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Blocking common gamma chain cytokine signaling ameliorates T-cell-mediated pathogenesis in disease models

ABSTRACT: The common γ chain (γc; IL2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL2, IL4, IL7, IL9, IL15, and IL21. Because of the lack of appropriate neutralizing antibodies recognizing IL2RG, it has been difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. To determine whether γc cytokines might be targeted for T-cell-mediated disease prevention and treatment, we generated a new γc cytokine receptor antibody, REGN7257. Biochemical, structural and in vitro analysis showed that REGN7257 binds with high affinity to IL2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T-cells without impacting granulocytes, platelets or red blood cells. Using REGN7257, we showed that γc cytokines drive T-cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis, by impacting multiple aspects of the pathogenic response. Importantly, we discovered that our xenogeneic GVHD mouse model recapitulates hallmarks of both acute and chronic GVHD, with T-cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. And we showed that γc cytokines contribute to disease pathology by driving all of these features. Overall, by demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T-cell responses, offering a potentially novel strategy for the management of T-cell-mediated diseases.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE214625 | GEO | 2022/10/04

REPOSITORIES: GEO

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Project description:During inflammatory diseases, infiltrating immune cells can induce endothelial activation and angiogenesis by cytokines and other mediators. The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, there is limited evidence on initial mechanisms of both processes. We show in experimental models that angiogenesis precedes leukocyte infiltration during graft-versus-host disease (GVHD). GVHD, a systemic inflammatory disease caused by host-reactive T cells primarily attacking the epithelial cells of the GVHD target organs liver, skin and intestines, leads to substantial morbidity and mortality after allogeneic hematopoetic stem cell transplantation. A key feature of GVHD is the incompletely understood organ tropism to skin, liver and the intestines. We demonstrate that angiogenesis initiates GVHD in target organs whereas in non-target organs no angiogenesis and no subsequent inflammation occurred. To shed light into the initiation phase of angiogenesis we looked at classical endothelial cell activation signs, such as upregulation of the Vegfa/VEGFR1+2 pathway or adhesion molecules, but could not find an association. However, endothelial cells in early GVHD showed profoundly higher deformation in real-time deformability cytometry suggesting enhanced migratory and proliferating potential of endothelial cells during the initiation of angiogenesis in GVHD target organs. We used microarrays to detect alternative pathways in endothelial cells of the GVHD target organ colon that could be responisble for initial angiogenesis in GVHD. We identified several up-and down-regulated genes during this process. Strikingly, we found several cytoskeleton as well as metabolic-associated and related gene alterations which may explain the enhanced migration and proliferation of endothelial cells in initiating GVHD. Our study adds evidence to the hypothesis that angiogenesis can initiate inflammation and provides novel insight in pathophysiology and tropism of GVHD.

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Blocking common gamma chain cytokine signaling ameliorates T-cell-mediated pathogenesis in disease models

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