Although IL-13 clearly plays an important role in the schistosomiasis model, it remains unclear to what extent targeting this pathway might be useful in the treatment of other fibroproliferative diseases. Therefore, we have begun to investigate the role of Th2-type cytokines in other models of fibrosis to determine whether there are common as well as distinct mechanisms of fibrosis in various organ systems and/or diseases. The models that were set up in the lab over the past few years include a mouse model of chronic asthma, which is being used to investigate the mechanisms pulmonary remodeling in response to chronic allergen challenge, and the bleomycin models of lung and skin fibrosis. Projects completed: Dysfunctional regulatory T cells have been identified in allergic individuals and in glucocorticoid-resistant patients, implying that this defect contributes to the development of atopy and Th2-driven allergic disorders. Successful immunotherapy and treatment of allergic individuals often correlates with an increase in Tregs, supporting the notion that Tregs are central regulators of allergic reactivity and Th2 responses more generally. Several studies in mice have illustrated a significant role for regulatory T cells in restraining pulmonary inflammation and preventing immune-mediated pathology, such as fibrosis, following exposure to aeroallergens. Recent studies demonstrated that while IL-2 is not required for thymic Treg development, it is essential for optimal extra thymic Treg homeostasis. These studies tied together observations made in IL-2/ mice and endogenous Treg deficient (Foxp3/) mice, both of which rapidly succumb to hyper-proliferative autoimmune disorders. Although IL-2 was previously considered to function as a pan-T cell growth factor, new roles are emerging, with IL-2 possibly playing a more critical role in tolerance via the maintenance/induction of regulatory T cell populations. Using several airway allergy systems, we examined whether IL-2 in complex with anti-IL-2 mAb could boost CD4+ Treg frequencies, with the aim of suppressing allergen-induced airway inflammation through Treg expansion. This study built upon recent advances in Treg immunobiology and the regulation of allergic airway inflammation and described a novel strategy whereby IL-2:anti-IL-2 complexes are used to expand endogenous IL-10-secreting Tregs that can control Th2-mediated airway pathologies such as allergic asthma and pulmonary fibrosis.
| Gieseck 3rd, Richard L; Wilson, Mark S; Wynn, Thomas A (2018) Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 18:62-76 |
| Vannella, Kevin M; Wynn, Thomas A (2017) Mechanisms of Organ Injury and Repair by Macrophages. Annu Rev Physiol 79:593-617 |
| Singh, Brijendra; Kasam, Rajesh K; Sontake, Vishwaraj et al. (2017) Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L796-L806 |
| Eming, Sabine A; Wynn, Thomas A; Martin, Paul (2017) Inflammation and metabolism in tissue repair and regeneration. Science 356:1026-1030 |
| Hart, Kevin M; Choy, David F; Bradding, Peter et al. (2017) Accurately measuring and modeling Th2 and Th17 endotypes in severe asthma. Ann Transl Med 5:91 |
| Citrin, Deborah E; Prasanna, Pataje G S; Walker, Amanda J et al. (2017) Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res 188:1-20 |
| Hart, Kevin M; Fabre, Thomas; Sciurba, Joshua C et al. (2017) Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-?. Sci Transl Med 9: |
| Sun, Rex; Urban Jr, Joseph F; Notari, Luigi et al. (2016) Interleukin-13 Receptor ?1-Dependent Responses in the Intestine Are Critical to Parasite Clearance. Infect Immun 84:1032-1044 |
| Vannella, Kevin M; Ramalingam, Thirumalai R; Borthwick, Lee A et al. (2016) Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 8:337ra65 |
| Ramalingam, Thirumalai R; Gieseck, Richard L; Acciani, Thomas H et al. (2016) Enhanced protection from fibrosis and inflammation in the combined absence of IL-13 and IFN-?. J Pathol 239:344-54 |
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