Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY / ABSTRACT Clinical and preclinical studies indicate that autoimmunity and chronic inflammation, resulting from abnormalities in regulatory T cells (Tregs), contribute to the development and progression of pulmonary arterial hypertension (PAH). Treg dysfunction affects males and females differently and may arise because of pathogenic gene variants and an inflamed tissue microenvironment. Treg infusion, as a cell-based therapy, restores immune regulation, reduces vascular inflammation, and prevents animals from developing PAH. In a novel transgenic rat model of hereditary PAH, monoallelic mutations in bone morphogenetic protein receptor 2 (Bmpr2) and lung inflammation elicit severe disease. In these Bmpr2 mutant animals, as well as the athymic rat model of disease, the predisposition to PAH may relate to abnormal Treg development and function. Infusion of genetically- corrected (Bmpr2 wildtype) Tregs into Bmpr2 mutant animals, or injection of Tregs into athymic rats, restores immune regulation, prevents vascular remodeling and ameliorates PAH. A number of Treg-infusion clinical trials are being tested for autoimmune and inflammatory conditions and have shown early promise. Given the future potential of Treg therapy in treating human PAH, this proposal tests the hypothesis that genetic and environmental cues trigger Treg abnormalities that exacerbate PAH and that restoration of Treg function may be sufficient to reverse severe disease. This proposal investigates how genetic (BMPR2 mutations) and environmental (pulmonary inflammation) risk factors contribute to Treg derangements and a predisposition to PAH, and how Treg infusion can limit vascular injury and reverse PAH. Proposed studies address a previously undocumented role of BMPR2 signaling in adaptive immune cells (i.e., Tregs). Specific Aim 1 evaluates the mechanisms by which Treg immunity in PAH is affected by Bmpr2 mutations, chronic lung inflammation and sex-related factors. Specific Aim 1 has two subaims which study thymic Treg development (Aim 1a) and pulmonary Treg phenotype and function (Aim 1b) in PAH. By understanding how Treg infusion quells lung inflammation and prevents vascular injury, Specific Aim 2 develops protocols to use ex vivo-expanded Tregs to treat established PAH. Specific Aim 2 has three subaims which first proposes to label and track infused Tregs after adoptive transfer (Aim 2a), then to assess Treg protective effects on pulmonary arterial vascular cells (Aim 2b), and, finally, to test the efficacy of various Treg infusion strategies in reversing advanced PAH (Aim 2c).These studies help unify the concepts of genetic vulnerability and immune dysregulation as related risk factors predisposing to PAH, which may offer clear directions for future therapeutic avenues, most especially Treg immunotherapy.
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