Blockade of tumor necrosis factor superfamily members CD30 and OX40 abrogates disease activity in murine immune-mediated glomerulonephritis.

Autor:	Artinger K; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Kirsch AH; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Mooslechner AA; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Cooper DJ; Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham, UK; Division of Global and Tropical Health, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia., Aringer I; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Schuller M; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Schabhüttl C; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Klötzer KA; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Schweighofer K; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Eller P; Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Yagita H; Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan., Illert AL; Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Rosenkranz AR; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Lane PJ; Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham, UK., Eller K; Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address: kathrin.eller@medunigraz.at.
Jazyk:	angličtina
Zdroj:	Kidney international [Kidney Int] 2021 Aug; Vol. 100 (2), pp. 336-348. Date of Electronic Publication: 2021 Mar 27.
DOI:	10.1016/j.kint.2021.02.039
Abstrakt:	Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitro stimulation and proliferation studies were performed with CD4 + cells from wild type and CD30/OX40 double knock-out (CD30OX40 -/- ) mice. In vivo studies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40 - /- , CD30 -/- , OX40 -/- , reconstituted Rag1 -/- and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40 -/- mice, but not CD30 -/- or OX40 -/- mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1 -/- mice injected with CD4 + T cells from CD30OX40 -/- mice compared to Rag1 -/- mice injected with CD4 + T cells from wild type mice. Furthermore, CD4 + T cells deficient in CD30OX40 -/- displayed decreased expression of CCR6 in vivo. CD30OX40 -/- cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivo and in vitro compared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease. (Copyright © 2021 International Society of Nephrology. All rights reserved.)
Databáze:	MEDLINE
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