The Early Course of Kidney Allograft Rejection: Defining the Time When Rejection Begins

We studied the early events in mouse kidney allografts and isografts to define when allorecognition begins and when alloimmune tissue injury begins. Allografts but not isografts showed T‐cell infiltration in perivascular areas from day 1, but tubulitis and arteritis did not develop until day 7. Flow cytometry confirmed the early allospecific CD3+CD8+ T‐cell infiltrate. At day 1, both allografts and isografts showed extensive transcriptome changes, reflecting the response to surgery, but only allografts showed expression of interferon‐gamma (IFN‐γ)‐inducible transcripts and T‐cell‐associated transcripts. Although the number of CD68+ myeloid cell numbers did not increase in day 1 isografts or allografts, mRNA expression for myeloid markers was increased in isografts and allografts, suggesting activation of resident cells of the macrophage‐dendritic cell series (MMDCs) in response to injury, followed by increased CD68+ cell numbers from day 2. By day 3, an interstitial T‐cell and MMDC infiltrate was established in allografts, corresponding with the emergence of allospecific tissue injury, as reflected by decreased parenchymal transcripts. Thus, in renal allografts, allorecognition by T cells occurs in perivascular sites by day 1, but alloimmune parenchymal damage begins at day 3, coinciding with the emergence of the interstitial T‐cell–MMDC infiltrate. In mouse kidney allografts, CD8 T cell infiltration appears by 24 hours in perivascular tissue, associated with interferon‐γeffects, but rejection (epithelial deterioration) coincides with the appearance of interstitial infiltrate at day 3.