Abstract
Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.
| Original language | English (US) |
|---|---|
| Article number | e15455 |
| Journal | HLA |
| Volume | 103 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Funding
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI170728. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was further supported by grants from the Michael Abecassis Transplant Innovation Endowment (2019, and 2021), and by a generous contribution from the Paul I Terasaki Memorial Research Fund. Some of the analysis reported here are based on data that have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government. The authors further thank the National Marrow Donor Program (NMDP) and the CIBMTR for sharing the NMDP de-identified 9-locus haplotype frequency data (HLA). The authors thank all laboratories that submitted data to the immunogenic epitopes, antibody component of the 18th IHWC. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI170728. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was further supported by grants from the Michael Abecassis Transplant Innovation Endowment (2019, and 2021), and by a generous contribution from the Paul I Terasaki Memorial Research Fund. Some of the analysis reported here are based on data that have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government. The authors further thank the National Marrow Donor Program (NMDP) and the CIBMTR for sharing the NMDP de\u2010identified 9\u2010locus haplotype frequency data (HLA). The authors thank all laboratories that submitted data to the immunogenic epitopes, antibody component of the 18th IHWC.
Keywords
- HLA-DQ
- epitope
- histocompatibility
- immunogenicity
- organ-transplantation
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Genetics