ReviewMechanisms of transplant tolerance induction using costimulatory blockade
Introduction
The use of reagents blocking costimulation signals proved surprisingly effective in prolonging cell and organ allograft survival in various animal models, including nonhuman primates [1]. The two groups of reagents that have been most commonly used and whose effects have been delineated in some detail in transplantation systems will be the focus of this review; namely, CTLA4Ig or monoclonal antibodies (mAbs) against CD80/CD86 (B7.1/B7.2) or CD28, aimed at interfering with the CD28/CD80/CD86 pathway, and mAbs against CD40 — or, more commonly, against CD154 — aimed at manipulating the CD40/CD154 pathway (Fig. 1). For reasons of convenience and convention, the term ‘costimulatory blockade’ will be used solely to indicate the application of such reagents, realizing that in many cases it has not been firmly established that antibody-mediated mechanisms other than blocking do not play a role.
At first, costimulatory blockade was evaluated alone for the induction of tolerance in numerous solid-organ transplantation models. Once their powerful effects became apparent, costimulation blockers were also evaluated as a component of bone marrow transplantation (BMT) regimens for inducing mixed chimerism. Since these two applications differ substantially in several aspects, they will be discussed separately.
Section snippets
The importance of costimulation during T cell interactions with antigen-presenting cells
About 30 years ago it was proposed that additional, costimulatory signals are required as well as the specific signal through the TCR to fully activate a T cell and that the blockade of such signals can lead to tolerance 2., 3., 4.. Later, classical anergy was induced in vitro by blocking antigen-presenting cell (APC) function [5]. Subsequently, it was demonstrated that such anergy can be induced by blocking CD28, the most powerful costimulatory signal known to date for CD4 T cells 6., 7.. The
The use of costimulation-blocking reagents for tolerance induction via mixed chimerism
In the models described above, costimulatory blockade was used in combination with solid organ or islet transplantation to induce hyporesponsiveness to the donor tissue. Although encouraging results have been achieved, robust tolerance — as measured by specific unresponsiveness to fully MHC-mismatched skin grafts in euthymic mice — has not been achieved with this approach (except for the combination of costimulatory blockade with rapamycin).
By contrast, it has long been known that BMT can
Conclusions
Costimulation blockade with anti-CD154 and/or CTLA4Ig exerts its powerful beneficial effects in transplant models through numerous mechanisms. Evidence for immune regulation/suppression/deviation, anergy and clonal deletion has been variably found in models relying on costimulation blockade alone and in protocols employing costimulation blockade as part of a BMT protocol. Although these mechanisms lead to impressive results in various models, it appears that only when life-long profound clonal
Update
Recent work shows that costimulation blockade is relatively inefficient in tolerizing the direct pathway of allorecognition [88]. Further evidence for regulatory cells was found in a murine model, in which ex vivo use of anti-CD154 induced suppressor cells that protected against graft-versus-host disease in vivo [89]. Sensitized T cells prevented the effects of DST+anti-CD154 in a murine heart graft model [90], potentially elucidating another factor contributing to costimulation-resistant
Acknowledgements
We thank Leo Bühler for critical review of the manuscript, and Robin Laber for expert assistance with the manuscript. This work was supported in part by National Institutes of Health grants #R01 HL49915 and #1T32 AI-07529 and by BioTransplant, Inc. (Charlestown, MA, USA).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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