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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3951-3959.
Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-11-3763.
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TRANSPLANTATION
Transplantation tolerance induced by intranasal administration of HY peptides
Jian-Guo Chai,
Edward James,
Hamlata Dewchand,
Elizabeth Simpson, and
Diane Scott
From the Transplantation Biology Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
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  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.
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