- Dr He Xu, Principal Investigator
- Dr Jennifer Cheesemen, Res. Specialist
- Emory University, Atlanta, USA
- Differential Influence of Belatacept and Rapamycin Regimen on Allo- and Viral-specific Immunity in Renal Allografts
The optimized patient management depends on individualized immunosuppressive regimen selection to prevent rejection without impairing protective immunity. Calcineurin inhibitors (CNls) can effectively prevent alloimmunity in most recipients. Unfortunately, they similarly impair viral-specific immunity such as CMV, EBV, and BK virus. Belatacept, a B7 costimulation inhibitor, has recently been approved as a CNls replacement. Clinical studies suggest that belatacept prevents rejection in unsensitized patients with reduced effects against established immune responses, both allo- and viral-specific, but increases the risk of EBV-associated disease in viral naive patients. Thus, belatacept may be a rational alternative to CNls in properly selected, perhaps viral-experienced and allo-naive, patients. This selection is confounded by heterologous immunity, which evokes alloimmunity through viral experience.
We will specifically examine the balance between allo- and viral-specific immunity with regard to its relevance for guiding the choice between CNls and belatacept-based regimens. We will exploit access to a unique cohort of renal transplant patients treated with belatacept regimen, and patients receiving CNls- and belatacept-based regimens, to determine the factors driving allo- or viral-immune failure. This study will test the hypothesis that belatacept effectively prevents naive allo-specific effector functions while preserving viral-specific responses in viral-experienced recipients. It will leverage ample preliminary studies examining the effect of CNls and belatacept on viral- and allo-immunity. We will define, compare and contrast the characteristics of CMV-, EBV-, and BK virus-specific and allospecific T cells present prior to, and emerging after, transplantation under the influence of belatacept or tacrolimus. We will examine the role of homeostatic repopulation in activating belatacept-resistant cells through examination of a unique cohort of belatacept patients induced with alemtuzumab. This study will examine the role of adhesion molecules as potential targets for controlling belatacept-resistant T cells, identifying strategies that may inform the selection of proper adjuvant therapies to be paired with belatacept.