Abstract
BackgroundThe co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, allows calcineurin-inhibitor-free immunosuppression in kidney transplantation. However, aggressive T-cell mediated allogeneic responses have been observed in belatacept-treated patients, which could be explained by effector-memory T-cells that lack membrane expression of CD28, i.e. CD28-negative (CD28NULL) T-cells. CD28-positive (CD28POS) T-cells that down regulate their surface CD28 after allogeneic stimulation could also pose a threat against the renal graft. The aim of this study was to investigate this potential escape mechanism for CD28POS T-cells under belatacept treatment.Materials & MethodsPBMCs, isolated T-cell memory subsets and isolated CD28POS T-cells were obtained from end-stage renal disease (ESRD) patients and co-cultured with allo-antigen in the presence of belatacept to mimic allogeneic reactions in kidney-transplant patients under belatacept treatment. As a control, IgG was used in the absence of belatacept.ResultsDespite high in vitro belatacept concentrations, a residual T-cell growth of ±30% was observed compared to the IgG control after allogeneic stimulation. Of the alloreactive T-cells, the majority expressed an effector-memory phenotype. This predominance for effector-memory T-cells within the proliferated cells was even larger when a higher dose of belatacept was added. Contrary to isolated naïve and central-memory T cells, isolated effector-memory T cells could not be inhibited by belatacept in differentiation or allogeneic IFNγ production. The proportion of CD28-positive T cells was lower within the proliferated T cell population, but was still substantial. A fair number of the isolated initially CD28POS T-cells differentiated into CD28NULL T-cells, which made them not targetable by belatacept. These induced CD28NULL T-cells were not anergic as they produced high amounts of IFNγ upon allogeneic stimulation. The majority of the proliferated isolated originally CD28POS T-cells, however, still expressed CD28 and also expressed IFNγ.ConclusionThis study provides evidence that, apart from CD28NULL T-cells, also CD28POS, mostly effector-memory T-cells can mediate allogeneic responses despite belatacept treatment.
Highlights
The co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, is a promising alternative for calcineurin-inhibitors in kidney transplantation.[1,2,3] This co-stimulatory inhibitor does not directly down-regulate or block CD28 on T-cells, but induces T-cell anergy by depriving T-cells from the necessary co-stimulatory signal from CD80/86 on antigen-presenting cells. [4] Aggressive T cell-mediated allogeneic responses have been observed in belatacept-treated patients.[1]
Despite high in vitro belatacept concentrations, a residual T-cell growth of ±30% was observed compared to the IgG control after allogeneic stimulation
Contrary to isolated naïve and central-memory T cells, isolated effectormemory T cells could not be inhibited by belatacept in differentiation or allogeneic IFNγ production
Summary
The co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, is a promising alternative for calcineurin-inhibitors in kidney transplantation.[1,2,3] This co-stimulatory inhibitor does not directly down-regulate or block CD28 on T-cells, but induces T-cell anergy by depriving T-cells from the necessary co-stimulatory signal from CD80/86 on antigen-presenting cells. [4] Aggressive T cell-mediated allogeneic responses have been observed in belatacept-treated patients.[1]. Seemingly opposing functions of CD28NULL T-cells have been reported These cells can have immunoregulatory functions, [11, 12], show features of immunoquiescence [10], as well as mediate allogeneic or anti-viral immune responses.[5,6,7, 13, 14] One study reported CD4POSCD28NULL T-cells could play an important role in glucocorticoidresistant rejection occurring during belatacept treatment.[8] No studies on peripheral blood mononuclear cells (PBMCs) derived from end-stage renal disease (ESRD) patients have been conducted to determine the ability of their CD28POS T-cells to down regulate surface CD28 in the presence of belatacept, making them resistant to blockade of the CD28-CD80/86-pathway. The aim of this study was to investigate this potential escape mechanism for CD28POS T-cells under belatacept treatment
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