Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives

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.

Keywords: chimerism and tolerance; clinical protocol; kidney; mixed chimerism; transplantation.

Figure 1

Schematic representation of the mechanisms involved in chimerism-based tolerance to kidney allografts. (A) The induction of full-donor chimerism through hematopoietic stem cell (HSC) infusion along with facilitating cells (FC) after non-myeloablative conditioning results in destruction of host HSC, presumably by graft-versus-host reaction (GvHR) from infused donor T cells, and durable engraftment of donor hematopoietic precursors. After thymic repopulation by donor-derived dendritic cells (dDC), donor-reactive T cells from the donor (dR-dT) undergo clonal deletion in the thymus (central tolerance). Host-reactive donor T cells (hR-dT) are incompletely deleted, reflecting the absence of a self-renewing source of recipient APCs, but functional tolerance to the recipient may be achieved by a combination of mechanisms (anergy and selection of host-specific Tregs) that involve recipient thymic epithelial cells (hTEC). (B) Destruction of hTEC and thymic structure by GvHR may cause failure of negative selection and precipitate graft-versus-host disease (GVHD). (C) In durable mixed chimerism, donor-derived precursors populate the host thymus and differentiate into DC (dDC) without depletion of their host-derived counterparts (hDC). Donor- and host-reactive T cells from both the donor and the host undergo negative selection, allowing allograft tolerance without GVHD. Treg-mediated suppression may also play a role in experimental regimens where clonal deletion is incomplete. (D) In CKBMT patients receiving a siplizumab-based conditioning regimen and unprocessed bone marrow, transient mixed chimerism promotes peripheral tolerance. Host Tregs are relatively spared from global T cell depletion, and donor-reactive host Tregs (dR-hTreg) are expanded by antigenic pressure from the graft. Emerging donor-reactive T cells, which are not subjected to central deletion, are suppressed by dR-hTreg and ultimately undergo peripheral deletion over time.