancer. The conjugate of BR96 mAb with adriamycin (BR96-DOX) is effective against a number of human carcinoma xenografts in rodents 45 . The efficacy of immunotherapy or immunoconjugates is limited by poor penetration in solid tumors. Additionally, antibodies do not cross the BBB. We are investigating the use of radiolabeled tumor-specific antibodies against brain tumors an approach which could be further optimized by BBBD to achieve global delivery 46 .

In Vivo Evidence for DCs As Strong Adjuvants

There is a large body of literature involving animal models of tumor immunity in which DCs loaded with tumor-associated antigens (TAAs) are able to induce protective antitumor responses. When tested, DCs can be superior to other vaccination strategies (24). There also are reports in which DC immunization produces significant therapeutic immunity to established tumors (reviewed in ref. 25). A number of trials have now utilized TAA-loaded DCs as vaccines in humans. Initial pioneering studies involved patients with lymphoma and melanoma (26,27). Some clinical and immune responses (T-cell proliferation and delayed-type hypersensitivity DTH ) without any major toxicity have been observed. More recent DC vaccination studies put further emphasis on the elicited immune responses and have included control antigens for CD4+ and CD8+ T-cell responses (28-31). Several of these studies are reviewed elsewhere in this handbook. Inclusion of control antigens helps to verify that the DCs are...

Summary And Future Questions

Much has been learned about the class IIa HDACs in the short time since they were discovered. A host of interaction partners have been identified, mediating targeting to specific promoters, recruitment of different enzymatic activities such as histone methylation, and regulation of subcellular localization. Many of these interactions have been tied to the signal-dependent regulation of specific target genes that play important roles in differentiation processes in heart, skeletal muscle, and the immune system and in the regulation of viral latency. Other biological roles are being defined in the context of knockout animals. However, many questions remain to be answered.

Peptide Binding Versus Adjuvanticity

The conserved heat shock protein (HSP) families are a group of molecular chaperones expressed in all prokaryotic and eukaryotic cells. HSP are the most abundant consti-tutively expressed proteins in cells. The expression of many HSP is also induced during cellular stress responses such as those caused by exposure to toxins, glucose starvation, anoxia, irradiation and heat (Hassen et al., 2005 Maytin, 1992 Spence et al., 1990 Zimmerman et al., 1991). The major functions ascribed to HSP are in the assembly and disassembly of proteins, the prevention of aggregation and their ability to bind the hydrophobic regions of nascent polypeptide chains (Gething and Sambrook, 1992 Richarme and Kohiyama, 1993). As discussed above, this latter function has generated immense interest amongst immunologists, as HSP-derived from tumor cells have been shown to confer tumor specific immunity (Richarme and Kohiyama, 1993 Srivastava, 2002a). This has led to the identification of several HSP with...

Effects of Enteric Microbiota in the Healthy Intestine

In addition, the integrity of the mucosa requires cell signaling between the microbiota, epithelium, and mucosal immune system (7). Without the microbiota, mucosal associated lymphoid tissue is underdeveloped and cell mediated immunity is defective. The enteric microbiota plays an important role in immune system education by fine-tuning T-cell repertoires and Th1 Th2 cytokine profiles (11). Compared with conventional animals, germ-free animals have reduced mucosal cell turnover, cytokine production, mucosal associated lymphoid tissue and lamina propria cellularity leading to an ineffective cell mediated immunity, decreased vascularity and less muscle wall thickness (25-27). There are also differences in intraepithelial lymphocytes (28,29). The intestinal microbiota primes the mucosal immune response and keeps it in a state of controlled physiological inflammation (26). Induction and or maintenance of oral tolerance to ingested antigens also require microbial colonization of the...

Clinical Trials With Modified Adenoviruses

RGDTKSSTR was used to demonstrate an important aspect of fiber modified Ads. Neutralizing antibodies (NAbs) are the main component of the humoral immune system responsible for inhibition of Ad infection, and are present in a large proportion of the population. Further, NAb titers are quickly induced following treatment with Ad (127). Many NAbs are conformation sensitive, and when the fiber shape is changed slightly, such as when incorporating a targeting moiety, partial escape from NAbs can be seen

Source Preparation and Antigen Loading Strategy

Several systems have been employed to load DCs with TAA. Loading MHC class I molecules with peptides derived from defined antigens is most commonly used, and is also applied to recently identified MHC class II helper epitopes. Although important for proof of concept studies, the use of peptides is limited because of their restriction to a given HLA type, the limited number of defined TAA, and the induction of a restricted repertoire of T-cell clones. Furthermore, quantity and longevity of peptide loading is difficult to control. Alternative strategies that provide both MHC class I and class II epitopes and lead to a diverse immune response involving many clones of CD4+ T cells and CTLs are needed. These include recombinant proteins, exosomes (vesicles rich in MHC-peptide complexes and heat shock proteins) (77), viral vectors, plasmid DNA, RNA transfection (78), dying tumor cells, opsonized tumors (38), immune complexes, or fusion of tumor cells and DCs (79). Few comparative data...

Hsp70 Family Members Danger Signals And Autoimmunity

Abstract The 70 kiloDalton family of heat shock proteins (Hsp70) are known to stimulate immune responses and have been increasingly implicated in autoimmune conditions. Hsp70 proteins are present in pathogens as well as in healthy cells. They can be expressed constitutively or elevated in response to heat or other cellular stress. Immune responses stimulated by Hsp70 family members include triggering of innate inflammatory responses, enhancing antigen presentation to self-reactive T cells, and cross priming of chaperoned tumor and other self antigens. In this chapter, we present an overview of immunomodu-latory activities described for Hsp70 proteins and review the evidence implicating Hsp70 activity in autoimmunity. The ability of Hsp70 to stimulate anti-self tumor immunity and the prospect of using Hsp70 in vaccines or as adjuvants for cancer immunotherapy will be examined. Finally we discuss potential mechanisms by which Hsp70 proteins act as danger signals and regulatory molecules...

Vertebrates Homo sapiens

The Homo sapiens genome, with 31,000 genes, has a predicted total of 518 protein kinase genes (1.7 of all genes) 8 . Of these 478 are in the canonical ePK family (Table 1), and the others are divided between 9 small aPK families, which include the PIKK (PI3 kinase-like kinase), the PDHK (pyruvate dehydrogenase kinase) and alpha kinase (E2F kinase) families. There are 90 tyrosine kinase genes (16 of all protein kinases) several of the tyrosine kinase families present in Drosophila and C. elegans have undergone significant expansion in mammals (e.g. Eph receptor tyrosine kinases, where there are 14 members in humans, and only 1 in Drosophila and 1 in C. elegans). The total number of protein kinases is about half that predicted 15 years ago 1 , but it is still a strikingly large number, comprising about 1.7 of all human genes. Moreover, the total number of protein kinase gene products is surely much greater than 518, due to the expression of alternatively spliced forms, which are known...

The Origin of Blood Cells

Blood cells originate in bone marrow from hemocyto-blasts, a type of stem cell (fig. 14.3). A stem cell can differentiate into any of a number of specialized cell types. As hemocytoblasts divide, the new cells respond to different secreted growth factors, called colony-stimulating factors, that turn on some genes and turn off others. This exposure to growth factors ultimately sculpts the distinctive formed elements of blood, including the cellular components of the immune system. A protein called thrombopoietin (TPO) stimulates large cells called megakaryocytes to proliferate. These cells eventually come apart to yield platelets.

The Elusive Cancer Cell

Cancer cells may evade recognition by the immune system through several mechanisms (9) (1) down-regulation of antigen processing and presentation, (2) loss of some TAA which may alert the immune system, and (3) secretion of soluble signals which can modify the ability of DCs to effectively present antigens to na ve T-cells. Examples of such secreted factors include interleukin (IL)-10, which inhibits DC maturation, and transforming growth factor (TGF)- , which is secreted by cells in the eye to prohibit destructive inflammation (9,10). Although it is unclear to what extent these mechanisms are involved in tumor persistence, it is clear that tumor cells have developed ways to avoid immune rejection.

Human immunodeficiency virus infection could it be HIV

The benefit of early diagnosis has become even more impressive since the discovery that HIV is not a latent infection throughout most of its course. Soon after initial infection, an explosive replication of HIV occurs, which is brought under control by the immune system in 6 to 8 weeks as the host-versus-virus interaction reaches an active and dynamic equilibrium. This dynamic situation continues throughout a person's lifetime, with as many as 10 billion new virions produced and up to 2 billion CD4 lymphocytes

Adjuvants and Costimulation

Adjuvants are defined as anything added to a vaccine that increases the immune response in terms of magnitude, duration, or time of onset (72). By this definition even micro-injury during inoculation with vaccine formulations (73-75) or the haplotype of an individual (76) can be conceivably called an adjuvant. As it relates to DCs, adjuvancy can be more tightly defined as anything that induces progression toward an optimal level of signal 1 (antigen presentation enhancements such as in delivery systems) and signal 2 (such as costimulatory molecule and cytokine up-regulations by using immunostimulatory adjuvants ). Enhancing the presentation to signal 1 seems fairly straightforward by increasing expression of the antigen in the proper cell type. However, methods for enhancing the optimal presentation of signal 2 remain unclear, in part because of the complex dialogue between lymphocytes. It is clear, however, that signal 2 requires the up-regulation of costimulatory...

Mhcdependent Mating Preferences In Other Taxa

Offspring at the MHC and, more specifically, at the peptide-binding region, presumably in order to provide them with better defense against parasites and pathogens (Landry et al., 2001). Milinski and his colleagues found that female three-spined sticklebacks (Gasterosteus aculeatus) are attracted to the scent of males that have many MHC alleles, but only if they have few alleles themselves (Aeschlimann etal., 2003 Reusch etal., 2001). When females have many alleles, then they prefer males with few alleles. To understand these preferences, Milinski and his colleague examined how MHC influences resistance to infection by parasites. They found that individuals with intermediate levels of MHC hetero-zygosity are most resistant to three common parasites (Wegner et al., 2003). It would be interesting to know whether these mating preferences produce offspring with intermediate MHC diversity. Increasing the number of MHC molecules expressed during development is probably beneficial, but the...

Tomorrows Genetic Vaccines

The efficiency of nonviral gene delivery is still far below that of viral vectors. However, research in the field has come a long way toward identifying key mechanisms responsible for optimizing immune response. For example, the use of protein transduc-tion domains and alphaviral replicons has allowed fundamental viral mechanisms to be incorporated into completely synthetic delivery systems. There is no reason to doubt that further understanding of viral gene delivery mechanisms will inspire synthetic versions of these functionalities which will serve the same purpose, and someday allow for completely synthetic, yet fully potent, gene delivery with minimal safety concerns. This ideal genetic vaccine formulation has already been described as having the following properties (1) low dose frequency, (2) low cost, (3) effective immune response, (4) high reproducibility, (5) pharmaceutical acceptability, and (6) a high safety profile (134). However, effective immune response, by definition,...

Directed Evolution of Nucleic Acid Polymerases

Polynucleotide polymerases attract much attention - not only because of their central role in DNA metabolism, which suggests an important link to various diseases like tumor growth, defects of the immune system, stress-associated mu-tagenesis, or viral infections. Several polymerases are indispensable tools for molecular biotechnology, and could be even more valuable if the range of substrates accepted, or their stability and activity, could be ''tuned'' to specific requirements.

HHV6 has the ability to integrate into host cell chromosomal DNA

The hypothesis that HHV-6 may contribute to the development of LD by deregulation of cytokine control rather than by direct oncogenic involvement has been suggested. Recently, Takaku et al. (2005) studied the network of dynamic gene and protein interactions occurring during the infection of an adult T-cell leukaemia cell line by HHV-6B using a microarray and analysing the data by the Bayesian statistical framework. They reported the possible association between chemokine genes regulating the Th1 Th2 balance and genes regulating T-cell proliferation. Moreover, a gene encoding a TEC-family kinase, ITK, might be a putative modulator of the host immune response against HHV-6B infection. An interesting approach consisted in the design of a computer model in order to simulate cell changes happening in LD and disturbances of the T-cell immune system (Krueger et al., 2003). The model uses the concept that these disturbances, identified as proliferation, differentiation and inhibition factors,...

Biological effects of exosomes

Likewise, it is also conceivable that exosomes are involved in peripheral tolerance and inhibition of immune responses. Experiments in rats reported that intraperitoneal injections of exosomes derived from a gut epithelial cell line loaded with Ag led to a decrease of the Ag specific delayed-type hypersensitivity reaction (38). Moreover, in allogeneic cardiac transplantation models, Cuturi and colleagues showed that donor LEW.1W DC exosomes injected intravenously induce LEW.1W heart allograft tolerance in LEW.1A rat recipients. Prophylactic usage of exosomes in recipients was more efficient in prolonging allograft survival than therapeutic usage (39). Finally, recent studies showed that T cells can acquire peptide MHC class II complexes from APCs (10,13). These T lymphocytes were killed by neighboring lymphocytes, suggesting that fratricidial T-cell killing could represent a negative feedback loop of immune responses (40). The role of exosomes in such a membrane exchange has not been...

HSP Release from Damaged and Necrotic Cells

And calreticulin (Basu et al., 2000). The increased release of HSP from necrotic rather than apoptotic cells has been used to support their roles as danger signals, as apoptosis is a controlled process involved in cell homeostasis and there would normally be no reason to alert the immune system to cells undergoing apoptosis (Johnson and Fleshner, 2006a Matzinger, 1994 Todryk et al., 2003). Release from necrotic cells, however, is not only due to simple coincidental loss of HSP resulting from damage to the cell. Necrotically dying cells were recently shown to increase HSP expression prior to death by activation of HSF1 (Saito et al., 2005), showing a stress response. Hsp90, Hsp72, Hsp73, Hsp60, Hsp47, Hsp40, and Hsp27 were released from the dying cells in response to acrylamide treatment, leading to the term 'dying messages' being suggested by the authors as well as 'danger signals' (Saito et al., 2005). expressed on the exosomal membrane (Bausero et al., 2005). Exosomal membrane Hsp72...

Extracellular Hsp72 A Doubleedged Sword For Host Defense

Abstract Environmental or emotional challenge triggers a cascading series of physiological responses which are collectively termed the stress response . The stress response can be assessed at the behavioral, neural, hormonal, immunological and single cell, levels and evolved to benefit an organism's chance of survival during times of acute challenge. The stress response has been studied for many years, however, its impact on specifically immune function has only recently been appreciated. Acute activation of the stress response has both inhibitory and stimulatory effects on immunity. The focus of this chapter is on a novel mechanism for the immunostimulatory effects of stress. Specifically, we propose that an endogenous, ubiquitous cellular stress protein, heat shock protein 72, when found in the extracellular environment may contribute to stress-induced potentiation of innate immunity. We develop the hypothesis that the release of extracellular heat shock protein 72 (eHsp72) is a...

Trafficking of Transferred T Cells

If adoptive immunotherapy is envisioned for disseminated metastatic disease, it is essential that the activated T cells retain the capacity to traffic to all anatomic sites following adoptive transfer. We have confirmed the efficacy of adoptive immunotherapy with activated LN cells against tumor in all tested anatomic locations including lung, liver, subcutaneous tissue, and brain (36-38). Tagged T cells avidly infiltrate tumors in all anatomic sites although the initial infiltration of tumors by activated T cells is not antigen specific (39). It is essential that T cells retain the ability to traffic to tumors because if they are pharmacologically prevented from undergoing diapedesis they lose efficacy when systemically transferred even though they are still functional when coinoculated in a Winn assay (40). Treatment with high-dose IL-2 has been used in conjunction with T-cell adoptive immunotherapy in most applications with the rationale that it preserves the viability and...

Immunogenicity and Serum Level

In a study to assess immunogenicity, 21 of patients possessed IgG antibody to IL13-PE prior to drug administration as determined by qualitative enyme-linked immunosorbent assay. Two of 7 (29 ) and 11 of15 (73 ) evaluable patients in the IL13PEI-002 and IL13PE-103 studies, respectively developed IgG Ab to IL13-PE following drug administration. The IgG Ab produced in response to IL13-PE was specific for PE and not to the IL-13 portion of the molecule. The higher frequency of antibody development in IL13PEI-103 study patients may be related to the intratumoral delivery exposing the humoral immune system to the drug either through blood-tumor barrier disruption or local lymphocytic infiltration.

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