Anti-CD154 mAb and rapamycin induce T regulatory cell mediated tolerance in rat-to-mouse islet transplantation.
BACKGROUND
Anti-CD154 (MR1) monoclonal antibody (mAb) and rapamycin (RAPA) treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Treg) in the induction and maintenance of the ensuing tolerance.


RESULTS
C57BL/6 mice were treated with MR1/RAPA and received additional monoclonal anti-IL2 mAb or anti CD25 mAb either early (0-28 d) or late (100-128 d) post-transplantation. Treg were characterised in the blood, spleen, draining lymph nodes and within the graft of tolerant and rejecting mice by flow cytometry and immunohistochemistry. Fourteen days of RAPA/MR1 combination therapy allowed indefinite islet graft survival in >80% of the mice. Additional administration of anti-IL-2 mAb or depleting anti-CD25 mAb at the time of transplantation resulted in rejection (100% and 89% respectively), whereas administration at 100 days post transplantation lead to lower rejection rates (25% and 40% respectively). Tolerant mice showed an increase of Treg within the graft and in draining lymph nodes early post transplantation, whereas 100 days post transplantation no significant increase of Treg was observed. Rejecting mice showed a transient increase of Treg in the xenograft and secondary lymphoid organs, which disappeared within 7 days after rejection.


CONCLUSIONS
These results suggest a critical role for Treg in the induction phase of tolerance early after islet xenotransplantation. These encouraging data support the need of developing further Treg therapy for overcoming the species barrier in xenotransplantation.
Muller
Yannick D
YD
Surgical Research Unit, Department of Surgery, University Hospital Geneva, Geneva, Switzerland. leo.buhler@hcuge.ch
Mai
Gang
G
Morel
Philippe
P
Serre-Beinier
Véronique
V
Gonelle-Gispert
Carmen
C
Yung
Gisella Puga
GP
Ehirchiou
Driss
D
Wyss
Jean-Christophe
JC
Bigenzahn
Sinda
S
Irla
Magali
M
Heusser
Christoph
C
Golshayan
Déla
D
Seebach
Jörg D
JD
Wekerle
Thomas
T
Bühler
Leo H
LH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D023201:CD40 Ligand / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D020123:Sirolimus