Operational tolerance in kidney transplantation and associated biomarkers

Abstract

In 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, non-antigen-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.

Keywords: biomarker; cellular assays; immunoquiescence; kidney transplantation; operational tolerance.

Figure 1

The multiplicity of factors that influence blood transcriptomic signatures. The four men represent specific patient group signatures (CR, STA, TOL and HV represent patients in chronic rejection, stable patients under immunosuppression, operationally tolerant patients and healthy volunteers, respectively). In the absence of univocal diagnostic criteria for operational tolerance, the STA group is contaminated by unrecognized tolerant patients. The boxes above the figures contain non‐exhaustive lists of confounding factors that can alter a group's signature if they arise as uncontrolled stratification factors. The circles below the figures represent the factors that will affect certain patient groups selectively. None of the groups are distinct from tolerant patients solely by lack of tolerance. Overall, the heterogeneity of factors, particularly in the context of small group sizes, promotes bias and complicates generalisation.

Figure 2

A schematic view of alloreactive immune cells during kidney transplantation. Unique unbalanced compositions of alloreactive cells, varying in subset, function, reactivity, and memory ensure graft rejection or acceptance. Current immunosuppressive regimens are thought to crush down all alloreactive responses and beyond. Immunosuppression is compulsory to avoid rejection but to a certain extent – we are not yet able to determine individually – compromises the rise of regulatory responses needed to promote long‐term graft acceptance, tolerance and reduced reliance on immunosuppression.