An MHC Class II Disparity Raises the Threshold for Tolerance Induction in Pulmonary Allografts in Miniature Swine

Abstract

Objectives-The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. We have induced robust tolerance to class I-disparate lung allografts in miniature swine using an intensive 12-day course of tacrolimus. Here, we test whether a tolerant state can be induced in swine receiving fully mismatched lung allografts.Methods-Orthotopic left lung allografts were performed using MHC class I-disparate (Group 1: n = 3) or fully disparate (Group 2: n = 6) donors. The recipients received a 12-day post-operative course of tacrolimus (continuous IV infusion; target level = 35-50 ng/ml) as their only immunosuppression.Results-All swine in Group 1 maintained their grafts long term without developing any lesions of chronic rejection (> 497, > 432, and > 451 days). These recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity (CML) and mixed lymphocyte reaction (MLR) assays. In Group 2, 5 of the 6 recipients maintained their grafts long term (sacrificed on PODs 515, 389, 429, 481, and 438 with viable grafts). Isolated lesions of obliterative bronchiolitis (OB) were occasionally seen on biopsy, and donor-specific hyporesponsiveness on MLR and CML assays was consistently observed. The remaining recipient rejected its graft on POD 103 with histologic findings of OB.Conclusions-We now report long-term graft acceptance without chronic immunosuppression in 5 of 6 recipients across a full MHC disparity, albeit with some evidence of OB. These data suggest that the class II disparity inherent in a fully mismatched transplant increases the requirement for tolerance induction.

Organ-specific differences in achieving tolerance

“…Graft survival data compiled as follows: kidney alone (38), lung alone (39), heart alone (40), heart and kidney (40). …”

“…Long term tolerance was easily induced in renal allografts (38), whereas lung survival ranged from 100 to >500 days (39) and hearts only survived 18-35 days (40)(Fig 1). …”

Effects of Lung Cotransplantation on Cardiac Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Miniature Swine

“…In another earlier study, five of six lung transplant recipients demonstrated donor-specific hyporesponsiveness postoperatively; animal no. 15616 demonstrated antidonor responsiveness on day of lung rejection (POD 103, group 3, Table 1) (12). Of note, one heart recipient (no.…”

“…The addition of a 12-day course of calcineurin inhibition prolonged class I and full MHC-mismatched heart allograft survival slightly; however, all grafts rejected by postoperative day (POD) 55 (8,9). In contrast, calcineurin inhibition can lead to tolerance of class I and full MHC-mismatched kidney allografts (10,11), as well as full MHC-mismatched lung allografts (12). …”

Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance

“…Using MHC class I disparate inbred miniature swine, Shoji et al demonstrated that a 12 day post-operative course of continuous intravenous tacrolimus without further immunosuppression resulted in long term lung graft survival without evidence of chronic rejection [87]. This was followed by a study with full MHC disparity with similar graft longevity, but some evidence of OB on pathology [88]. A recent development in the prevention of OB includes the use of mesenchymal stem cells.…”