Cytotoxicity and T-B Cell Crosstalk in Belatacept-Treated Kidney Transplant Patients

Abstract

In this dissertation, we aimed to learn more about the immune mechanisms involved in alloreactivity in patients treated with belatacept or tacrolimus after kidney transplantation. In particular, we sought to explain the higher acute rejection rate in belatacept-treated patients by studying cytotoxic cell populations which are potentially less susceptible to co-stimulatory inhibition, and to explain the lower incidence of DSA in previous trials by studying the effects of belatacept on Tfh-B cell interaction. We found that next to CD28- T cells also a part of CD28+ T cells are not susceptible to inhibition by belatacept. These cells could still divide and produce cytokines in the presence of belatacept. In addition, belatacept was not as effective as tacrolimus in preventing Tfh-B cell interaction and the subsequent formation of plasmablasts. Additionally, we tried to characterize belatacept-resistant rejection clinically and immunologically, and to find a biomarker to distinguish between patients who will reject under belatacept-treatment and those who will not. We found that belatacept-treated patients had a higher acute rejection risk compared to tacrolimus-treated patients (55% versus 10%), and that these rejections could not be predicted by cellular biomarkers before transplantation, i.e., CD8+CD28- T cells, CD4+CD57+PD-1- T cells and CD8+CD28++ EMRA T cells. Baseline characteristics did not differ between (future) rejectors and non-rejectors in belatacept-treated patients. Mostly effector-memory T cells, both CD28+ and CD28-, infiltrated a rejected kidney graft during belatacept-treatment. These cells produced large amounts of IFN-gamma and granzyme B. For now, belatacept does not meet the requirements to be the new corner stone in immunosuppression after kidney transplantation, because short-term outcomes are inferior to tacrolimus. However, belatacept-treatment could be beneficial and increase quality of life for a selected group of patients. The search for an immunosuppressive drug or combination of immunosuppressants, possibly including belatacept, to further improve kidney transplant patients’ outcomes continues