TUBULITIS AFTER RENAL TRANSPLANTATION: DEMONSTRATION OF AN ASSOCIATION BETWEEN CD103+ T CELLS, TRANSFORMING GROWTH FACTOR ??1 EXPRESSION AND REJECTION GRADE 1

Abstract

Tubulitis is a defining feature for the diagnosis and management of acute renal allograft rejection. Lymphocytes extracted from rejecting renal tissue are known to express the αEβ7-integrin (CD103), a receptor for E-cadherin expressed on epithelial cells. In this study, expression of CD103 was examined in situ in tubulitis associated with acute rejection. Immuno-labeling detected CD8+ and CD103+ lymphocytes and E-cadherin on epithelial cells in cryostat sections from 34 diagnostic biopsy specimens and a limited number of transplant nephrectomies. CD8+ and CD103+ intratubular cells were enumerated as mean numbers per tubular cross-section and median values were compared between rejection grades as were median ratios of CD103+ to CD8+ cells. Active transforming growth factor (TGF) β1 was quantified in paraffin sections by immunofluorescence and confocal microscopical analysis. A parallel in vitro study quantified CD103+ T cells after allospecific activation with and without exogenous TGFβ1. CD8+ T cells were present in tubules and tubular interstitium in acute rejection. CD103+ T cells were restricted exclusively to the tubules. The numbers of intratubular CD8+ and CD103+ cells and the ratio of intratubular CD103+ to CD8+ cells increased significantly with tubulitis score (P values 0.005, 0.009, and 0.02, respectively). TGFβ1 expression was widespread in tubules also increasing significantly with tubulitis score (P =0.034). In chronic rejection, CD103+ T cells and TGFβ1 were present within both tubules and interstitial cell populations. The in vitro study demonstrated that addition of TGFβ1 to activated, alloantigen-specific T cells increased the proportion of CD8+ cells that also expressed CD103. These data indicate that specific up-regulation of the αEβ7-integrin by activated, intratubular T cells in acute renal allograft rejection could be a consequence of exposure to high local concentrations of TGFβ1. The capacity of CD103+ T cells to bind E-cadherin on tubular epithelial cells may be an important factor in the pathogenesis of specific tissue damage observed in acute renal allograft rejection.