Characteristics of Class I Peptides

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Epitopes recognized by CD8+ T cells are, in general, peptides of 8-10 amino acids in length anchored at each end within the major groove of MHC class I molecules. As a consequence, class I molecules exhibit more amino acid sequence specificity based on these anchoring residues, than class II molecules, which may be more promiscuous in the binding of peptides. Most investigators have focused on defining class I epitopes for human leukocyte antigen (HLA)-A2 molecules (Table 1). Most likely the interest in HLA-A2 is fueled by the increased prevalence of this allele in many human populations. However, as early studies of peptide-based vaccines have shown that cancer patients can be immunized against a variety of tumor antigens, more studies are focusing on HLA-A alleles other than A2 as well as HLA-B motifs. The frequency of common HLA-B alleles is shown in Table 2. A potential problem in the development of CTL epitope-based vaccines is the large degree of MHC polymorphism and the need for knowledge of HLA restrictions in the population to be vaccinated. However, it is now known that that HLA class I molecules can be divided into several families or supertypes based on similar peptide-binding repertoires (5). For example, the A2 supertype consists of at least eight related molecules and of these, the most frequently observed are HLA-A*0201, A*0202, A*0203, A*0206, and A*6802. In addition, the A2 supertype is expressed in all major ethnicities; 39-46% range of most common populations. Many peptides that bind A*0201 also exhibit degenerate binding, i.e., binding to multiple alleles; thus, an A2 supertype multiepitope vaccine could be designed to provide broad population coverage (5). Recent investigations have demonstrated that peptides that bind HLA-A0201 with high affinity will cross-react with other A2 family alleles (6). Studies of in vitro binding of peptides to other HLA-A molecules demonstrated that over 70% of peptides that bound HLA-A0201 with high affinity bound at least two other members of the A2 superfamily. Although class I motifs have been assumed to be very specific and restrictive, studies such as those described above suggest large overlaps in specificity can be found. As newer clinical trials translate these in vitro observations of the broadening of class I activity in vivo, it may be that class I peptide vaccines will be less restrictive in use than what had been previously assumed.

Table 1

Genotypic Frequency of Common HLA-A Antigens in the North American Population

Table 1

Genotypic Frequency of Common HLA-A Antigens in the North American Population

Population

%HLA-A1

%HLA-A2

%HLA-A3

Caucasian

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