Transplantation tolerance

Abstract

Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.

Fig. 1

Cross-platform biomarker signature of kidney transplant recipients determined by the Indices of Tolerance consortium (reproduced from Heidt and Wood 2012 [68], used with permission). The signature is dominated by B cell features, such as elevated expression of mainly B cell-specific genes, the absence of donor-specific HLA antibodies in the serum and elevated levels of (naive and transitional) peripheral B cells. Other markers that make up the tolerance signature are the ratio of FOXP3 to α-1,2-mannosidase gene expression, a low donor-specific direct T cell response and decreased levels of activated T cells.