Transplantation tolerance induced by intranasal administration of HY peptides

Abstract

Induction of antigen-specific tolerance to transplantation antigens is desirable to control host-versus-graft and graftversus-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 rejec- IntroductionHY antigens are the male-specific, Y chromosome-encoded minor histocompatibility (H) antigens, 1 others being encoded by autosomal genes. Antigenicity and allelism are created by sequence differences of peptides derived from intracellular proteins expressed at the cell surface following incorporation into major histocompatibility complex (MHC) class I and II molecules. 2 A poorly understood mechanism of immunodominance operates to select only a small number of minor H epitopes as the focus of T-cell responses when grafts are exchanged between MHCmatched, multiple minor H-mismatched donor/recipient pairs. [3][4][5] This raises the possibility of modulating the immune response to grafts by inducing linked suppression via tolerance to immunodominant epitopes. 6 Clinical responses of patients undergoing femaleto-male bone marrow transplantation suggest that HY responses can be immunodominant over autosomally encoded minor H antigens in humans 7 ; thus induction of tolerance to HY antigens provides a model for inducing tolerance to autosomal minor H antigens via linked suppression.Syngeneic male skin and bone marrow grafts are rejected by female mice of high responder H2 b strains, such as C57BL/6 (B6) and F 1 females with one H2 b parent. 1 Rejection requires both CD4 ϩ and CD8 ϩ T cells 8 recognizing peptides derived from proteins encoded by the genes, Smcy, Uty, and Dby. [9][10][11][12] Humans make male-specific T-cell responses to HY peptides from the same genes, SMCY, UTY, and DBY, strongly conserved across mammalian species, and from additional ubiquitously transcribed human Y chromosome genes, RPS4Y and DFFRY. [13][14][15][16][17][18][19] We have previously described using immature, bone marrowderived dendritic cells (BMDCs) pulsed with the immunodominant MHC class I (H2D b )-restricted HY peptide, WMHHNMDLI, encoded by the Uty gene, (HY Db Uty) 20 to induce tolerance to syngeneic male skin grafts in...

Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung

“…45,46 We, therefore, administered CD4 and CD8-immuno dominant SeV epitopes to the lungs of mice 10 days before DF/SeV. While tolerance experiments in mouse models have tended to rely on a form of 'highdose' tolerance at 100 mg or greater, 23,47 we found, in line with recent findings from clinical studies, 25 that tolerance was actually induced after a single dose of 1 mg peptide, and not at higher doses. Interestingly, a single tolerizing dose of the CD4 epitope largely abrogated not only the response of T cells to this epitope, but also to the immunodominant CD8 class I restricted epitope, presumably because the latter response is dependent on help from CD4T cells.…”

“…20 Route of administration is one important factor, oral and intranasal pre-administration of soluble peptide having been shown to induce tolerance in murine models of autoimmunity, transplantation and allergy. [21][22][23][24] Induction of tolerance by peptide has also been successfully applied to humans. 25,26 There has been less impetus to investigate the induction of therapeutic tolerance to eliminate antiviral responses, but a number of examples have been described.…”

Induction of antigen-specific regulatory T cells in wild-type mice: Visualization and targets of suppression

“…Tolerance to male tissue also was achieved by intranasal infusion of HY peptide (25). However, the nature of the cells mediating tolerance in that system remained unknown.…”

New approaches for preventing and treating chronic graft-versus-host disease

“…75 The intranasal route has been used to tolerize female mice to male HY peptides, resulting in acceptance of male skin grafts and bone marrow cells that are rejected in controls. 76 The mechanism of oral tolerance is hypothesized to be induction of a regulatory T cell of Th3 phenotype that secretes high amounts of TGF-␤. 77 …”