The Clinical Relevance of the Infiltrating Immune Cell Composition in Kidney Transplant Rejection.

BACKGROUND: The link between the histology of kidney transplant rejection, especially Antibody-mediated rejection, T cell-mediated rejection and Mixed rejection, and the types of infiltrating immune cells is currently not well charted. Cost and technical complexity of single cell analysis hinder large scale studies of the relationship between cell infiltrate profiles and histological heterogeneity.

METHODS: In this cross-sectional study, we assessed the composition of nine intragraft immune cell types by using a validated kidney transplant-specific signature matrix for deconvolution of bulk transcriptomics in three different kidney transplant biopsy datasets (N=403, N=224, N=282). The association and the discrimination of the immune cell types with the Banff histology and the association with graft failure were assessed individually and with multivariable models. Unsupervised clustering algorithms were applied on the overall immune cells composition and compared to the Banff phenotypes.

RESULTS: Banff-defined rejection was related to high presence of CD8+ effector T cells, Natural Killer cells, monocytes/macrophages and to a lesser extent B cells, whereas CD4+ memory T cells were lower in rejection compared to no rejection. Estimated intragraft effector memory-expressing CD45RA (TEMRA) CD8+ T cells were strongly and consistently associated with graft failure. The large heterogeneity in immune cell composition across rejection types prevented supervised and unsupervised methods to accurately recover the Banff phenotypes based solely on immune cell estimates. The lack of correlation between immune cell composition and Banff-defined rejection types was validated using multiplex immunohistochemistry.

CONCLUSIONS: Although some specific cell types (FCGR3A+ myeloid cells, CD14+ monocytes/macrophages and NK cells), partly discriminate between rejection phenotypes, the overall estimated immune cell composition of kidney transplants is ill related to main Banff-defined rejection categories and adds to the Banff lesion scoring and evaluation of rejection severity. The estimated intragraft CD8temra cells bear strong and consistent association with graft failure and independent of Banff-grade rejection.