Wednesday May 03, 2023 - 11:00 to 12:35
Martin L Mak, Canada has been granted the The American Association of Immunologists Awards
Defining Protective and Pathogenic Resident Immune Cells in Kidney Transplantation
Martin Mak1,2,3, Julia M Murphy1,2,3, Jessica A Andrews1,2,3, Shenghui Su3, Ana Konvalinka2,3,4,5,6, Sarah Q Crome1,2,3.
1Department of Immunology, University of Toronto, Toronto, ON, Canada; 2Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; 3Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada; 4Department of Medicine, University of Toronto, Toronto, ON, Canada; 5Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 6Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Ischemia reperfusion injury (IRI) leading to delayed graft function (DGF) is associated with a 41% increased risk of graft loss within 3 years and a 38% increased risk of acute rejection. In patients receiving kidney transplants from deceased donors, the incidence of DGF ranges from 20-50%, compared to only 4-10% in recipients of living donor kidney1. Murine studies have demonstrated that specific kidney-resident immune cells can either promote or protect from IRI and DGF2,3, yet to date human resident immune populations in allografts that contribute to or protect from IRI and DGF have not been well defined. Here, we are examining whether alterations in resident immune cells within deceased donor allografts correlate with DGF following transplantation, and are identifying protective and pathogenic resident immune populations in kidney transplantation.
We are harnessing 10X Genomics single cell RNA sequencing (scRNAseq) of 19 pre-implantation living donor kidney biopsies and 3 deceased donor biopsies to date to define tissue resident immune cells that contribute to IRI and DGF in kidney transplantation. Biopsies are taken after organ perfusion and flushing prior to transplantation to ensure we captured resident and not circulating immune cells. Using cell interaction analysis, we are also identifying parenchymal cell interactions that contribute to altered immune infiltration or functions. Comparisons with other publicly available deceased donor datasets are then used to validate key findings.
We observe that deceased donor kidneys are characterized by higher expression of macrophage migration inhibitory factor (MIF) by both T cells and myeloid populations, whereas living donor biopsies are enriched for NK and myeloid cells expressing tissue reparative factor amphiregulin. Proximal tubular (PT) cells from deceased donors display increased expression of MIF and SPP1 (osteopontin), with gene set enrichment analyses demonstrating PT cells have increased interactions with lymphoid populations.
Here we identify differences in kidney-resident immune populations between living and deceased donor kidney allografts. Deceased donor immune cells exhibit a more inflammatory profile and upregulate cytokines associated with renal inflammation, while deceased donor parenchymal populations display increased potential to recruit and interact with these immune populations. Ongoing studies are comparing our findings across independent datasets and investigating potential mechanisms by which immune cells in deceased donor kidney contribute to pathology.
M.L.M is supported by the Frederick Banting and Charles Best Canada Graduate Scholarships. J.M. was supported by QE II/Aventis Pasteur Graduate, Dick and Peggy Sharp and Peterborough K.M. Hunter Foundation scholarships. . SQC is supported by a Tier 2 Canada Research Chair in Tissue-Specific Immune Tolerance, Canadian Foundation for Innovation (#38308) and the Medicine By Design Program (Canada First Research Excellence Fund).. This project is supported by funding from CIHR and was made possible by surgeons and patients within the Ajmera Transplant Centre. We thank the Princess Margaret Flow Cytometry Facility and the Princess Margaret Genomics Centre for technical support and assistance..
 Yarlagadda, S. et al (2008). Nephrol Dial Transplant. 24(3), 1039-1047.
 Cao, Q. et al. (2018). J Am Soc Nephrol, ASN.2017070774.
 Huang, Q. et al. (2020). EMBO Mol Med, 12(11), e12305.