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a Binding scores were determined using BIMAS (100).

a Binding scores were determined using BIMAS (100).

acid sequence homology between anti-id antibody and the corresponding TAA may not be required for the sharing of a T cell defined epitope, since three examples of recognition of structurally different MHC class I antigen-peptide complexes by a single T-cell receptor have been recently described [97-99]. The anti-id antibody reactive T cells which recognize TAA may control tumor growth by secreting cytokines such as IFN-y that induce CTL proliferation [31], A mechanism for tumor control by anti-id antibody reactive T cells which do not recognize TAA is suggested by the results obtained in an animal model system. A T-cell line induced by an anti-id mAb could recognize the anti-id mAb bound to tumor cells coated with the corresponding anti-TAA mAb [96]. Therefore one might suggest that TAA binding anti-anti-id antibodies induced by the idiotypic cascade triggered by the administration of an anti-TAA mAb may mediate the binding of anti-id antibodies to tumor cells, anti-id antibodies in turn, may target to tumor cells anti-id antibody reactive T cells which do not recognize TAA. The sequence of events we have suggested for TAA reactive T cells could then take place.

In two studies, immunization with anti-id mAb has generated or enhanced the level of cytotoxic cells which lyse autologous tumor cells or tumor cells expressing the TAA mimicked by the immunizing anti-id mAb [66, 67, 12}. In at least one study [72], the cytotoxicity of tumor cells is mediated by MHC class I antigen restricted, TAA specific CTL. The association with an improved prognosis of the disease, of tumor cell cytotoxicity found in patients immunized with anti-id mAb argues in favor of its clinical relevance. This possibility is supported by data obtained in animal model systems [89, 90, 96],

Induction of MHC class I antigen restricted, TAA specific CTL by anti-id antibodies is an unexpected finding, since idiotopes which mimic determinants expressed on TAA result in the majority of cases from the association of the heavy and light chain variable regions of anti-id antibodies. The results described by Pride et al. [72] are therefore noteworthy. These authors have presented rather convincing evidence that anti-id antibodies which mimic HMW-MAA have induced HLA class I antigen restricted, HMW-MAA specific CTL in patients with melanoma, since cytotoxicity of HMW-MAA bearing melanoma cells by CTL is restricted by HLA-A2 antigens and in the few cases tested, is inhibited by anti-HLA class I anti bodies. In an attempt to identify the peptide(s) which generate(s) CTL and that (those) which are the targets of the immune response, we have analyzed the amino acid sequence of the heavy and light chain variable regions of the anti-id mAb Mel-1 used as an immunogen and that of the HMW-MAA core protein used as a target. This analysis could not be performed with the anti-id mAb Mel-2, which was also used as an immunogen, since no information is available about the amino acid sequence of its heavy and light chain variable regions. Analysis with the Bio-informatics and molecular analysis software (BIMAS) [100] has identified two peptides with HLA-A2 antigen binding motifs in the heavy and light chain variable region of anti-id mAb Mel-1. The sequence of the peptides with the binding scores to HLA-A2 antigen is shown in Table 7. Only the peptide LLVLLYSKL derived from the framework region 1 of the heavy chain variable region of anti-id mAb Mel-1 has homology with the amino acid sequence LLQLYSGR from residue 75 to 80 in the HMW-MAA core protein [101]. However, the latter peptide does not have the anchor residues required for binding to HLA-A2 antigen and therefore is not likely to be recognized by HLA- A2 antigen restricted, HMW-MAA specific CTL generated by the anti-id mAb Mel-1. Table 8 lists the peptides with HLA-A2 binding motifs derived from the HMW-MAA core protein. These peptides have no homology with the HLA-A2 antigen binding peptides derived from the anti-id mAb Mel-1. Nevertheless HMW-MAA derived peptide(s) may still be recognized by HLA-A2 antigen restricted, HMW-MAA specific CTL elicited by anti-id mAb, since recognition of structurally different MHC class I antigen-peptide complexes by a single T-cell receptor has been recently described [97-99].

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