Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice.
Human CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) prevent allogeneic graft rejection by inhibiting T cell activation, as has been shown in mouse models. Recently, low-dose IL-2 administration was shown to specifically activate Tregs but not pathogenic conventional T cells, leading to resolution of type 1 diabetes in nonobese diabetic mice. We therefore tested the ability of low-dose IL-2 to prevent allogeneic skin graft rejection. We found that while IL-2 alone was inefficient in preventing rejection, combined with rapamycin, IL-2 treatment promoted skin graft survival both in minor disparate and semi-allogeneic skin graft combinations. Tregs are activated by this combined treatment while conventional CD4(+) cell expansion and activation are markedly inhibited. Co-administration of anti-CD25 antibodies dramatically reduces the effect of the IL-2/rapamycin treatment, strongly supporting a central role for Treg activation. Thus, we provide the first preclinical data showing that low-dose IL-2 combined with rapamycin can significantly delay transplant rejection in mice. These findings may form the rational for clinical evaluation of this novel approach for the prevention of transplant rejection.
Faculté de Médecine, Université Paris-Est Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale (IMRB), INSERM U 955, Créteil, France; AP-HP, Groupe Hospitalier Henri-Mondor Albert-Chenevier, CIC-BT-504, Créteil, France.
C B
CB
Pilon
S
S
Petillon
S
S
Naserian
G H
GH
Martin
C
C
Badoual
P
P
Lang
D
D
Azoulay
E
E
Piaggio
P
P
Grimbert
J L
JL
Cohen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011183:Postoperative Complications; D020123:Sirolimus / Q000008:administration & dosage*; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D020123:Sirolimus
Basic (laboratory) research; alloantigen; graft survival; immune modulation; immune regulation; immunobiology; immunosuppression; murine; tissue (nonvascularized); tolerance; translational research; transplantation