Amplification of Natural Regulatory Immune Mechanisms for Transplantation Tolerance1

Abstract

There is a need to derive donor-specific tolerance in clinical organ transplantation, where potential benefits remain overshadowed by chronic rejection and side effects of continual immunosuppressive therapy. It is known that the mature immune system in mice can be reprogrammed to accept a foreign graft as if it were "self." Here we show that, once generated, this state of operational tolerance becomes self-sustaining, imposing itself on new cohorts of lymphocytes as they arise. These new cohorts retain specificity for the tolerizing antigen and can be selectively amplified to tolerate new antigens that have linked expression with the original tolerogen. Regulation is critically dependent upon the continuous presence of tolerizing antigen and is mediated by the CD4+ lymphocyte population. We propose that such natural mechanisms of immune regulation may eventually be exploited for transplantation tolerance, even in fully immune-competent recipients.

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

“…Hence, our results demonstrate that 1) Ad-IL-4 gene transfer potentiates the operational activity of regulatory cells, and 2) regulatory cells maintain MHC specificity of the infectious tolerance pathway. CD4 ϩ T cells are instrumental in that pathway, as their selective depletion in the original tolerant animals or after transfer into new cohorts of test recipients prevents induction of tolerance (3,31,32). In all animal models tested to date, the maintenance of regulatory T cells was shown to depend on the presence of donor Ag (30).…”

Leukaemia inhibitory factor (LIF) is functionally linked to axotrophin and both LIF and axotrophin are linked to regulatory immune tolerance

“…In self-tolerance, CD4 + CD25 + regulatory T lymphocytes arise within the thymus and protect against auto-immunity in a forkhead transcription factor P3 (Foxp3)-dependent manner [1]. Mouse allograft models have shown that peripheral, naive CD4 + lymphocytes may also be guided towards regulatory tolerance by therapeutic manipulation of signal transduction pathways at the time of initial antigen engagement [2][3][4]. Once established, a self-sustaining state of donor-specific tolerance occurs: this requires continuous presence of donor antigen and is capable of being adoptively transferred to fully immune competent recipients of a donor-type graft via ''tolerant'' lymphocytes [2].…”

“…Mouse allograft models have shown that peripheral, naive CD4 + lymphocytes may also be guided towards regulatory tolerance by therapeutic manipulation of signal transduction pathways at the time of initial antigen engagement [2][3][4]. Once established, a self-sustaining state of donor-specific tolerance occurs: this requires continuous presence of donor antigen and is capable of being adoptively transferred to fully immune competent recipients of a donor-type graft via ''tolerant'' lymphocytes [2]. Ex vivo analyses of tolerant splenocytes revealed leukaemia inhibitory factor (LIF) release in response to donor antigen [5].…”

Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model.

“…The "re-educated" regulatory T cells could then be transplanted to a naïve animal and induce donor-specific tolerance to a skin graft (1). In another experiment, Chen et al were able to demonstrate that CD4+ T cells transfused from a mouse tolerant of a fully mismatched vascularized heart were able to induce donor-specific tolerance in a syngeneic recipient (2). In the same study, Chen et al also showed that this process could be repeated for up to 10 subsequent generations of adoptively transferred cell recipients (2).…”

“…In another experiment, Chen et al were able to demonstrate that CD4+ T cells transfused from a mouse tolerant of a fully mismatched vascularized heart were able to induce donor-specific tolerance in a syngeneic recipient (2). In the same study, Chen et al also showed that this process could be repeated for up to 10 subsequent generations of adoptively transferred cell recipients (2). Since the publication of these seminal studies, several authors have developed adoptive transfer models in mice and rats, using different cells populations to transfer tolerance, such as PBMCs, splenocytes, lymph nodes or graft infiltrating cells (GILs) (1;13;14).…”