Abstract
Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.
Highlights
A high-affinity cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-Ig, belatacept, was approved by the US Food and Drug Administration in 2011 for the prophylaxis of organ rejection in EBV-positive renal transplant recipients [1]
We showed that treatment with CTLA4-Ig on day 6 post-heart transplantation inhibited donor-specific antibody (DSA) production and rescued fully MHC and minor mismatched heart grafts from acute rejection [21]
Observations from experimental models of heterologous memory [24, 48] together with clinical observations of belataceptresistant acute rejection [8,9,10, 49] support a hypothesis that memory T cells do not require CD28–CD80/86 interactions for their re-stimulation, or that there is redundancy of activating costimulatory molecules. This hypothesis appears to be at odds with the clinical observations that despite the occurrence of acute rejection in patients on belatacept [9.1–14.2% biopsyproven acute rejection at 36 months posttransplantation [8, 9]], once acute rejection is successfully treated with bolus steroids, the grafts go on to survive at rates that are comparable to conventional cyclosporine-based immunosuppression [4.7–5.4% graft loss for belatacept vs. 9.8% for cyclosporine at 84 months posttransplantation [10]]
Summary
A high-affinity CTLA4-Ig, belatacept, was approved by the US Food and Drug Administration in 2011 for the prophylaxis of organ rejection in EBV-positive renal transplant recipients [1]. Possible explanations include: CsA being an inferior immunosuppressant compared to tacrolimus, CsA’s nephrotoxicity, CsA-mediated reduction of mycophenolic acid exposure, and a significantly lower incidence of donor-specific antibody (DSA) development (1.9 and 4.6%) in the belatacept medium and low-intensity treatment groups, compared to 17.8% in the CsA-treatment cohort [10, 11]. The observations of increased incidence of acute rejection but reduced DSA and superior outcome in patients treated with belatacept are intriguing and have prompted renewed investigations into the effect of CTLA4-Ig on established B cell/DSA and T cell responses, and for treating acute rejection [18,19,20,21,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
