Identification of immunodominant donor MHC peptides following rejection and donor strain transfusion-induced tolerance of heart allografts in adult rats

Denderen, Bryce van; Pêche, Hélène; Gagne, Katia; Usal, Claire; Cuturi, Maria‐Cristina; Soulillou, Jean‐Paul

doi:10.1002/1521-4141(200105)31:5<1333::aid-immu1333>3.0.co;2-1

Cited by 10 publications

(7 citation statements)

References 27 publications

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“…Overlapping peptide libraries (16-mer) with 4 aa lagging were designed to cover the entire polymorphic sequences of MHC-I RT1. A u (α1, -2, and -3 domains), MHC II RT1.B u (all domains), and MHC II RT1.D u (α2 and β1 domains), as previously published (17)(18)(19), and were manufactured by GL Biochem Ltd. Lyophilized peptides were dissolved in 0.4% sterile DMSO/sterile water and stored at -80°C. For control peptides, we used allogeneic nonactivating peptides 7, 26, and 39 in vitro and peptide 31 in vivo.…”

Section: Methodsmentioning

confidence: 99%

MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

et al. 2014

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In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8 + CD45RC lo regulatory T cells (CD8 + CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II-derived peptide (Du51) that is recognized by TCR-biased CD8 + CD40Ig Tregs and activating CD8 + CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1. A a /Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.A a / Du51-specific CD8 + CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8 + CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function.

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Section: Methodsmentioning

confidence: 99%

MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

et al. 2014

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“…The heart allografts were evaluated daily by palpation through the abdominal wall. Rejection was defined as a complete cessation of palpable beating as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

Induction of Tolerance by Exosomes and Short-Term Immunosuppression in a Fully MHC-Mismatched Rat Cardiac Allograft Model

Pêche

Renaudin

Bériou

et al. 2006

American Journal of Transplantation

119

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Exosomes are MHC-bearing vesicles secreted by a wide array of cells. We have previously shown that donor-haplotype exosomes from bone marrow dendritic cells (DCs) injected before transplantation significantly prolong heart allograft survival in congenic and fully MHC-mismatched Lewis rats. Here we show that donor exosomes administered after transplantation are similarly able to prolong allograft survival, however, without inducing tolerance. We therefore tested the effect of exosomes combined with shortterm LF 15-0195 (LF) treatment, which blocks the maturation of DCs, so that donor-MHC antigens from exosomes could be presented in a more tolerogenic environment. LF treatment does not preclude the development of a strong antidonor cellular response, and while LF, but not exosome, treatment inhibits the antidonor humoral response and decreases leukocyte graft infiltration, allografts from LF-treated recipients were either acutely or strongly chronically rejected. Interestingly, when combined with LF treatment, exosomes induced a donor-specific allograft tolerance characterized by a strong inhibition of the antidonor proliferative response. This donor-specific tolerance was transferable to naïve allograft recipients. Moreover, exosomes/LF treatment prevented or considerably delayed the appearance of chronic rejection. These results suggest that under LF treatment, presentation of donor-MHC antigens (from exosomes) can induce regulatory responses that are able to modulate allograft rejection and to induce donor-specific allograft tolerance.

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“…Synthetic peptides 16 amino-acids in length and spanning the polymorphic regions of RT1.A u (a1, a2 and a3 domains), RT1.B u (b1 domain) and RT1.D u (b1 domain) or the invariable regions of RT1.A (a2 and a3 domains) molecules (13) (Figure 1) were prepared by Genepep (France). Lyophilized peptides were dissolved in deionized water/0.4% DMSO and used in cultures at a final concentration of 10 lg/mL.…”

Section: Peptide Synthesismentioning

confidence: 99%

Indirect CD4+ TH1 Response, Antidonor Antibodies and Diffuse C4d Graft Deposits in Long-Term Recipients Conditioned by Donor Antigens Priming

Ballet

Renaudin

Degauque

et al. 2009

American Journal of Transplantation

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Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.D u molecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4 + indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibodymediated rejection in human.

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Identification of immunodominant donor MHC peptides following rejection and donor strain transfusion-induced tolerance of heart allografts in adult rats

Cited by 10 publications

References 27 publications

MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

Induction of Tolerance by Exosomes and Short-Term Immunosuppression in a Fully MHC-Mismatched Rat Cardiac Allograft Model

Indirect CD4+ TH1 Response, Antidonor Antibodies and Diffuse C4d Graft Deposits in Long-Term Recipients Conditioned by Donor Antigens Priming

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