Cyclosporine A (CsA) is a potent immunosuppressive drug that inhibits the transcription of several proinflammatory cytokines including interleukin-2. In contrast, CsA stimulates transcription of the pleuripotent cytokine, transforming growth factor-β (TGFβ). Since the effect of CsA in transplant recipients is unpredictable, we examined whether tissue levels of TGFβ protein in renal allografts correlate with in vivo CsA responsiveness. Intra-allograft TGFβ protein content was assessed in renal biopsies by immunohistochemical means using the mouse anti-TGFβ monoclonal antibody (Mab), 1D11. We studied 68 specimens: 21 with acute CsA toxicity (ACT), 11 with acute tubular necrosis (ATN) and 36 with acute cellular rejection (ACR). Intensity of TGFβ immunostaining was evaluated in a blinded fashion using a scale from 0 to 3+. In biopsies with histological evidence of CsA toxicity, 77% demonstrated intense (2 to 3+) TGFβ immunostaining. TGFβ protein was detected in both proximal and distal tubules but was either absent or present in low levels within glomeruli and interstitium. In contrast, only one of the 11 biopsies with ATN had minimal staining (1+) for TGFβ. The remaining 10 biopsies with ATN were negative for TGFβ immunostaining. In biopsies with ACR, the levels of renal TGFβ were more variable with 36% showing intense (2 to 3+) staining and 64% having minimal or no (0 to 1+) tubular TGFβ. Within the first 18 months post-transplantation, patients with intense TGFβ staining and ACR underwent an average of 4.1 ± 1.8 allograft biopsies and suffered 33% graft losses. During the same period of time, the patients with ACR and absent or low (0 to 1+) TGFβ levels underwent only 2.1 ± 1.2 biopsies, maintained better late renal function and suffered 4% graft losses. In conclusion, we demonstrate that TGFβ protein levels in renal allografts correlate with CsA effect and differentiate ACT from ATN. In CsA treated patients who develop ACR, TGFβ levels predict the subsequent clinical course and graft function. Therefore, evaluating tissue levels of TGFβ may offer unique diagnostic and prognostic benefits in the care of patients receiving CsA based immunosuppression.
Bibliographical noteFunding Information:
review of the manuscript. We are also grateful to Ms. Wendy Waegell and the Celtrix Corporation for providing critical reagents for these experi- ments. Dr. Pankeycz is a recipient of a 1995 American Heart Association Career Development Award.