TGF-β: A Link Between Immunosuppression, Nephrotoxicity, and CsA

Khanna, Ashwani; Cairns, Victor; Becker, Carl G.; Hosenpud, Jeffrey D.

doi:10.1016/s0041-1345(98)00102-x

Cited by 20 publications

(12 citation statements)

References 31 publications

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“…Under our conditions, CsA treatment did not aVect IL-10 gene expression but the expression of TGF-was enhanced, in agreement with studies showing that this cytokine is one of the most potent mediators of the immunosuppressive eVect of CsA [17]. However, TGF-is a polyfunctional molecule involved in several biological processes other than immunosuppression [13,23,33] TGF-is a well-known regulator of tissue Wbrogenesis by stimulating Wbroblast proliferation, promoting collagen synthesis and inhibiting collagen degradation.…”

Section: Discussionsupporting

confidence: 92%

Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model

et al. 2008

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Recent studies indicate that mesenchymal stem cells (MSC) exhibit a degree of immune privilege due to their ability to suppress T cell mediated responses causing tissue rejection; however, the impact of allogeneic MSC in the setting of organ transplantation has been poorly investigated so far. The aim of our study was to evaluate the eVect of intravenous donor MSC infusion for clinical tolerance induction in allogeneic skin graft transplantations in rats. MSC were isolated from Wistar rats and administered in Sprague-Dawley rats receiving Wistar skin graft with or without cyclosporine A (CsA). Graft biopsies were performed at day 10 post transplantation in all experimental groups for histological and gene expression studies. Intravenous infusion with donor MSC in CsA-treated transplanted rats resulted in prolongation of skin allograft survival compared to control animals. Unexpectedly, donor MSC infusion in immunocompetent rats resulted in a faster rejection as compared to control group. Cytokine expression analysis at the site of skin graft showed that CsA treatment signiWcantly decreased pro-inXammatory cytokines IFN-and IL-2 and reduced TNF-gene expression; however, the level of TNF-is high in MSC-treated and not immunosuppressed rats. Results of our study in a rat tissue transplantation model demonstrated a possible immunogenic role for donor (allogeneic) MSC, conWrming the need of adequate preclinical experimentation before clinical use.

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Section: Discussionsupporting

confidence: 92%

Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model

et al. 2008

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“…Although the present results are directed at an understanding of cyclosporine nephrotoxicity, our previous studies 15,[25][26][27][28][29] also demonstrate that TGF-␤ participates in both the immunosuppressive and nephrotoxic effects of tacrolimus and sirolimus. It is not known whether adjunctive therapy with a TGF-␤-neutralizing agent would also reduce the nephrotoxic effects of these 2 immunosuppressants.…”

Section: Discussionmentioning

confidence: 91%

“…Furthermore, by in vitro, in vivo, and clinical studies, we have demonstrated induction of TGF-␤ with other immunosuppressive agents such as tacrolimus and sirolimus. [25][26][27][28][29] Therefore, it is attractive to hypothesize that anti-TGF-␤ antibody may provide similar benefits to counteract adverse nephrotoxic effects observed with long-term use of these drugs as well.…”

Section: Discussionmentioning

confidence: 99%

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

et al. 2004

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Background-Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-␤ (TGF-␤) is one of the most potent mediators of the fibrogenic effects of cyclosporine. Methods and Results-With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-␤ in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-␤ antibody to determine whether anti-TGF-␤ antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-␤, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-␤ protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-␤ protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-␤ antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. Conclusions-These results provide credence to the pivotal role of TGF-␤ in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-␤ antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

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“…We and others have demonstrated that both cyclosporine and tacrolimus induce TGF-␤, which has both potent antiproliferative as well as fibrogenic effects (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The significance of these latter effects on the immunosuppressive properties of these agents is still under active investigation; however, our own studies have suggested that TGF-␤ appears to mimic much of the in vivo effects of cyclosporine in a mouse model (2).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclosporine and tacrolimus, in addition to their effect on inhibiting IL-2, induce the expression of TGF-␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). This effect may be partially responsible for the antiproliferative effects of cyclosporine as well as responsible for the majority of the fibrogenic-related toxic effects of this agent, most importantly the nephrotoxicity.…”

Section: In Vitro and In Vivo Transfection Of P21 Gene Enhancesmentioning

confidence: 99%

In Vitro and In Vivo Transfection of p21 Gene Enhances Cyclosporin A-Mediated Inhibition of Lymphocyte Proliferation

Khanna

Hosenpud

2000

The Journal of Immunology

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Cyclosporine has potent antiproliferative properties, some of which may be via the induction of the cyclin inhibitor p21. In this study, we describe the effects of in vitro and in vivo transfection of p21 in lymphoid and nonlymphoid cells. For in vitro studies, p21 sense plasmid DNA was transfected in A-549 cells (lung adenocarcinoma cell line) and Jurkat cells (human lymphoid cell line). This in vitro transfection of p21 resulted in the inhibition of spontaneous and mitogen-induced cellular proliferation ([3H]thymidine uptake) and also augmented the antiproliferative effects of cyclosporine. In vivo transfection of p21 was accomplished in mice via the i.m. injection of p21 sense plasmid DNA complexed with cationic lipids. As was the case in the cell lines, p21 mRNA was augmented in heart, lung, liver, and spleen 7 days after i.m. injection of p21 sense plasmid DNA. The mitogen (anti-CD3)-induced proliferation of splenocytes from p21-overexpressing mice was significantly decreased, and again this effect was augmented by cotreatment with cyclosporine. These novel findings demonstrate the potential of targeting the cell cycle directly to inhibit alloimmune activation in organ transplantation. This may serve as an alternate strategy to induce immunosuppression, perhaps with less toxicity than that which is seen with conventional immunosuppressive agents.

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TGF-β: A Link Between Immunosuppression, Nephrotoxicity, and CsA

Cited by 20 publications

References 31 publications

Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model

Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

In Vitro and In Vivo Transfection of p21 Gene Enhances Cyclosporin A-Mediated Inhibition of Lymphocyte Proliferation

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