Hechinger, AK, Smith, BA, Flynn, R, Hanke, K, McDonald-Hyman, C, Taylor, PA, Pfeifer, D, Hackanson, B, Leonhardt, F, Prinz, G, Dierbach, H, Schmitt-Graeff, A, Kovarik, J, Blazar, BR and Zeiser, R (2014) Therapeutic activity of multiple common gamma chain cytokine inhibition in acute and chronic GvHD. Blood.

Abstract

The common gamma chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GvHD), we reasoned that inhibition of CD132 could have a profound effect on GvHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GvHD potently with respect to survival, production of TNF, IFN-gamma and IL-6, and GvHD histopathology. Anti-CD132 mAb afforded protection from GvHD partly via inhibition of granzyme B production in CD8 T cells, while exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray based analyses and showed reduced JAK3 phosphorylation upon activation. Consistent with a role of JAK3 in GvHD, Jak3-/- T cells caused less severe GvHD. Additionally, anti-CD132 mAb treatment of established chronic GvHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GvHD and chronic GvHD, caused by T cells activated by common gamma chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation

Item Type:	Article
Additional Information:	NIBR author: Kovarik, J institute: NIBR contributor address: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, United States;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, United States;Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, United States;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research Goettingen, Germany;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;Novartis Institutes for Biomedical Research, Basel, SwitzerlandDepartment of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, United States;Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; robert.zeiser@uniklinik-freiburg.de
Date Deposited:	13 Oct 2015 13:11
Last Modified:	13 Oct 2015 13:11
URI:	https://oak.novartis.com/id/eprint/24260