title: 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.
  
  
  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.
authors.affiliation: Division of Cardiothoracic Surgery, Columbia-Persbyterian Medical Center, New York, NY 10032, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lietz
authors.forename: Ranjit
authors.initials: R
authors.lastname: John
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Burke
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.forename: Tyson B
authors.initials: TB
authors.lastname: Rogers
authors.forename: Nicole
authors.initials: N
authors.lastname: Suciu-Foca
authors.forename: Donna
authors.initials: D
authors.lastname: Mancini
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000097:blood; D016022:Case-Control Studies; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control; D006681:HLA-D Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D006650:Histocompatibility Testing; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D006681:HLA-D Antigens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D023201:CD40 Ligand