Anti-CD40 therapy extends renal allograft survival in rhesus macaques.
BACKGROUND
Organ transplant recipients currently require lifetime immunosuppressive therapy, with its accompanying side effects. Biological agents that block T-cell costimulatory pathways are important components of strategies being developed to induce transplantation tolerance. The aim of this study was to test the effect of a novel chimeric anti-human CD40 monoclonal antibody (Chi 220), either alone or in combination with CTLA4-Ig, on the survival of renal allografts in a nonhuman primate model.


METHODS
Captive-bred adolescent male rhesus monkeys (Macaca mulatta) (4-10 kg) were used as recipients and donors. Four treatment protocols were tested: Chi220 monotherapy, CTLA4-Ig monotherapy, Chi220 combined with CTLA4-Ig, and H106 (anti-CD40L) combined with CTLA4-Ig. Control animals received human albumin. Recipients were followed for survival, renal allograft function as determined by measurement of serum blood urea nitrogen (BUN) and creatinine, chemistries (sodium, potassium, chloride, and bicarbonate), complete blood cell count (CBC) with differential, and the development of donor-specific alloantibody.


RESULTS
Treatment with Chi220 for 14 days prolonged renal allograft survival (MST 38.5 vs. 7 days in untreated controls). Notably, simultaneous blockade of the CD28/B7 pathway did not further augment graft survival but did suppress the development of donor-specific antibodies, an effect not achieved with Chi220 alone, despite peripheral B cell depletion. Finally, treatment with Chi220 suppressed the primary immune response to cytomegalovirus, resulting in severe systemic manifestations.


CONCLUSIONS
Blockade of the CD40 pathway with anti-CD40 mAb is immunosuppressive in a large animal, preclinical renal transplant model. The potential effect of this therapy on viral immune responses will be important to consider for the design of safe clinical trials.
Pearson
Thomas C
TC
Emory Transplant Center, Department of Surgery, Emory University, Atlanta, Georgia 30322, USA.
Trambley
Joel
J
Odom
Kris
K
Anderson
Daniel C
DC
Cowan
Shannon
S
Bray
Robert
R
Lin
Angello
A
Hollenbaugh
Diane
D
Aruffo
Alejandro
A
Siadak
Anthony W
AW
Strobert
Elizabeth
E
Hennigar
Randall
R
Larsen
Christian P
CP
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D018106:CD28 Antigens / Q000187:drug effects; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D060908:CTLA-4 Antigen; D003586:Cytomegalovirus Infections / Q000139:chemically induced / Q000473:pathology; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D007518:Isoantibodies / Q000276:immunology; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008253:Macaca mulatta; D008297:Male; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000906:Antibodies; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D023201:CD40 Ligand; D000069594:Abatacept