Specific Donor HLA-DR Types Correlate with Altered Susceptibility to Development of Chronic Lung Allograft Dysfunction

AbstractBackgroundThe greatest challenge to long-term graft survival is the development of chronic lung allograft dysfunction (CLAD). Th17 responses to collagen type V (colV) predispose lung transplant patients to the severe obstructive form of CLAD, known as bronchiolitis obliterans syndrome (BOS). In a previous study cohort (n=54), pre-transplant colV responses were increased in recipients expressing HLA-DR15, consistent with the high binding avidity of colV(α1) peptides for HLA-DR15, while BOS incidence, which was known to be strongly associated with post-transplant autoimmunity to colV, was higher in patients who themselves lacked HLA-DR15, but whose lung donor expressed it.MethodsTo determine if this DR-restricted effect on BOS incidence could be validated in a larger cohort, we performed a retrospective analysis of outcomes for 351 lung transplant recipients transplanted between 1988 and 2008 at the University of Wisconsin. All subjects were followed until graft loss, death, loss to follow-up, or through 2014, with an average follow-up of 7 years. Comparisons were made between recipients who did or did not develop BOS. Grading of BOS followed the recommendations of the international society for heart and lung transplantation.ResultsDonor HLA-DR15 was indeed associated with increased susceptibility to severe BOS in this population. We also discovered that HLA-DR7 expression by the donor or HLA-DR17 expression by the recipient decreased susceptibility.ConclusionWe show in this retrospective study that specific donor HLA class II types are important in lung transplantation, as they are associated with either protection from or susceptibility to development of severe BOS. Background The greatest challenge to long-term graft survival is the development of chronic lung allograft dysfunction (CLAD). Th17 responses to collagen type V (colV) predispose lung transplant patients to the severe obstructive form of CLAD, known as bronchiolitis obliterans syndrome (BOS). In a previous study cohort (n=54), pre-transplant colV responses were increased in recipients expressing HLA-DR15, consistent with the high binding avidity of colV(α1) peptides for HLA-DR15, while BOS incidence, which was known to be strongly associated with post-transplant autoimmunity to colV, was higher in patients who themselves lacked HLA-DR15, but whose lung donor expressed it. Methods To determine if this DR-restricted effect on BOS incidence could be validated in a larger cohort, we performed a retrospective analysis of outcomes for 351 lung transplant recipients transplanted between 1988 and 2008 at the University of Wisconsin. All subjects were followed until graft loss, death, loss to follow-up, or through 2014, with an average follow-up of 7 years. Comparisons were made between recipients who did or did not develop BOS. Grading of BOS followed the recommendations of the international society for heart and lung transplantation. Results Donor HLA-DR15 was indeed associated with increased susceptibility to severe BOS in this population. We also discovered that HLA-DR7 expression by the donor or HLA-DR17 expression by the recipient decreased susceptibility. Conclusion We show in this retrospective study that specific donor HLA class II types are important in lung transplantation, as they are associated with either protection from or susceptibility to development of severe BOS. To whom correspondence should be addressed: William J. Burlingham, burlingham@surgery.wisc.edu, G4/701 CSC, 600 Highland Avenue, Madison, WI 53792-7375 Authorship: Participated in research design- LDH, WJ, JM, KCM, WJB Participated in the writing of the paper – LDH, WJB, GL, KCM Participated in the performance of the research LDH, WJ, GL Participated in data analysis LDH, GL Disclosures- the authors declare no conflicts of interest This work was supported by NIH grants RO1AI119140 and PPG AI084853. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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