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(Circulation. 2005;112:2468-2476.)
© 2005 American Heart Association, Inc.

Transplantation

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

Katherine Lietz, MD, PhD; Ranjit John, MD; Elizabeth Burke, ANP; Michael Schuster, MS; Tyson B. Rogers, MS; Nicole Suciu-Foca, PhD; Donna Mancini, MD; Silviu Itescu, MD

From the Division of Cardiology (D.M.), Division of Cardiothoracic Surgery (K.L., R.J., E.B., M.S., S.I.) and Department of Pathology (N.S.-F.), Columbia-Presbyterian Medical Center, New York, NY, and the Division of Cardiology (K.L.), Division of Cardiothoracic Surgery (R.J.), and Department of Internal Medicine (T.R.), University of Minnesota Medical Center, Minneapolis, Minn.

Correspondence to Silviu Itescu, MD, Director of Transplantation Immunology, Departments of Medicine and Surgery, Columbia-Presbyterian Medical Center, PH14 East, 630W 168th St, New York, NY 10032. E-mail si5{at}columbia.edu

Received June 15, 2004; revision received June 14, 2005; accepted July 29, 2005.

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 (P<0.001), a higher cumulative rejection frequency (P=0.002), accelerated development of TCAD (P=0.04), and decreased late survival (P=0.03). Conversely, the persistence of IgM anti-HLA antibodies against class II but not against class I antigens for >30 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.

Key Words: antibodies • coronary disease • transplantation

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