Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms.
BACKGROUND
CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined.


METHODS
Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6).


RESULTS
CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy.


CONCLUSIONS
CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.
Azimzadeh
Agnes M
AM
Division of Cardiac Surgery, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA. aazimzadeh@smail.umaryland.edu
Pfeiffer
Steffen
S
Wu
Guosheng
G
Schröder
Carsten
C
Zorn
George L
GL
Kelishadi
Shahrooz S
SS
Ozkaynak
Engin
E
Kehry
Marilyn
M
Atkinson
James B
JB
Miller
Geraldine G
GG
Pierson
Richard N
RN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D060889:Inducible T-Cell Co-Stimulator Protein; D007518:Isoantibodies / Q000096:biosynthesis; D008252:Macaca fascicularis; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D007518:Isoantibodies; D023201:CD40 Ligand; D016572:Cyclosporine; C470330:toralizumab