Transplantation tolerance induced by intranasal administration of HY peptides.
Induction of antigen-specific tolerance to transplantation antigens is desirable to control host-versus-graft and graft-versus-host reactions. Following molecular identification of a set of minor histocompatibility (H) antigens, we have used selected HY peptide epitopes for this purpose. Intranasal administration of individual major histocompatibility complex (MHC) class II-restricted HY peptides induces indefinite survival of syngeneic male skin grafts and allows engraftment of male bone marrow. Tolerance involves linked suppression to additional HY epitopes on test grafts. Long-term tolerance also requires suppression of emerging thymic emigrants. It does not involve deletion. HY peptide-specific CD4(+) and CD8(+) T cells expand on re-exposure to male antigen; these expansions are smaller in tolerant than control mice and fewer HY-specific cells from tolerant females secrete interferon gamma and interleukin 10 (IL-10). Significantly, CD4(+) cells from peptide-pretreated females fail to make IL-2 responses to cognate peptide, limiting expansion of the HY-specific CD8(+) populations that can cause graft rejection. Consistent with this, tolerance induction by HY peptide is abrogated by coadministration of lipopolysaccharide. IL-10 does not appear to be critically involved because tolerance is inducible in IL-10-deficient mice. Adoptive transfer of tolerance into naive neonatal recipients by splenocytes from long-term tolerant donors provides evidence for involvement of regulatory cells.
Chai
Jian-Guo
JG
Transplantation Biology Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
James
Edward
E
Dewchand
Hamlata
H
Simpson
Elizabeth
E
Scott
Diane
D
D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006085:Graft Survival; D006182:H-Y Antigen / Q000008:administration & dosage*; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology; D016378:Tissue Transplantation / Q000379:methods*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D016207:Cytokines; D006182:H-Y Antigen