Specific transplantation tolerance induced by autoimmunization against the individual's own, naturally occurring idiotypic, antigen-binding receptors.

Abstract

Serum or urine from normal adult Lewis rats can be shown to contain detectable amounts of idiotypic, antigen-binding receptors with specificity for the major histocompatibility complex locus antigens of the rat, the Ag-B locus antigens. Such purified naturally occurring receptor molecules, be they of T- or B-lymphocyte origin, can be used in a polymerized form to provoke the production of auto-anti-idiotypic antibodies when injected back into normal Lewis rats. As a consequence of this autoimmunity, lymphocytes of these Lewis rats can be shown to be depleted of cells carrying the relevant idiotypic receptors signifying reactivity against a given Ag-B locus-determined antigen(s). This specific lack of idiotypic lymphocytes is manifested as a selective loss of reactivity against the relevant Ag-B-incompatible antigens as measured by graft versus host or MLC reactions. Furthermore, autoimmune Lewis rats display specific transplantation tolerance against the skin grafts from the relevant strain, as demonstrated by specific prolongation of graft survival. A further indication of the specific tolerence state of these rats comes from the highly reduced ability to produce circulating antibodies against the relevant Ag-B antigens. No side effects of these autoimmunization procedures have been noted so far. It would thus seem clear that a prolonged state of specific transplantation tolerance can be achieved via autoimmunization against the individual's naturally occurring idiotypic, antigen-binding receptors.

Prolongation of survival of rat cardiac allografts by T cell vaccination.

“…The major difference between our results here and in the MLR (8), and those reported by Binz and Wigzell concern the degree ofspecificity: In contrast to the nonspecific inhibition we observed, Binz and Wigzell reported no inhibitory effect on a third party allograft after their procedure (16)(17)(18)(19)(20). The difference in results might be because ofthe different reagents and methods used for vaccination: Binz and Wigzell used either antibodies or T cells generated by in vitro MLR and injected them in CFA (16)(17)(18)(19)(20); in contrast, we used the Con A-activated T cells from in vivo primed rats, fixed with a chemical cross-linker, and administered without CFA or other adjuvants. These diverse forms of immunization may have triggered different regulatory mechanisms, resulting in diverse forms of alloantigen unresponsiveness.…”

“…Previously, Binz and Wigzell immunized mice and rats with anti-MHC antibodies in CFA, or with purified MLR-activated T lymphoblasts in CFA ( 16,17). They reported MHC-restricted reduction of MLR, cell mediated lymphotoxicity, graft versus host disease, and prolongation of skin allograft survival.…”

Suppression of Rejection of Organ Allografts by Alloantibody*

“…Some striking examples of the suppression of immune responses to histocompatibility antigens in this way have been demonstrated, as for example illustrated by the experiments of Binz et al (1973) in the rat. This anti-idiotype antibody would also react with receptor sites for that antigen on T lymphocytes e.g.…”

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“…The new approach used herein to induce anti-TCR immunity is based on conventional idiotypic immunization in which antigenized antibodies mimic the immunogenic properties of soluble TCR functioning as a surrogate internal image [45] in much the same way as previously demonstrated for a non-self antigen [31]. The present approach is reminiscent of experiments in which induction of anti-idiotypic immunity against TCR with specificity for MHC was obtained by immunization with soluble alloantibodies of relevant specificity [46,47], or by immunization with autologous idiotype positive molecules that are shed from the cell surface in the serum [48]. Thus, antibodies purposely modified to express selected loops of the TCR obviate the necessity to purify the receptor, isolate idiotypic TCR molecules from the serum, or use antigen-specific T cell blasts.…”