Landscape of innate immune system transcriptome and acute T cell-mediated rejection of human kidney allografts.

TitleLandscape of innate immune system transcriptome and acute T cell-mediated rejection of human kidney allografts.
Publication TypeJournal Article
Year of Publication2019
AuthorsMueller FB, Yang H, Lubetzky M, Verma A, Lee JR, Dadhania DM, Xiang JZ, Salvatore SP, Seshan SV, Sharma VK, Elemento O, Suthanthiran M, Muthukumar T
JournalJCI Insight
Date Published2019 07 11
KeywordsAdult, Allografts, Biomarkers, Biopsy, Dendritic Cells, Female, Gene Expression Profiling, Graft Rejection, Humans, Immunity, Innate, Kidney, Kidney Transplantation, Macrophages, Male, Metabolic Networks and Pathways, Middle Aged, Receptors, Pattern Recognition, RNA, Messenger, RNA-Seq, Signal Transduction, T-Lymphocytes, Transplantation, Homologous

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Alternate JournalJCI Insight
PubMed ID31292297
PubMed Central IDPMC6629252
Grant ListK08 DK087824 / DK / NIDDK NIH HHS / United States
R37 AI051652 / AI / NIAID NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States