Induction of regulatory cells and control of cellular but not vascular rejection by costimulation blockade in hamster-to-rat heart xenotransplantation.
BACKGROUND
In heart allograft in the rat, a sustained costimulation blockade with CTLA4Ig prevents alloreactive T-cell activation and promotes a long-term graft survival through the action of tolerogeneic dendritic cells. It is unclear whether similar mechanisms might occur after xenotransplantation. To test that hypothesis, we have analyzed the action of CTLA4Ig in a model of CD4(+)T cell-mediated xenograft rejection.


METHODS
Hamster hearts were transplanted into LEW.1A rats receiving an accommodation-inducing treatment consisting of a short course administration of LF15-0195 and a daily administration of cyclosporine A (CSA). To achieve long-term delivery of CTLA4Ig, an intravenous administration of an adenovirus vector coding for mouse CTLA4Ig (Ad-CTLA4Ig) was added to the accommodation induction protocol. On day 40 post-transplantation, rejection was induced by CSA withdrawal. In other xenograft recipients, CD28/B7 costimulation was inhibited at that time only by injections of CTLA4Ig or anti-CD28 antibodies. Graft survival, immunohistology, as well as development of antibodies and regulatory cells were examined.


RESULTS
Xenografts survived 6 days after CSA withdrawal in controls and were rejected, as previously described, through the action of CD4(+) xenoreactive T cells. Interfering with CD28/B7 costimulation inhibited this xenoreactive T cell response and delayed rejection to day 10. In recipients that had received Ad-CTLA4Ig, survival was prolonged to day 19 and this was accompanied by the appearance of regulatory cells exhibiting non-donor-specific suppressive activity dependent on IL-2, NO, and IDO. These regulatory cells were different from those previously identified after Ad-CTLA4Ig administration in heart allograft in the rat. In these recipients, rejection occurred as a consequence of an evoked anti-donor IgM response and complement activation and not of a cellular rejection as complement inhibition with cobra venom factor further prolonged xenograft survival.


CONCLUSIONS
CD28/B7 blockade delays CD4(+) T cell-mediated rejection after CSA withdrawal in accommodated recipients of hamster heart xenografts. In addition, a sustained expression of CTLA4Ig has the potential of inducing cellular regulatory mechanisms. However, such treatment does not prevent the development of xenoreactive IgM antibodies that participate in vascular rejection processes in a complement-dependent manner.
Séveno
Céline
C
INSERM U643, Nantes, ITERT, Nantes, Univ Nantes, UFR of Medicine, Nantes, France.
Coulon
Flora
F
Haspot
Fabienne
F
Mérieau
Emmanuel
E
Renaudin
Karine
K
Martinet
Bernard
B
Vanhove
Bernard
B
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D002318:Cardiovascular Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002478:Cells, Cultured; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000276:immunology*
D018122:B7-1 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D000069594:Abatacept; D016572:Cyclosporine