Operational tolerance in kidney transplantation and associated biomarkers

Abstract

SummaryIn the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients -i.e. patients who maintain allograft function in the absence of immunosuppression -are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, nonantigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective -identifying tolerant patients, enabling tolerance trials -as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.

The emerging role of regulatory T cells following lung transplantation

“…144 Kidneys, unlike the liver, are unable to regenerate after insult and even mild episodes of rejection can cause permanent damage that increases the risk of eventual graft failure. 144 Kidneys, unlike the liver, are unable to regenerate after insult and even mild episodes of rejection can cause permanent damage that increases the risk of eventual graft failure.…”

“…In contrast to liver transplantation, operational tolerance after kidney transplantation is rare. 144 Kidneys, unlike the liver, are unable to regenerate after insult and even mild episodes of rejection can cause permanent damage that increases the risk of eventual graft failure. Past studies have shown that withdrawal or slight alteration of immunosuppression after kidney transplantation is associated with rejection.…”

The five dimensions of B cell tolerance

“…[126][127][128][129] Some of these "tolerant" recipients have antibodies in the circulation specific for antigens in the graft. What is important for the present is that these mechanisms limit the im- to have spontaneously developed tolerance to their grafts.…”

“…[126][127][128][129][130] One might expect that tolerance to a transplant would be readily identified. Yet, investigation of autoimmune-and alloimmunemediated disease usually focuses on changes in the immune response rather than susceptibility to injury.…”

“…Transplant recipients who discontinue immunosuppressive therapy and do not suffer rejection are sometimes postulated to have spontaneously developed tolerance to their grafts. [126][127][128][129] Some of these "tolerant" recipients have antibodies in the circulation specific for antigens in the graft. Likewise, individuals with "autoimmune disease" with circulating autoantibodies sometimes have no overt manifestations of disease.…”