What's new in transplantation tolerance?

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Solid organ transplantation continues to save the lives of patients with end-stage organ failure, but imperfect control of the immune system and side-effects of immunosuppressive drugs result in chronic graft loss that is often unavoidable. Achieving donor-specific transplantation tolerance following a short course of conditioning therapy is still an attractive goal toward maintaining a healthy organ for the life of the recipient [1]. Long-term study of the few patients in whom transplantation tolerance has been successfully achieved (either revealed following withdrawal of immunosuppression for medical, compliance, or financial reasons, or prospectively induced using combined transplantation of donor hematopoietic stem cells and solid organ), and the recognition of tolerance loss in some patients after years of stability [2–5], have enabled insights into the mechanisms maintaining transplantation tolerance and into the inflammatory challenges that can occasionally break it. For instance, severe infections can be modeled in mice to precipitate transplant rejection acutely in stably tolerant animals [6]. Experimental and clinical results have led Miller et al.[7] to propose that transplantation tolerance, rather than reflecting a binary all or none state, can exist at different levels of robustness, depending on the quality and quantity of peripheral mechanisms of T-cell tolerance that may additively or synergistically cooperate to maintain it. In mice, maintenance of robust transplantation tolerance, a state in which graft function is retained despite inflammatory challenges, depends on the coexistence of several mechanisms of T-cell tolerance such as limiting the frequency of alloreactive T cells, and reducing their function via both intrinsic inhibitory molecules such as programmed death (PD)-1, and extrinsic suppression via T regulatory cells (Tregs) [8]. Interestingly, when stable transplantation tolerance is acutely broken following a severe infection, it can reemerge after resolution of the inflammatory event, such that the memory of transplantation tolerance that existed before the inflammatory challenge dominates over the memory of inflammation-driven graft loss [9]. A similar memory of tolerance may have been observed in a nonhuman primate model of combined donor bone marrow and kidney transplantation, where administration of interleukin-2 precipitated graft dysfunction, but its subsequent withdrawal was followed by graft recovery [10]. Such memory of transplantation tolerance is reminiscent of tolerant self-specific T cells that transiently recover function in lymphopenic conditions but return to a tolerant state upon lymphorepletion [11]. Return of tolerance to self in this latter case correlates with T-cell intrinsic epigenetic imprinting [11]. In transplantation however, the tolerance that returns following the resolution of inflammation appears less robust than that before the rejection event, as elimination of Tregs is sufficient to prevent acceptance of a second donor-matched graft in hosts in which infection precipitated graft loss, but not in uninfected mice [9]. Even in hosts in which infection provokes a rejection crisis rather than a complete graft loss, the tolerance becomes eroded long term, because late blockade of PD-1 precipitates allograft rejection in postinfected but not uninfected hosts [12].
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