HLA-C mismatching improves outcomes following lung transplantation

Area of Science:

• Transplantation immunology
• Immunogenetics
• Allograft rejection

Background:

• Human Leukocyte Antigen (HLA) molecules are critical for transplant success, influencing T-cell and Natural Killer (NK) cell responses.
• HLA-C molecules, categorized as C1 or C2 ligands, modulate NK cell function and are implicated in transplant outcomes.
• Chronic Lung Allograft Dysfunction (CLAD) remains a significant challenge in lung transplantation (LTx).

Purpose of the Study:

• To investigate the association between donor/recipient HLA-C mismatching and the development of CLAD after lung transplantation.
• To evaluate the impact of specific HLA-C allotypes (C1 and C2) on LTx outcomes.
• To explore the potential benefits of HLA-C mismatching in donor-recipient pair selection.

Main Methods:

• Next Generation Sequencing was used to assess HLA-C C1 and C2 allotypes in 310 lung transplant donor/recipient pairs.
• PIRCHE scores quantified HLA mismatching at the amino acid level, stratifying recipients into low, moderate, and high mismatch groups.
• Cox regression models and survival curves analyzed the association between HLA-C ligands and freedom from CLAD.

Main Results:

• Recipients with C2/C2 genotypes experienced less CLAD compared to those with C1/C1 or C1/C2 genotypes (p<0.05).
• C2/C2 recipients receiving a mismatched C1/C1 allograft showed a lower incidence of CLAD, with approximately 80% remaining CLAD-free for 10 years.
• Increased HLA-C mismatching was significantly associated with reduced CLAD development, independent of other HLA loci (p<0.05).

Conclusions:

• HLA-C plays a significant role in the development of CLAD following lung transplantation.
• HLA-C mismatching appears to be potentially beneficial, rather than detrimental, to LTx outcomes, challenging conventional matching paradigms.
• These findings suggest a paradigm shift in donor-recipient matching strategies for lung transplantation, potentially improving long-term graft survival.