The Function of T-bet, Innate Immunity and Type-2 Cytokines in Scleroderma

Laurie Glimcher, MD
Harvard University

Project Summary:

Scleroderma is an autoimmune disorder characterized by excessive fibrosis of the skin and internal organs. Certain growth factors, cytokines, are secreted by cells of the immune system and promote inflammation as well as fibrosis. A shift in the T cell cytokine profile towards “profibrotic” cytokines (referred to as Type 2), such as Interleukin-4, Interleukin-13 (IL-13) and Transforming Growth Factor-beta (TGF-beta), and away from the protective Type 1 cytokine, Interferon-alpha, 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, T-bet activates and represses Type 1 and Type 2 cytokines, respectively. Dr. Glimcher and her colleagues have recently found that mice deficient in the transcription factor T-bet develop more severe bleomycin-induced skin fibrosis, a model of the distinctive skin changes of scleroderma. Interestingly, the action of T-bet was mapped to cells in the innate immune system, where T-bet represses IL-13. Dr. Glimcher and her colleagues are translating these findings to a more relevant mouse model of human scleroderma, chronic graft versus host disease. They believe that scleroderma may be prevented or treated by blocking IL-13 or augmenting the activity of T-bet in the immune system.

Research Update:

In collaboration with Dr. Mike Whitfield, Dr. Glimcher was able to assess the relevance of these animal models to the human disease using the gold standard microarrays that Dr. Whitfield has established over many years. In particular, the inflammatory subset of SSc patients that Dr. Whitfield sees is the type of dysregulation (inferred to be the type of disease). Also, work progressed in identifying IL-13 as playing a key role in the onset of scleroderma in the animal models.

Dr. Glimcher is looking to further establish with anti-IL-13 agents the role of this factor. She hypothesizes that blockers to IL-13 may impact fibrosis.

In future studies, the lab will return to its examination of the innate immune system to examine the mechanisms of its interface with SSc.

What this project means for people with scleroderma:

Blocking IL-13 is predicted to ameliorate the pro-fibrotic response in the skin and internal organs of patients with scleroderma.In addition to understanding the role other cytokines may play in naturally opposing or enhancing IL-13 activity, this work should provide targets for antibody or soluble receptor therapies (e.g., Enbrel®, Humira®). There are a broad range of such therapies in clinical trials today.

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