The Systems Biology of Clinical Organ Transplantation

13:25 Tracking Human Alloantigen-specific B Cells
Neal N. Iwakoshi, Emory University, Atlanta, USA

Success in kidney transplantation has resulted from control of T-cell-mediated acute rejection. The use of increasingly potent T-cell-directed immunosuppressants has led to reduced graft loss from acute rejection. However, little has been done to improve the fate of patients who possess pre-transplant donor-specific antibodies (DSA), and no proven therapies exist to specifically prevent DSA formation post-transplant. As such, sensitized patients are the most challenging patients to transplant. While methods to detect and characterize DSAs are clearly useful, the B-cell subsets that produce DSAs or, more importantly, sustain their production are poorly characterized with regard to phenotype, survival mechanisms and anatomical locations. DSA-mediated disease is thus a growing problem in clinical transplantation. We hypothesize that the donor-specific memory B cells are comprised of subsets with relatively distinct phenotypic and functional signatures, and anatomical distributions that correlate with de novo and anamnestic alloantibody responses. We have assembled and developed novel murine systems and assays to study polyclonal donor-specific B cells and plasma cells over time in vivo. We have adapted these novel technologies from the murine system into tools for quantitating human B cell responses in highly sensitized patients. By translating these novel methods for use in human studies, we hope to develop novel therapies to control the production of alloantibody in sensitized patients.