Marginal Zone B Cell Targeting Limits Alloantigen Availability to Follicular Dendritic Cells and Mitigates Antibody-Mediated Rejection.

Chronic antibody-mediated rejection is a leading cause of allograft loss, with limited therapies that effectively target humoral immunity. Current immunosuppressive regimens primarily target T cells, leaving a critical gap in strategies to suppress antibody-driven rejection. Marginal zone (MZ) B cells are innate-like cells that can rapidly generate antibodies, but their role in donor-specific antibody generation and chronic rejection remains unclear. We developed novel murine models of chronic antibody-mediated rejection using HLA-A2 transgenic heart and kidney transplants that recapitulate clinical features of human disease. Using an anti-Notch2 antibody to selectively target MZ B cells, we observed reduced antigen-specific humoral responses, including decreases in germinal center B cells, plasma cells, donor-specific antibodies, and C4d deposition, alongside improved graft structure and function. Mechanistically, the reduction of MZ B cells disrupted antigen shuttling to follicular dendritic cells (FDCs), leading to decreased FDC-associated alloantigen clusters and impaired germinal center reactions. These findings establish MZ B cells as key drivers of alloantibody formation and highlight Notch2 as a promising therapeutic target.