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UBC Theses and Dissertations

Idiotypic networks and immunoregulation Singhai, Rakesh


The role of an idiotype borne on a monoclonal antibody (Fd-B2) against the C-determinant of the protein ferredoxin (Fd) was investigated in mice of the B10.D2 (H-2[sup d]) non-responsive strain. It had previously been shown that when anti-idiotype (anti-Id) plus complement (C) treated T cells and non-immune untreated B cells were adoptively transferred into irradiated syngeneic B10.D2 mice, the mice response to Fd by making anti-Fd antibodies, suggesting a role for Id-bearing T cells in Fd-specific non-responsiveness. In this series of experiments, it was shown that when T cells were treated with Id+C and adoptively transferred to B10.D2 in an analogous manner, such mice also became responsive to Fd, suggesting that Id-mediated network at the T cell level may control non-responsiveness in animals. This possibility was confirmed when it was shown that adoptive co-transfer of both of the T cell populations (each in itself confering responsiveness) restored the network as manifested by re-establishment of non-responsiveness in recipient animals. Panning studies demonstrated that anti-idiotypic (Id⁻) T cells are Lytl⁺2⁻3 whereas Fd-B2 Id⁺ T cells are Lyt l⁻2⁺3. T cell lines and clones were derived from B10.D2 mice which had been converted to responsiveness to Fd by the Id or anti-Id as above. One T cell line, and a clone derived from it, was shown to secrete interleukin-2 (IL-2) not only in the presence of anti-Fd-B2 idiotype antibodies but also in the presence of Fd. Both of these reactivities were found to be MHC-restricted. This shows that non-responder status of H-2[sup d] mice is not due to a defect at the level of antigen presentation. Fine specificity analysis of one Id⁺ T cell cloned line showed that it was reactive only to the anti-idiotypes or the fragment of Fd containing the C-determinant but not to the peptide fragment of Fd devoid of this determinant. Furthermore, it was found that presentation of both the antigen and the anti-Id to the specific clone could be blocked by the Fd-B2 monoclonal antibody, indicating that the anti-id represents an internal image of the Fd molecule at the level of the C-determinant. Idiotype-mediated network interactions were also found to regulate the anti-P815 mastocytoma immune response. It was shown that when the idiotype-bearing P815-specific DBA/2 T cell hybridoma product, A10, is injected into DBA/2 mice on days -14 and 0 prior to tumour cell challenge, the animals, upon subsequent challenge, show a significant tumour regression over the controls. The activity of the A10-defined idiotype was demonstrated to be both tumour and strain specific. Using A10- and rabbit-(anti-A10)-antibody-coated dishes as panning surfaces, it was shown that the removal of A10⁺ (Id⁺) - but not anti-A10 (Id⁻) T cells leads to a significant regression of tumour. When both Id⁺ and Id⁻ T cell populations are adoptively co-transferred to irradiated syngeneic recipients, the tumour growth of specifically treated animals resembles that of the controls. This suggests that a strong similarity but not identity exists between anti-Fd and anti-P815 immunoregulatory mechanisms.

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