HLA-C mismatching improves outcomes following lung transplantation
Lucy Sullivan1,4, Steven Hiho2,3, Gregory I Snell3, Bronwyn J Levvey3, Andrew G Brooks4, Glen P Westall3.
1South Australian Transplantation and Immunogenetics Service, Australian Red Cross Lifeblood, Adelaide, Australia; 2Victorian Transplantation and Immunogenetics Service, Australian Red Cross Lifeblood, Melbourne, Australia; 3Lung Transplant Service, Alfred Hospital, Melbourne, Australia; 4Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
Introduction: The major barriers to transplant success are polymorphic human leukocyte antigens (HLA) that divide into class I (HLA-A, B, C) and class II (HLA-DR, DP, DQ) molecules. HLA-A and HLA-B molecules are known as the principal ligands for CD8+ T cells, whereas HLA-C molecules are better known as ligands for Killer cell Immunoglobulin-like Receptors (KIR), which control the function of Natural Killer (NK) cells. HLA-C molecules are designated as “C1” or “C2” ligands based on their ability to interact with KIR2DL2/L3, or KIR2DL1, respectively. Historically, HLA-C has been overlooked as a determinant of matching lung transplant (LTx) donors with a suitable recipient. Here, we aimed to determine if donor/recipient mismatches in HLA-C impacted on the development of chronic lung allograft dysfunction (CLAD) following LTx.
Method: We assessed the presence of C1 and C2 allotypes in LTx donor/recipient pairs and correlated this with CLAD in a cohort of 310 recipients. We also used the HLA-EMMA tool to compare donor-recipient compatibility at the amino acid level (called eplet mismatching (epMM)) to stratify patients in low, moderate or high epMM (n=103-104 per group).
Results: Recipients homozygous for HLA-C2 (C2/C2, n=42) had significantly less CLAD than C1/C1 (n=138) or C1/C2 heterozygous recipients (n=130) (p<0.05). Strikingly, the incidence of CLAD was further reduced in C2/C2 recipients that received a completely mismatched C1/C1 allograft (n=14), compared to receiving a completely matched allograft (n=8) or an allograft from a heterozygous donor (n=20). Indeed, ~80% of completely mismatched HLA-C LTx recipients remained CLAD-free for up to 10 years post LTx. Moreover, donors and recipients that had higher epMM across HLA-C had significantly less CLAD (p<0.05), an observation that was not by explained by linkage disequilibrium with other HLA molecules.
Conclusion: Our data implicates a role for HLA-C in the development of CLAD. Contrary to the principles that govern alloreactive T and B cell responses, HLA-C mismatching was not detrimental to LTx outcome, but potentially beneficial, representing a paradigm shift in assessing donor-recipient HLA matching. Our project may lead to better selection of donor-recipient pairs and potentially more targeted approaches to treating CLAD following LTx.
Lungitude Foundation.
