The Function of the IL4 Receptor Axis and the Chemokine CCL2 in Both Mouse and "Humanized" Mouse Models of Scleroderma

Laurie Glimcher, MD
Harvard University

Antonios Aliprantis, MD, PhD
Harvard University

Project Summary:

Scleroderma is an autoimmune disorder characterized by excessive fibrosis (hardening) of the skin and internal organs. Certain growth factors and cytokines (regulatory proteins) are secreted by cells of the immune system and promote inflammation as well as fibrosis. A shift in the cytokine profile towards "profibrotic" cytokines (referred to as Type 2), such as Interleukin-4, Interleukin-13 (IL13) and transforming growth factor-beta (TGF-beta), and away from the protective Type 1 cytokine, Interferon-gamma, has been documented in patients with scleroderma and in mouse models of this disease. Transcription factors shape immune responses by regulating the expression of cytokines. For example, the T-bet transcription factor activates and represses Type 1 and Type 2 cytokines, respectively. Drs. Glimcher and Aliprantis found that mice deficient in T-bet develop more severe bleomycin-induced skin fibrosis, a model of the skin changes of scleroderma. Interestingly, the action of T-bet was mapped to cells in the innate immune system, an evolutionarily ancient host defense arm, where T-bet represses IL13. These findings were published in 2008 in the Proceedings of the National Academy of Sciences.

Recently, the Glimcher-Aliprantis lab established a different mouse model of scleroderma called sclerodermatous chronic graft versus host disease (sclGVHD). This model is an outgrowth of the observation that some patients who have undergone bone marrow transplantation develop a scleroderma-like illness called chronic GVHD.  In a manuscript provisionally accepted in the American Journal of Pathology,written in close collaboration with fellow SRF investigator Michael Whitfield, SRF-funded investigators at Harvard report that sclGVHD approximates an inflammatory subset of scleroderma estimated to represent 17-36% of patients with diffuse, 28% of limited and all localized scleroderma patients.  The lab also reports that both sclGVHD and thisinflammatoryscleroderma subset demonstrate IL13 cytokine pathway activation. Interestingly, genetic deficiency for either IL13 or IL4Rα, an IL13 signal transducer, protects the host from sclGVHD. To define new therapeutic targets, investigators explored the intersection of genes coordinately upregulated in sclGVHD, the human inflammatory subset and IL13 treated fibroblasts and identified chemokine CCL2. Accordingly, treatment with CCL2 antibodies prevents sclGVHD. Lastly, results show that IL13 pathway activation in scleroderma patients correlates with clinical skin scores, a marker of disease severity. The lab concludes that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade. These results highlight their approach to scleroderma research, which is to test hypotheses in validated animal models and to return at the first opportunity to patient derived samples to confirm the relevance of the lab's findings.

Their current efforts are aimed at defining the innate immune cell in sclGVHD and inflammatory scleroderma patients that makes IL13 and testing whether the cytokine IL33 is an upstream activator of this cell. IL33 is expressed in cell nuclei and released from cells after stress events culminating in necrosis, leading to the suggestion that IL33 is an "alarmin" (a molecular danger signal). IL33 expression has been demonstrated in endothelial and epithelial cells as well as fibroblasts and smooth muscle cells. Conspicuously, these are the same cells whose cellular physiology is dysregulated in scleroderma. Importantly, IL33 is a potent inducer of IL13 expression and IL13-dependent fibrosis in animal models.  Furthermore, expression of IL33 and its receptors are increased in scleroderma skin and serum, as well as in the skin of sclGVHD.  The Glimcher-Aliprantis lab speculates that cellular insults arising from either immune cell activation, inflammation, hypoxia related to vasospasm or environmental toxins could result in necrosis and the release of IL33, initiating an IL13-mediated fibrotic response. Given the success of cellular and anti-cytokine therapies in other rheumatic diseases, such as inflammatory arthritis and vasculitis, they are hopeful that their findings will translate to new treatments for scleroderma patients. To facilitate this, the investigators are validating a humanized version of sclGVHD, which develops in a subset of mice that undergo engraftment of a human immune system. This model may provide a pre-clinical platform to test therapeutics that target human cells and cytokines.

What this project means for people with scleroderma:

Blocking IL33, IL13 or CCL2, or deleting the cells that make these cytokines, may ameliorate the pro-fibrotic response in the skin and internal organs of patients with scleroderma. In addition to understanding the role that cytokines and chemokines may play in naturally opposing or enhancing IL13, IL33 or CCL2 activity, this work should provide targets for antibody or soluble receptor therapies. Encouragingly, a broad range of such therapies has been successfully used to treat numerous rheumatologic diseases to date.

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