IFN-gamma production is specifically regulated by IL-10 in mice made tolerant with anti-CD40 ligand antibody and intact active bone.
We have developed a strategy to induce tolerance to allografts, involving cotransplantation of allogeneic intact active bone and transient anti-CD40 ligand mAb therapy. Tolerance induced by this approach in C57BL/6 mice receiving BALB/c hearts is not mediated by deletional mechanisms, but by peripheral regulatory mechanisms. Tolerance is associated with diminished ex vivo IFN-gamma production that is donor specific, and a reduction in the frequency of IFN-gamma-producing cells. Splenocytes from mice tolerant to BALB/c grafts, but sensitized to third-party C3H skin grafts, demonstrated normally primed ex vivo IFN-gamma responses to C3H stimulators. Neutralizing anti-IL-10 and anti-IL-10R, but not anti-TGF-beta, anti-IL-4, or anti-CTLA-4, Abs restored the ex vivo IFN-gamma response to BALB/c stimulators. There was no significant difference in IL-2 or IL-4 production between tolerant and rejecting mice, and anti-IL-10 mAbs had no effect on IL-2 or IL-4 production. The Cincinnati cytokine capture assay was used to test whether suppression of IFN-gamma production in vivo was also a marker of tolerance. In naive mice, we observed a dramatic increase in serum IFN-gamma levels following challenge with allogeneic BALB/c splenocytes or hearts. Tolerant mice challenged with allogeneic BALB/c splenocytes or hearts made significantly less or undetectable amounts of IFN-gamma. No IL-4 or IL-10 production was detected in tolerant or rejecting mice. Collectively, our studies suggest that active suppression of IFN-gamma production by IL-10 is correlated with, and may contribute to, tolerance induced with intact active bone and anti-CD40 ligand mAbs.
Yin
Dengping
D
Department of General Surgery, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
Dujovny
Nadav
N
Ma
Lianli
L
Varghese
Anncy
A
Shen
JiKun
J
Bishop
D Keith
DK
Chong
Anita S
AS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology*; D016025:Bone Transplantation / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology; D014019:Tissue Donors; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D007106:Immune Sera; D016753:Interleukin-10; D023201:CD40 Ligand; D007371:Interferon-gamma