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

Abstract

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-c )-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.

Derivation and Validation of a Cytokine-Based Assay to Screen for Acute Rejection in Renal Transplant Recipients

“…Acute allograft rejection is a T-or B-cell-mediated process associated with a stereotyped, inflammatory response involving cells of the adaptive and innate immune systems (23)(24)(25). Experiments in animal models showed that although acute rejection is initiated by T cells, the damage to the allograft parenchyma appears concurrent with monocyte recruitment and massive inflammation (26). Because monocytes are known to secrete inflammatory cytokines, notably IL-1b, IL-6, and TNF-a, in renal transplant recipients (8), it follows that the inflammatory process occurring during an acute rejection episode would translate into measurable changes in the peripheral blood.…”

A molecular classifier for predicting future graft loss in late kidney transplant biopsies

“…They serve as an annotation tool, with which genes identified in our analysis can be assigned to biological processes relevant to transplantation. PBTs were derived previously from mouse transplant models and in vitro human cell lines (15,29,30,(34)(35)(36)(37)(38)(39)(40). The definitions and algorithms for the PBTs referenced in the tables can be found in Supplemental Table 2.…”

Relationships among injury, fibrosis, and time in human kidney transplants

“…IL1B, TNF, and OSM are the part of the inflammasome in macrophages and contribute to the response to wounding (53,62). It may be significant that OSMR, ITGB6, and MIR21 are among the top TxBx-corrected transcripts.…”