Immunoglobulin M-to-Immunoglobulin G Anti-Human Leukocyte Antigen Class II Antibody Switching in Cardiac Transplant Recipients Is Associated With an Increased Risk of Cellular Rejection and Coronary Artery Disease

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Abstract
Background— Activation of T cells induces immunoglobulin (Ig)M-to-IgG B-cell isotype switching via costimulatory regulatory pathways. Because rejection of transplanted organs is preceded by alloantigen-dependent T-cell activation, we investigated whether B-cell isotype switching could predict acute cellular rejection and the subsequent development of transplantation-related coronary artery disease (TCAD) in cardiac transplant recipients. Methods and Results— Among 267 nonsensitized heart transplant recipients, switching from IgM to IgG anti-human leukocyte antigens (HLA) antibodies directed against class II but not against class I antigens was associated with a shorter duration to high-grade rejection, defined as International Society for Heart and Lung Transplantation grade 3A or higher (P30 days and the lack of IgG isotype switching were associated with protection against both acute rejection (P=0.02) and TCAD (P=0.05). Alloisotype switching coincided with T-cell activation, as evidenced by increased serum levels of soluble CD40 ligand costimulatory molecules. Finally, a case-control study showed that reduction of cardiac allograft rejection by mycophenolic acid was accompanied by reduced CD40 ligand serum levels and the prevention of IgM-to-IgG anti-HLA class II antibody switching. Conclusions— T-cell-dependent B-cell isotype switching and the consequent production of IgG anti-HLA class II antibodies are strongly correlated with acute cellular rejection, a high incidence of recurrent rejections, TCAD, and poor long-term survival. Detecting this isotype switch is a clinically useful surrogate marker for in vivo T-cell activation and may provide a noninvasive approach for monitoring the efficacy of T-cell targeted immunosuppressive therapy in heart transplant recipients.