No synergy between ATG induction and costimulation blockade induced kidney allograft survival in rhesus monkeys.
BACKGROUND
Costimulation blockade with antibodies directed against human CD40 and CD86 leads to prolonged kidney allograft survival in rhesus monkeys, but fails to induce permanent graft acceptance. We have tested whether costimulation blockade is more effective after peripheral T-cell ablation with antithymocyte globulin (ATG), with the aim to remove already primed autoreactive cells present in the normal repertoire.


METHODS
Rhesus monkeys were transplanted with a mismatched kidney allograft. ATG was given around the time of transplantation (day -1 and 0). Costimulation blockade with anti-CD40+anti-CD86 was given at tapering dosages from day -1 to 56. Cyclosporin A (CsA) was given from day 42 onwards and first rejections occurring after day 42 were treated with prednisone.


RESULTS
We observed accelerated rejection in ATG-treated monkeys, compared to animals receiving only costimulation blockade. The accelerated rejection of the kidney allograft occurred despite the application of rejection therapy with steroids and CsA. Three of the five ATG-treated animals were found seropositive for donor-specific alloantibodies. Early biopsies (day 21) from animals treated with ATG and anti-CD40+anti-CD86 show substantially reduced expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and forkhead box P3 (FOXP3) in focal infiltrates as compared to animals treated with only costimulation blockade. Furthermore, we observed the rapid reappearance of CD8 T-cells with a memory phenotype (disappearance of naive CD95/CD11a T-cells) in peripheral blood.


CONCLUSIONS
We conclude that (subtotal) T-cell depletion using ATG does not add to costimulation blockade induced kidney allograft survival.
Haanstra
Krista G
KG
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, the Netherlands. haanstra@bprc.nl
Sick
Ella A
EA
Ringers
Jan
J
Wubben
Jacqueline A M
JA
Kuhn
Eva-Maria
EM
't Hart
Bert A
BA
Boon
Louis
L
Jonker
Margreet
M
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D051940:B7-2 Antigen / Q000187:drug effects; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D060908:CTLA-4 Antigen; D004357:Drug Synergism; D051858:Forkhead Transcription Factors / Q000032:analysis; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000961:Antilymphocyte Serum; D051940:B7-2 Antigen; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D051858:Forkhead Transcription Factors