Donor-derived mitochondrial DNA variant peptides elicit allo-specific immune response in transplant patients

Abstract In stem cell transplant, mitochondrial DNA (mtDNA) nonsynonymous single nucleotide variants (SNVs) between donor and recipient (D-R) trigger alloimmune responses and transplant rejection. Whether similar alloimmune responses occurs in solid-organ transplantation remains unknown, particularly with the presence of human leukocyte antigen mismatches. This study characterized mtDNA SNVs between D-R of 163 human lung transplant pairs, and then, post-transplantation, assessed alloimmune responses against donor-derived mitochondrial peptides using ELISpot to measure interferon gamma (IFNγ) release from recipient’s monocytes. We identified a median of 6 nonsynonymous mtDNA SNVs (Interquartile Range = 4 – 9) per D-R pair. SNVs were predominantly located at MT-CYB, MT-ATP6 , and MT-ND3 genes. The number of SNVs was higher in D-R race non-concordant pairs than in race-concordant pairs. Donor-derived mitochondrial peptides triggered a 19.8-fold higher IFNγ release compared to recipient-derived peptide. These findings were validated in heart transplantation and show that donor-derived mitochondrial peptides trigger allo-specific immune responses after transplantation.