Abstract
Chronic rejection and immunosuppression-related toxicity severely affect long-term outcomes of kidney transplantation. The induction of transplantation tolerance – the lack of destructive immune responses to a transplanted organ in the absence of immunosuppression – could potentially overcome these limitations. Immune tolerance to kidney allografts from living donors has been successfully achieved in humans through clinical protocols based on chimerism induction with hematopoietic cell transplantation after non-myeloablative conditioning. Notably, two of these protocols have led to immune tolerance in a significant fraction of HLA-mismatched donor-recipient combinations, which represent the large majority of cases in clinical practice. Studies in mice and large animals have been critical in dissecting tolerance mechanisms and in selecting the most promising approaches for human translation. However, there are several key differences in tolerance induction between these models and humans, including the rate of success and stability of donor chimerism, as well as the relative contribution of different mechanisms in inducing donor-specific unresponsiveness. Kidney allograft tolerance achieved through durable full-donor chimerism may be due to central deletion of graft-reactive donor T cells, even though mechanistic data from patient series are lacking. On the other hand, immune tolerance attained with transient mixed chimerism-based protocols initially relies on Treg-mediated suppression, followed by peripheral deletion of donor-reactive recipient T-cell clones under antigenic pressure from the graft. These conclusions were supported by data deriving from novel high-throughput T-cell receptor sequencing approaches that allowed tracking of alloreactive repertoires over time. In this review, we summarize the most important mechanistic studies on tolerance induction with combined kidney-bone marrow transplantation in humans, discussing open issues that still need to be addressed and focusing on techniques developed in recent years to efficiently monitor the alloresponse in tolerance trials. These cutting-edge methods will be instrumental for the development of immune tolerance protocols with improved efficacy and to identify patients amenable to safe immunosuppression withdrawal.
Highlights
Renal transplantation is the established treatment of choice for kidney failure, as it confers both the highest survival and the best quality of life compared to other renal replacement therapies [1]
Tolerance in kidney transplantation can be functionally defined by stable renal function and absence of histologic, immune and molecular signs of rejection on a kidney biopsy obtained after complete withdrawal of immunosuppression for at least one year
Those protocols that have succeeded in patients entail combined kidney and bone marrow transplantation (CKBMT) as a strategy to induce chimerism, a state wherein donor hematopoietic cells engraft into the recipient bone marrow at a level sufficient to be detected by conventional methods
Summary
Renal transplantation is the established treatment of choice for kidney failure, as it confers both the highest survival and the best quality of life compared to other renal replacement therapies [1]. Approximately half of the kidney transplants lost are due to death with a functioning graft: the impact of chronic immunosuppression has potentially devastating consequences in terms of cardiovascular disease, infection and malignancy [3,4,5], and may severely impair recipients’ quality of life. Among the different methods used to induce tolerance in animal models of kidney transplantation, few have been successfully translated to clinical application. Those protocols that have succeeded in patients entail combined kidney and bone marrow transplantation (CKBMT) as a strategy to induce chimerism, a state wherein donor hematopoietic cells engraft into the recipient bone marrow at a level sufficient to be detected by conventional (as opposed to sensitive PCR-based) methods. As HLA mismatches are commonly present in solid organ transplantation, in this review we will discuss the features of these regimens and the novel mechanistic insights offered by recent studies in the field
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