title: Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.
abstract: The common γ 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 tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas 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 Janus kinase 3 (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 γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Hechinger
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Benjamin A H
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hanke
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Cameron
authors.initials: C
authors.lastname: McDonald-Hyman
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Björn
authors.initials: B
authors.lastname: Hackanson
authors.affiliation: 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, Göttingen, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Leonhardt
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Prinz
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Heide
authors.initials: H
authors.lastname: Dierbach
authors.affiliation: Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; and.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kovarik
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000037:antagonists & inhibitors*; D053616:Janus Kinase 3 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D053631:Interleukin Receptor Common gamma Subunit; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3