Clinical Significance Of The Humoral And Cellular Antiantiid Immune Response Elicited In Patients With Malignant Diseases

Studies in animal model systems have convincingly shown that anti-anti-id immune responses elicited with anti-id antibodies [88, 89], with anti-TAA mAb [90] or with peptides derived from the amino acid sequence of complementarity determining region (CDR) of anti-TAA mAb [90] can induce tumor rejection. These findings support the possibility that the association between improved prognosis and development of a humoral and cellular anti-anti-id response in patients with malignant diseases immunized with anti-id anti bodies or with anti-TAA antibodies might not be fortuitous, but might reflect an effect-cause relationship. As far as the mechanisms underlying these findings is concerned, the beneficial effect of TAA binding anti-anti-id antibodies on the clinical course of the disease is likely to reflect the complement and cell dependent lysis of tumor cells mediated by anti-anti-id antibodies and/or inhibition of the function of the corresponding TAA in malignant cells by anti-anti-id antibodies [91, 92], In contrast, the mechanisms underlying the association between enhancement of T cell mediated immunity in patients treated with anti-id mAb or with anti-TAA mAb and the induction of TAA specific CTL by anti-id mAb are not readily apparent. Therefore potential mechanisms which may account for these findings will be discussed in some detail. In one study [86, 87] administration to patients with metastatic colorectal carcinoma, of an anti-TAA mAb has induced T cells reactive with an anti-id mAb which bears the internal image of the TAA. Most, although not all of these T-cell populations recognize also the corresponding TAA, as measured by proliferative assays. The statistically significant association between the development of a T cell response following administration of an anti-TAA mAb and tumor regression raises three questions: how can administration of an anti-TAA mAb induce anti-id antibody reactive T lymphocytes?, how can anti-id antibody reactive T cells effect tumor regression? and how can TAA reactive T cells without detectable in vitro cytotoxic activity cause tumor regression? Jerne's network theory [28], which has been convincingly proven in patients with neuroblastoma [85] and at the clonal level in several antigenic systems [93-95], predicts that administration of an antibody may trigger the idiotypic cascade. As a result, anti-id antibodies, some of which may bear the internal image of the nominal antigen, and anti-anti-id antibodies, some of which may be antigen binding, are generated. Therefore one can envision that anti-TAA mAb induce the formation of anti-id antibodies. The latter, in agreement with results obtained with exogenously administered anti-id antibodies in patients [31, 66-68] and in animal model systems [96], induce anti-id antibody reactive T cells. The ability of some of the latter T-cell populations to recognize the nominal antigen has been attributed in the past to the sharing of an amino acid sequence stretch between the nominal antigen and the immunizing anti-id antibody [31], However, amino t ©

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