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P156 Allelic and epitope HLA mismatch analysis in lung transplant
Abstracts / Human Immunology 78 (2017) 51–254
P156
ALLELIC AND EPITOPE HLA MISMATCH ANALYSIS IN LUNG TRANSPLANT John J. Sninsky a, Anna Lisa Fear b, David Lew a, Elizabeth Trachtenberg b, Iwijn De Vlaminck c, Kiran K. Khush d, Henry A. Erlich b, Robert N. Woodward a. aCareDx, Brisbane, CA, United States; bChildren’s Hospital Oakland Research Institute, Oakland, CA, United States; cCollege of Engineering Cornell University, Ithaca, NY, United States; dStanford University School of Medicine, Stanford, CA, United States. Aim: The urgent need for donor lungs and a shortage of suitable organs requires transplantation of HLA mismatched donor:recipient pairs. Post-transplant high resolution HLA typing of the donor and recipient, if available, presents a post hoc opportunity to investigate comparative allelic and epitope mismatch strategies to predict post-transplant events and optimize immunosuppressive therapy. Methods: Thirty donor-recipient lung transplant pairs with available extracted DNA were studied (De Vlaminck et al. (2015)). High resolution NGS HLA typing required targeted sequencing and was performed according to Moonsamy et al. (2013). Respective two-region HLA types were assigned using Conexio ASSIGN ATF 454 software and compared to the catalog of common and well-documented HLA alleles. Epitope mismatches were determined using HLAMatchmaker. Prior transplant studies noted the importance of HLA-A, HLA-B and DRB1 for short and long term survival and therefore were selected for this study. Results: Thirty lung transplant pairs had 3 (n = 1), 4 (5), 5 (10) and 6 (14) HLA-A, HLA-B and HLA DRB1 allelic mismatches. Epitope mismatches ranged from 16–51. The epitope mismatch extremes each had 6 allelic mismatches: 16: HLA-A,-B 9; DRB1 7 and 51: HLA-A,-B 19; DRB1 32. The single 3 allelic mismatch pair had 31 epitope mismatches: HLA-A,-B 10; DRB1 21. DRB1 epitope mismatch contribution to total epitope mismatches ranged from 19% to 63%. Conclusions: Allelic (antigenic) mismatches have a more limited range than epitope (immunogenic) mismatches, and mismatch burdens using these two models varied considerably in lung transplants in this study. The relative contribution of epitope mismatches in HLA-A, HLA-B and DRB1 varies in transplant donor recipient pairs. Prognostic estimates of antibody mediated rejection to inform surveillance and increased risk of post-transplant malignancies and infection to inform long term immunosuppressive therapy merit investigation using epitope mismatch burden.
D. Lew: 5. Employee; Company/Organization; CareDx. H.A. Erlich: 2. Consultant; Company/Organization; CareDx. R.N. Woodward: 5. Employee; Company/Organization; CareDx. 6. Stock Shareholder; Company/Organization; CareDx.
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P156
ALLELIC AND EPITOPE HLA MISMATCH ANALYSIS IN LUNG TRANSPLANT John J. Sninsky a, Anna Lisa Fear b, David Lew a, Elizabeth Trachtenberg b, Iwijn De Vlaminck c, Kiran K. Khush d, Henry A. Erlich b, Robert N. Woodward a. aCareDx, Brisbane, CA, United States; bChildren’s Hospital Oakland Research Institute, Oakland, CA, United States; cCollege of Engineering Cornell University, Ithaca, NY, United States; dStanford University School of Medicine, Stanford, CA, United States. Aim: The urgent need for donor lungs and a shortage of suitable organs requires transplantation of HLA mismatched donor:recipient pairs. Post-transplant high resolution HLA typing of the donor and recipient, if available, presents a post hoc opportunity to investigate comparative allelic and epitope mismatch strategies to predict post-transplant events and optimize immunosuppressive therapy. Methods: Thirty donor-recipient lung transplant pairs with available extracted DNA were studied (De Vlaminck et al. (2015)). High resolution NGS HLA typing required targeted sequencing and was performed according to Moonsamy et al. (2013). Respective two-region HLA types were assigned using Conexio ASSIGN ATF 454 software and compared to the catalog of common and well-documented HLA alleles. Epitope mismatches were determined using HLAMatchmaker. Prior transplant studies noted the importance of HLA-A, HLA-B and DRB1 for short and long term survival and therefore were selected for this study. Results: Thirty lung transplant pairs had 3 (n = 1), 4 (5), 5 (10) and 6 (14) HLA-A, HLA-B and HLA DRB1 allelic mismatches. Epitope mismatches ranged from 16–51. The epitope mismatch extremes each had 6 allelic mismatches: 16: HLA-A,-B 9; DRB1 7 and 51: HLA-A,-B 19; DRB1 32. The single 3 allelic mismatch pair had 31 epitope mismatches: HLA-A,-B 10; DRB1 21. DRB1 epitope mismatch contribution to total epitope mismatches ranged from 19% to 63%. Conclusions: Allelic (antigenic) mismatches have a more limited range than epitope (immunogenic) mismatches, and mismatch burdens using these two models varied considerably in lung transplants in this study. The relative contribution of epitope mismatches in HLA-A, HLA-B and DRB1 varies in transplant donor recipient pairs. Prognostic estimates of antibody mediated rejection to inform surveillance and increased risk of post-transplant malignancies and infection to inform long term immunosuppressive therapy merit investigation using epitope mismatch burden.
D. Lew: 5. Employee; Company/Organization; CareDx. H.A. Erlich: 2. Consultant; Company/Organization; CareDx. R.N. Woodward: 5. Employee; Company/Organization; CareDx. 6. Stock Shareholder; Company/Organization; CareDx.
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