Dax A. Guenther

Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.

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.

Advances in strategies for inducing central tolerance in organ allograft recipients

Abstract:  Encouraging results in large animal models and from the clinic have been reported recently suggesting that the deliberate induction of transplantation tolerance using central deletional protocols may be closer to becoming a reality. The induction of central tolerance would be especially applicable to pediatric organ transplant recipients. In this review, we discuss three promising protocols of central tolerance induction and why they are relevant to pediatric organ transplantation.

The Indirect Alloresponse Impairs the Induction but not Maintenance of Tolerance to MHC Class I-Disparate Allografts

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I‐mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor‐derived or control third‐party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T‐cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney–heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney–heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long‐term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.

Operational tolerance to class I disparate lungs can be induced despite pretransplant immunization with class I allopeptides

Background. Using a class I-disparate swine lung transplant model, we examined whether an intensive course of tacrolimus could induce operational tolerance and whether preoperative allopeptide immunization would prevent the development of tolerance. Methods. Left lung grafts were performed using class I-disparate (class II-matched) donors. Recipients were treated with 12 days of postoperative tacrolimus. Three recipients were immunized prior to transplantation with class I allopeptides. Three other recipients were not immunized. Results. The nonimmunized recipients maintained their grafts long term (>497, >451, and >432 days), without developing chronic rejection. The immunized swine also maintained their grafts long term (>417, >402, >401 days), despite developing a variety of in vitro and in vivo responses to the immunizing peptides, as well as having strong mixed lymphocyte reactions to donor cells prior to transplantation. Conclusions. Using only a brief course of tacrolimus, we have been able to induce a state of operational tolerance in a class I-disparate preclinical lung transplant model. Moreover, preoperative alloimmunization did not block tolerance induction or induce chronic rejection. These data show that it is possible to create a state of operational tolerance to lung allografts even in the presence of donor-sensitized cells.

Tolerance to cardiac allografts in miniature swine using donor-specific transfusions combined with cyclosporine but not with rapamycin

from FVB transgenic mice (b-CM Tg) (H-2) whose hearts are expressing b-CM in 85% in adult life. No immunosuppression was used. Graft function was monitored by palpation; rejection was confirmed histologically (HE CM-specific ELISA measured anti-CM autoantibodies in recipient’s sera. Control littermates donor hearts were all rejected within 7 days. Conversely, b-CM Tg grafts enjoyed long-term graft survival ( 100 days). Long-term survival of b-CM Tg grafts was associated with decrease in frequency of inflammatory IFNg-producing alloand a-CM-specific host T cells, and with expansion of IL-5-producing T cells. We also detected significant increase in titres of anti-CM antibodies in recipients of b-CM Tg hearts when compared to their controls (p 0.009). Our data show, that overexpression of b-CM in donor heart results in significant prolongation of cardiac allograft survival, even in fully mismatched combination. Long-term survival of b-CM allografts is accompanied by alterations in host anti-graft immunity, and suggests involvement of regulatory immune mechanisms associated with neonatal forms of cardiac myosin.