Reclassification of kidney transplant rejection and the role of innate allorecognition

Kidney transplant rejection is a complex interplay of the genetic disparity between donors and recipients and the immune system of the host by these mismatched antigens. We and others have demonstrated the role of innate allorecognition, as exemplified by NK cell–mediated microvascular inflammation through missing self, and by monocyte-driven allorecognition. The Banff classification for kidney transplant rejection does not represent the full spectrum of disease phenotypes and the novel allorecognition pathways. In this project, we aim to map the complex interplay of various allorecognition mechanisms and connect this to a spectral view of kidney transplant rejection, moving away from a monocausal and dichotomous approach to rejection classification. In three work packages, we will (1) evaluate the relative contributions of different allorecognition mechanisms in the phenotypic spectrum of rejection, (2) develop a causally informed reclassification system of rejection, including parameters of cell composition and disease stage (activity and chronicity) with biopsy-based transcript analyses, and (3) investigate the potential of deep learning on whole slide images of transplant biopsies with causal information and information on immune cell composition. This will allow better classification of rejection phenotypes according to the underlying cause, specific immune cell infiltration/activation pathways and disease activity/chronicity, paving the way for true precision medicine.