Major histocompatibility complex class I peptide-pulsed host dendritic cells induce antigen-specific acquired thymic tolerance to islet cells

Background As T-cell receptor-major histocompatibility complex (MHC) class I/self peptide interaction regulates T-cell development in the thymus, we r easoned that presentation of peptides by self dendritic cells (DC) to devel oping T cells in the thymus might induce acquired thymic tolerance. This hy pothesis is based on the finding that intrathymic injection of allopeptides in the adult animal induces acquired tolerance. To examine this hypothesis , we studied the effects of intrathymic (IT) injection of a single immunodo minant Wistar-Furth (WF) MHC class I (RT1.A(u)) peptide-pulsed host DC on i slet allograft survival in the WF-to-ACI rat combination, Methods, Bone marrow-derived ACI DC expressing MHC class I and II, OX62, an d ED2 present allopeptides to naive and specifically peptide-primed syngene ic T cells in mixed lymphocyte reaction, Host DC pulsed with RT1.A(u) pepti de 5 (residues 93-109) were injected into the thymus of streptozotocin-indu ced diabetic ACI that were transplanted 7 days later with donor-type (WF) o r third-party (Brown Norway [BN]) islets, Results. Whereas IT injection of 300 mu g of peptide 5 alone led to normogl ycemia and permanent islet survival in three of six diabetic ACI recipients , similar treatment combined with simultaneous intraperitoneal injection of 0.5 mi of anti-lymphocyte serum (ALS) on day -7 led to 100% permanent isle t allograft survival (>200 days) compared to a mean survival time of 15.0+/ -2.3 days in controls treated with ALS alone. In contrast, similarly prepar ed animals rejected the third-party (BN) islets in an acute fashion. To add ress the question of indirect allorecognition in acquired thymic tolerance, we examined the effect of peptide-pulsed host DC on graft survival. Wherea s IT injection of peptide-pulsed host DC alone resulted in permanent islet survival in two of five animals, IT injection of peptide-pulsed host DC com bined with 0.5 mi of ALS induced 100% donor-specific permanent islet allogr aft survival in the WF-to-ACI rat combination. These results suggest that t hymic DC take up, process, and present the administered peptide to the deve loping T cells by the indirect allorecognition pathway in the induction of acquired thymic tolerance, Conclusion. We have demonstrated a novel approach to inducing transplant to lerance to islet allografts with IT injection of allopeptide-pulsed host DC . This finding suggests that immunization strategies using DC expressing MH C allopeptides or peptide analogue might be potentially useful in the treat ment of autoimmune diabetes mellitus.