Intragraft TGF-β1 mRNA: A correlate of interstitial fibrosis and chronic allograft nephropathy

Abstract

Chronic allograft nephropathy is a relentlessly progressive process and a major cause of long-term graft dysfunction and ultimate failure. Interstitial fibrosis, tubular atrophy, and glomerular and vascular lesions characterize this mechanistically unresolved disorder. Given the prominent role of TGF-beta 1 in tissue repair and in fibrosis, we have explored the hypothesis that fibrosis and chronic allograft nephropathy would be distinguished by intragraft TGF-beta 1 mRNA expression. This postulate was tested by mRNA phenotyping of RNA isolated from 127 human renal allograft biopsies. Reverse transcription assisted polymerase chain reaction was used to amplify and identify ingraft gene expression. Our investigation demonstrated a significant correlation between intragraft TGF-beta 1 mRNA display and renal allograft interstitial fibrosis and chronic allograft nephropathy. In contrast, intragraft expression of mRNA encoding immunoregulatory cytokines, IL-2, IFN-gamma, IL-4, IL-10, or cytotoxic attack molecules, granzyme B and perforin was not a correlate of interstitial fibrosis or chronic allograft nephropathy. Our studies identify, for the first time, a significant association between intragraft TGF-beta 1 mRNA expression and renal allograft interstitial fibrosis, and advance a candidate molecular mechanism for chronic allograft nephropathy.

Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection.

“…In this report, we show that early blockade of CD28-B7 T-cell costimulation disrupts considerably later increases in intragraft gene transcript levels associated with T-cell (IL-2, IFN-,y, and IL-2 receptor) and macrophage (TNF-a and IL-6) activation, chemoattractants (MCP-1), and the fibrogenic growth factor TGF-,3; all gene products upregulated in allografts undergoing chronic rejection (15,(21)(22)(23). TGF-,B expression, in particular, has been recently demonstrated to correlate with existence of interstitial fibrosis and chronic dysfunction of human renal allografts (24,25). Our findings provide clear support for the hypothesis that T-cell recognition of alloantigen and activation are critical early events in the complex cellular and molecular processes leading to development of chronic rejection late after transplantation.…”

Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients

“…The final result is intimal thickening, flow obstruction, and tissue ischemia (23). CNI have the potential to initiate and sustain vascular injury and tissue ischemia, by an array of acute and chronic effects ranging from vasoconstriction to activation of endothelial cells, resulting in a significant increase in growth factors and cytokine synthesis and release, inhibition of endothelial nitric production, extracellular matrix accumulation, cell migration, and proliferation (24,25). The striking increase of ␣-SMA-positive cells in the vessel walls of renal biopsies of CNI-treated patients confirms the ability of this class of drugs to induce a significant increase in the proliferation rate of vascular SMC.…”

Current concepts in radiation enteritis and implications for future clinical trials

“…Biopsies of grafts from patients who underwent renal transplantation showed increased TGF-␤ mRNA levels in patients with CAN compared with patients without CAN. 100 Intra-allograft TGF-␤ protein levels were correlated with the degree of graft dysfunction. Patients who exhibited high levels of TGF-␤ experienced a rapid decline in renal function compared with patients who had minimally elevated TGF-␤ levels.…”

“…Ramos et al 69 Human IPF ELISA, RT-PCR Increased Ziesche et al 70 Human IPF ELISA, RT-PCR Increased, inhibited by IFN-␥ Gauldie et al 72 Rat EPF IH, CGT Increased Querfeld et al 74 Human SS IH, ISH Increased Ihn et al 75 Human SS ELISA, IB Increased, inhibited by TGF-␤ Ab Oh et al 83 Rat DN NB, MLEC Increased, inhibited by TGF-␤ Ab Hong et al 86 Mouse DN IH, ISH, SH Increased Sharma et al 87 Human DN ELISA Increased, inhibited by, captopril Helmich et al 88 Human DN SEI Increased Mezzano et al 90 Human MN IH, ISH Increased Honkanen et al 91 Human MN EIA Increased Diamond et al 92 Rat ON NB, IL Increased Isaka et al 96 Rat ON IH, NB, ISH, AODN transfer Increased, inhibited by TGF-␤ AODN Kaneto et al 97 Human ON IH, RT-PCR Increased Sharma et al 100 Human CAN RT-PCR Increased Cuhaci et al 101 Human CAN IH Increased Qi et al 104 Rat LC NB, AdCAT␤-TR transfection Inhibited by AdCAT␤-TR transfection Ueno et al 105 Rat LC IF, ELISA, AdT␤-ExR Inhibited by AdT␤-ExR injection Zhang et al 106 Rat LC ELISA Increased, inhibited by IFN-␥ gene transfer Bacr et al 107 Human LC NB, IH Increased …”