Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.
نویسندگان
چکیده
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.
منابع مشابه
Therapeutic activity of multiple common gamma chain cytokine inhibition in acute and chronic GvHD Running title: CD132 INHIBITION REDUCES GVHD
• Monoclonal antibody blockade of the common gamma chain attenuates acute and chronic GvHD. • Common gamma chain cytokines increase granzyme B levels in CD8 T cells, which is reduced upon CD132 blockade in vivo. 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 sh...
متن کاملTherapeutic activity of multiple common g-chain cytokine inhibition in acute and chronic GVHD
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, Minneapolis, MN; Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany; Department of Pathology, Freibu...
متن کاملKinetics of T Helper Subsets and Associated Cytokines Correlate Well with the Clinical Activity of Graft-Versus-Host Disease
BACKGROUND CD4(+)interferon (IFN)-γ(+) T cell (Th1) and CD4(+)interleukin (IL)-4(+) T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real w...
متن کاملReduced IFN-γ Production in Chronic Brucellosis Patients
Background: Brucella is a well-known intracellular bacterium entailing acute and chronic illnesses in humans and domestic animals. The infection chronicity may be affected by the cell-mediated immunity and cytokine patterns. Objective: To evaluate the patterns of T-helper cytokines in patients suffering from chronic and acute brucellosis. Methods: In this cross-sectional study, 22 individuals w...
متن کاملکاهش تولید IFN-γ همراه با افزایش تولید IL-12 در بیماران مبتلا به بروسلوز مزمن
Background and purpose:Brucellosis is a disease with zoonotic and transmissible world wide distribution which, often becomes chronic with high rate of recurrence. Since the immune responses during brucellosis have not been studied profoundly, therefore in this study cytokine production in the patients suffering from brucellosis and in healthy individuals has been evaluated. Materials and met...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Blood
دوره 125 3 شماره
صفحات -
تاریخ انتشار 2015