Indirect Recognition of MHC Class I Allopeptides Accelerates Lung Allograft Rejection in Miniature Swine

Abstract

The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection.

Immunosuppression for lung transplantation

“…Analysis of lymphocytes extracted from recipient nodal tissue in these experimental constructs confirmed the presence of a small population of self-restricted T lymphocytes that were able to respond to donor-derived peptides (11). More recent experimental studies have shown that pre-transplant immunization with donor-derived MHC allopeptides can accelerate heart and lung allograft rejection and vasculopathy in both murine (12)(13)(14) and porcine systems (15,16). In the clinical arena, many investigators have demonstrated a positive correlation between T-cell reactivity to synthetic allopeptides derived from the donor MHC and chronic graft rejection and dysfunction.…”

The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

“…[1][2][3][4] For instance, immunization with allogeneic HLA peptides presented by acceptor HLA class II significantly increases both acute and chronic rejection after organ transplantation. 5 In addition, CD4 ϩ T-cell help is necessary to facilitate full differentiation of graft-infiltrating CD8 ϩ T cells. [6][7][8] However, other studies have pointed to a protective role of alloreactive CD4 ϩ T cells, which are able to mediate immunologic tolerance to the graft.…”

Update on Chronic Lung Allograft Dysfunction

“…Allan has developed a miniature swine model of orthotopic lung transplantation which develops the spectrum of histopathological changes seen in human chronic lung rejection; this model has the benefit of allowing for surveillance biopsies that is not feasible in smaller animal models [54]. This group has used the miniature swine model to study the role of indirect allorecognition in developing CLAD [55]. Atanasova performed rat orthotopic lung transplants in the Fischer 344 → Lewis strain combination, treated the recipients with cyclosporine postoperatively and instilled lipopolysaccharide into their airways on postoperative day 28; this resulted in pulmonary fibrosis and fibroproliferation of airways resembling human BO [56].…”