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

Abstract

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.

The Natural History of Clinical Operational Tolerance After Kidney Transplantation Through Twenty-Seven Cases

“…This is further supported by the fact that approximately one third of patients displayed acute rejection episodes before IS withdrawal (not significantly different from IS-Controls). Moreover, we have previously reported that operationally tolerant patients respond "normally" (at least not differently from normal healthy individuals) to an immunological challenge such as flu vaccination (35). These patients displayed a transcriptional regulatory profile with over-expression of certain genes specific to Treg cells, suggesting active regulatory mechanisms rather than exhausted alloreactive cells (36).…”

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

“…We also observed that Du51 displayed an Arg at the C terminus end and thus could help RT1.A a accommodation of the peptide. Interestingly, some of the peptides that were tested by us were also tested by Ballet et al on CD4 + and CD8 + T cells isolated from untreated animals with graft rejection (including the dominant peptide Du51) in the same mismatched cardiac allograft model (LEW.1W into LEW.1A) as ours (18). They found two immunodominant peptides referred to by us as peptides 47 and 55 that were derived from LEW.1W RT1.D u molecules and were involved in acute rejection of grafts from unmodified LEW.1A recipients.…”

“…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.…”

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

“…47 and 55) derived from class II MHC were described to be recognized by T cells during acute rejection whereas another one (no. 51) was recognized by CD8 + regulatory T cells during prolongation of allograft survival (30,31). Therefore, as for T cells, effector and regulatory B cells may recognize different epitopes that could lead to different B cell responses.…”