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Intragraft expression of IL-10 messenger RNA: A novel correlate of renal allograft rejection. A major conceptual advance is the formulation that type I cytokines (such as IL-2 and IFN-γ) enhance cellular immunity and are host-protective, and that type II cytokines (such as IL-4 and IL-10) dampen cellular immunity and facilitate the progression of infection. We have explored the intragraft expression of type I and type II cytokines during human renal allograft rejection. RNA was isolated from 98 allograft biopsies, and reverse transcription-PCR was used to amplify and identify intragraft expression of mRNA encoding IL-2, IFN-γ, IL-4, or IL-10. Intragraft expression of IL-7 mRNA and TGF-β1 mRNA was also investigated. Our investigation demonstrated that: (a) intragraft expression of IL-10 mRNA and IL-2 mRNA are significant correlates of acute rejection; (b) IL-4, IL-7, IFN-γ and TGF-β1 mRNA expression do not correlate with acute rejection; and (c) IL-10 does not prevent in vivo expression of IFN-γ, IL-2, IL-7, or TGF-βl. Our studies identify, for the first time, a significant association between intragraft IL-10 mRNA expression and acute rejection, and suggest that treatment strategies capable of constraining IL-10 expression might be of value in the prevention of acute rejection.

Intragraft TGF-β 1 mRNA: A correlate of interstitial fibrosis and chronic allograft nephropathy . 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- β 1 in tissue repair and in fibrosis, we have explored the hypothesis that fibrosis and chronic allograft nephropathy would be distinguished by intragraft TGF- β 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 intra graft TGF- β 1 mRNA display and renal allograft interstitial fibrosis and chronic allograft nephropathy. In contrast, intragraft expression of mRNA encoding immunoregulatory cytokines, IL-2, IFN- γ , 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- β 1 mRNA expression and renal allograft interstitial fibrosis, and advance a candidate molecular mechanism for chronic allograft nephropathy.