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

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 (PϽ0.001), a higher cumulative rejection frequency (Pϭ0.002), accelerated development of TCAD (Pϭ0.04), and decreased late survival (Pϭ0.03). Conversely, the persistence of IgM anti-HLA antibodies against class II but not against class I antigens for Ͼ30 days and the lack of IgG isotype switching were associated with protection against both acute rejection (Pϭ0.02) and TCAD (Pϭ0.05). 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. (Circulation. 2005;112:2468-2476.)

Relevance of different antibody detection methods for the prediction of antibody-mediated rejection and deceased-donor kidney allograft survival

“…However, the B cells that produce them may activate and undergo isotype switching to IgG after encountering cognate antigens provided by the allograft [23,24]. Despite these considerations, most laboratories that use CDC for direct crossmatch do not test and/or disregard the presence of IgM alloantibodies.…”

Alloantibodies in heart transplantation

“…The negative effect of anti-HLA antibodies on allograft survival is now universally accepted [12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Allosensitization occurs after exposure to blood transfusion, pregnancy, or previous transplantations.…”

Randomized Trial of Tacrolimus Monotherapy: Tacrolimus In Combination, Tacrolimus Alone Compared (The TICTAC Trial)

“…This could be due unrestricted expression of anti-human leukocyte antigen antibodies. [17][18][19][20] However, the long- term single-center results with TAC monotherapy do not demonstrate excess vasculopathy. 3…”