Defining the Canonical Form of T‐Cell‐Mediated Rejection in Human Kidney Transplants

Banff defines T‐cell‐mediated rejection (TCMR) using nonspecific lesions and arbitrary cutoffs, with no external gold standard. We reexamined features of TCMR using exclusively molecular definition independent of histopathology. The definition was derived from mouse kidney transplants with fully developed TCMR, and is based on high expression of transcripts reflecting IFNG effects and alternative macrophage activation. In 234 human kidney transplant biopsies for cause phenotyped by microarrays, we identified 26 biopsies meeting these criteria. After excluding three biopsies with unrelated diseases, all 23 biopsies had typical Banff lesions of TCMR (inflammation, tubulitis), with v lesions in 10/23. Banff histopathology diagnosed 18 as TCMR, 1 as mixed and 4 as borderline. Despite marked changes in transcriptome indicating tissue injury and dedifferentiation, all kidneys with molecularly defined TCMR, even with v lesions or late rejection, demonstrated excellent recovery of function at 6 months with no graft loss (mean follow‐up 2.5 years). Thus TCMR defined exclusively by molecules manifests TCMR–related lesions and function impairment, but good recovery and survival, even with late rejection or arteritis. This combination of pathologic, clinical and molecular features constitutes the typical or canonical T‐cell‐mediated rejection. IFN‐gamma effects and alternative macrophage activation are features of severe T cell mediated rejection in human kidney transplant biopsies providing a method for identifying T cell mediated rejection independent of histopathology.