title: Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.
abstract: BACKGROUND
  Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive "induction" B cell depletion.
  
  
  METHODS
  αCD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbit antihuman thymocyte globulin.
  
  
  RESULTS
  Relative to previously reported reference groups, αCD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in αCD154-treated recipients (αCD154 + αCD20 graft median survival time > 90 days, n = 7, vs 28 days for αCD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin to αCD154 (n = 6) or αCD154 + αCD20 (n = 10) improved graft protection from graft rejection and failure during treatment but was associated with significant morbidity in 8 of 16 recipients (6 infections, 2 drug-related complications). In αCD20-treated animals, detection of antidonor Ab and relatively severe CAV were anticipated by appearance of CD20 cells (>1% of lymphocytes) in peripheral blood and were associated with low αCD154 trough levels (below 100 μg/mL).
  
  
  CONCLUSIONS
  These observations support the hypothesis that efficient preemptive "induction" CD20 B cell depletion consistently modulates pathogenic alloimmunity and attenuates CAV in this translational model, extending our prior findings with calcineurin inhibitors to the context of CD154 blockade.
authors.affiliation: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD. 2 Department of Surgery, Fourth Military Medical University, Xi'an, People's Republic of China. 3 Division of Vascular Surgery, Department of Surgery, George Washington University, Washington, DC. 4 VA Maryland Health Care System, Baltimore, MD.
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Shahrooz S
authors.initials: SS
authors.lastname: Kelishadi
authors.forename: Tiffany
authors.initials: T
authors.lastname: Stoddard
authors.forename: Natalie
authors.initials: N
authors.lastname: OʼNeill
authors.forename: Bao-Ngoc
authors.initials: BN
authors.lastname: Nguyen
authors.forename: Emily
authors.initials: E
authors.lastname: Welty
authors.forename: Christopher
authors.initials: C
authors.lastname: Avon
authors.forename: Mitch
authors.initials: M
authors.lastname: Higuchi
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Mitchell
authors.forename: Alena
authors.initials: A
authors.lastname: Hershfeld
authors.forename: Xiang-Fei
authors.initials: XF
authors.lastname: Cheng
authors.forename: Anthony
authors.initials: A
authors.lastname: Kronfli
authors.forename: Elana
authors.initials: E
authors.lastname: Rybak
authors.forename: Lars
authors.initials: L
authors.lastname: Burdorf
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000097:blood; D008212:Lymphocyte Depletion / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D000069283:Rituximab / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D000069283:Rituximab; C512542:thymoglobulin; C470330:toralizumab