Posttransplant administration of allochimeric major histocompatibility complex class-I-molecules induces true transplantation tolerance

Abstract

Allochimeric MHC class-I therapy is a unique and novel clinically applicable approach for induction of "true" transplantation tolerance where chronic rejection is concomitantly abrogated.

Enhancement of NKT Cells and Increase in Regulatory T Cells Results in Improved Allograft Survival

“…generated NKT cells post-transplant, either by prolonging subtherapeutic doses of FK506 or by continuous oral antigen ingestion, can prolong allograft survival even further. This would be consistent with reports that prolonged administration of post-transplant MHC molecules and subtherapeutic cyclosporine A or intraportal donor-specific blood transfusion prolong allograft survival [58,59].…”

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

“…Our studies imply an important role for both donor immunogenic epitopes a well as self-epitopes in peripheral transplantation tolerance by peritransplant administration since portal venous administration of either whole donor or recipient non-mutated class I antigens have not resulted in long-term allograft acceptance [25,41]. Concurrent presentation of self and dominant donor determinants, may have downmodulated the immune response to donor cardiac allografts.…”

Rock1 Inhibitor Abrogates Chronic Rejection in Rat Cardiac Model System

“…Cytokines analysis of long-term allografts revealed selective upregulation of IL-10, but marked inhibition of IL-2, IFN-γ, and IL-4. Furthermore, long-term allografts in allochimeric-conditioned hosts exhibited moderate B cell infiltration, limited monocyte and absent CD8 + cells [6][7][8][9]. In addition, our adoptive transfer studies showed that the secondary cardiac grafts from recipients exposed to allochimeric MHC I-conditioned splenic total T cells or CD4 + T cells showed significantly reduced neointimal index (NI) and apoptosis, and were selectively infiltrated with CD4 + Foxp3 + (T regulatory, Treg) cells [10].…”

“…Adult male inbred Wistar Furth (WF; RT1.A u ) and ACI (RT1.A a ) rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed in standard rat cages. Heterotopic cardiac transplants were placed intraabdominally as described previously [6][7][8][9][10][11][12][13][14][15]. Transplantation was performed as follows: 1) transplantation control group that received no treatment; 2) transplantation in the presence of high dose cyclosporine (CsA) delivered by gavage feed (10 mg/kg, day 0 -6); 3) transplantation in the presence of sub-therapeutic dose of CsA delivered by gavage (10 mg/kg, day 0 -2); 4) transplantation in the presence of Y-27632 inhibitor (Fisher Scientific, 2 mg/kg, day 0 -6) delivered by gavage; and 5) transplantation in the presence of sub-therapeutic dose of CsA (10 mg/kg, day 0 -2) in conjunction with Y-27632 inhibitor (2 mg/kg) which was gavage fed as a single dose before the transplantation.…”

“…At present, none of the available immunosuppressive drugs, while being effective in abrogating acute rejection, is able to inhibit chronic rejection [3][4][5]. In order to study the mechanisms and molecular pathways responsible for the chronic rejection and to identify potential molecular targets and therapeutic agents we previously developed the rat cardiac allograft model system in which the peri-operative treatment of recipients with an allochimeric MHC I induced indefinite survival and abrogated acute and chronic rejection of the allograft [6][7][8][9]. In this model system the dominant immunogenic epitopes were identified within the hypervariable regions of the α1 domain of RT1.A a , and RT1.A u .…”