Induction of long-term graft acceptance by a combination treatment of donor splenocytes and CTLA4Ig in a high responder rat liver transplantation model.
The CTLA4Ig has led to an improved survival rate in various allograft transplantation models. We investigated in a high responder rat model (Dark Agouti to Lewis) of orthotopic liver transplantation (ORLT), whether an additional adoptive cell transfer can enhance the effect of CTLA4Ig. After transplantation, recipients (n = 13/group) were treated with donor or third-party splenocytes alone or in combination with CTLA4Ig. Administration of splenocytes alone had no significant effect on survival (median 13 days, range 9-14) compared with untreated controls (median 10 days, range 8-12). CTLA4Ig monotherapy prolonged survival to a median of 30 days (range 11-150) but resulted in long-term graft rejection. The additional administration of third-party splenocytes showed no significant improvement over CTLA4Ig monotherapy. Only the combination of donor splenocytes with CTLA4Ig led to long-term graft acceptance (>150 days) without clinical and/or histological signs of rejection. A higher rate of apoptosis could be detected in livers at early time-points in long-term survivors receiving CTLA4Ig and donor splenocytes. Analysis of cytokine mRNA expression revealed a decrease of interleukin-2 at early time-points in all groups receiving CTLA4Ig; whereas, interferon-gamma was increased in long-term survivors receiving CTLA4Ig and donor cells or donor cells alone. The combination of CTLA4Ig and donor derived splenocytes is potent to induce long-term survival and graft acceptance. The mechanisms appear to involve the induction of an early inflammatory impulse and apoptosis.
Schmitz
Volker
V
Department of General, Visceral and Transplantation Surgery, Charité, Campus Virchow, Augustenburger Platz, Berlin, Germany. volker.schmitz@uchsc.edu
Neumann
Ulf P
UP
Fischer
Ursula
U
Langrehr
Jan
J
Neuhaus
Peter
P
D000069594:Abatacept; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002469:Cell Separation; D006084:Graft Rejection; D006085:Graft Survival; D018796:Immunoconjugates / Q000737:chemistry* / Q000276:immunology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D009336:Necrosis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D007371:Interferon-gamma; D011065:Poly(ADP-ribose) Polymerases