ABSTRACT Antibody-mediated rejection (AMR) of solid organ transplants is the leading cause of immunologic graft injury, shortening the half-life of transplants and consequently of transplant recipients. This immunologically mediated process depends on B lymphocyte activation with differentiation to plasma cells (PC) that produce antibodies to the donor organ. Once established, antibodies have proven difficult to eradicate. Establishing an effective and safe way to treat patients with established AMR would potentially increase the half-life of transplanted organs, extend the lives of patients, and reduce the need for re-transplantation, ultimately increasing the number of patients who could receive life-saving organ transplants. Our lab has described an effective therapy in a non- human primate (NHP) sensitized model of kidney transplantation for lowering donor-specific antibody (DSA) and preventing injury from AMR. The treatment depends on PC depletion in combination with germinal center disorganization which together lower alloantibody levels. Dual targeting of the immune system by complementary drugs is based on NHP and human data using a proteasome inhibitor and belatacept. B cell activation and differentiation is inhibited at the same time that PC are depleted. Consequently, DSA declines, inflammation in the kidney resolves, and renal function stabilizes. The impact of this intervention on infection risk is not well defined but is anticipated to increase. We propose to measure the impact of therapy on both HLA-specific and pathogen-specific B memory cells and PC. We hypothesize that there is a hierarchy of susceptibility to therapy, with protective immunity being more resistant than allogeneic B cell memory. We will evaluate the impact of the regimen on T-cell function focusing on cytomegalovirus (CMV). Current therapy of late AMR using therapeutic plasma exchange (TPE) and intravenous immune globulin (IVIG) with or without rituximab has shown variable results and frequent rebound of DSA. A low level of evidence supports the efficacy of these treatments, implying a tremendous need for well-conducted clinical trials to guide treatment of AMR. We propose a Phase I/II randomized, controlled, prospective interventional study of AMR in human kidney transplant patients using combined carfilzomib/belatacept (C/B) therapy with TPE and IVIG compared to TPE/IVIG alone. Outcomes will include the clinical impact of therapy on AMR using the recently validated iBox score for AMR assessment and the number and type of infections using standardized definitions of infection. We will measure the impact of therapy on HLA and pathogen-associated B memory and PC as well as CMV-specific polyfunctional T-cells. We will assess computational digital imaging analysis of AMR non-visual biopsy features to assess whether machine learning algorithms can improve on Banff criteria of AMR to better guide treatment and predict clinical outcome. Since late active and chronic ac...