PUBLISHED BY
Hiho, Steven J.; Levvey, Bronwyn J.; Diviney, Mary B.; Brooks, Andrew G.; Holdsworth, Rhonda; Snell, Gregory I.; Westall, Glen P.; Sullivan, Lucy C.
PUBLISHED IN
HLA
PATIENTS
310
ABSTRACT
HLA (HLA) are a major barrier to transplant success, as HLA-A and -B molecules are principal ligands for T-cells, and HLA-C for Killer cell Immunoglobulin-like Receptors (KIR), directing Natural Killer (NK) cell function. HLA-C molecules are designated “C1” or “C2” ligands based on residues 77 and 80, which determine the NK cell responses. Here, we investigated donor/recipient HLA-C mismatch associations with the development of chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx). 310 LTx donor/recipient pairs were Next Generation Sequenced and assessed for C1 and C2 allotypes. PIRCHE scores were used to quantify HLA mismatching between donor/recipients at amino acid level and stratify recipients into low, moderate or highly mismatched groups (n = 103–104). Associations between C ligands and freedom from CLAD was assessed with Cox regression models and survival curves. C2/C2 recipients (n = 42) had less CLAD than those with C1/C1 (n = 138) or C1/C2 genotypes (n = 130) (p < 0.05). Incidence of CLAD was lower in C2/C2 recipients receiving a mismatched C1/C1 allograft (n = 14), compared to matched (n = 8) or heterozygous (n = 20) allografts. Furthermore, 80% of these recipients (C2/C2 recipients receiving C1/C1 transplants) remained CLAD-free for 10 years post-LTx. Recipients with higher HLA-C mismatching had less CLAD (p < 0.05) an observation not explained by linkage disequilibrium with other HLA loci. Our data implicates a role for HLA-C in CLAD development. HLA-C mismatching was not detrimental to LTx outcome, but potentially beneficial, representing a paradigm shift in assessing donor/recipient matching. This may inform better selection of donor/recipient pairs and potentially more targeted approaches to treating CLAD.
HIGHLIGHTS
- HLA-C molecules interact with Killer cell Immunoglobulin-like Receptors (KIR) on NK cells, and are classified as "C1" or "C2" based on specific residues that affect NK cell responses.
- This study analyzed 310 lung transplant donor/recipient pairs using Next Generation Sequencing to assess HLA-C allotypes and PIRCHE scores to quantify HLA mismatches, categorizing them into low, moderate, or highly mismatched groups.
- C2/C2 recipients had a significantly lower incidence of chronic lung allograft dysfunction (CLAD) compared to C1/C1 or C1/C2 recipients, with ~80% of C2/C2 recipients with mismatched C1/C1 allografts remaining CLAD-free for 10 years post-transplant.
- Higher HLA-C mismatching correlated with less CLAD, suggesting that HLA-C mismatching may be beneficial and indicating a potential shift in how donor/recipient matching is assessed, which could improve donor selection and treatment strategies for CLAD.
