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- Title
Effects of B Cell Depletion by CD19-Targeted Chimeric Antigen Receptor T Cells in a Murine Model of Systemic Sclerosis.
- Authors
Avouac, Jérôme; Cauvet, Anne; Orvain, Cindy; Boulch, Morgane; Tilotta, Françoise; Ly Tu; Thuillet, Raphaël; Ottaviani, Mina; Guignabert, Christophe; Bousso, Philippe; Allanore, Yannick
- Abstract
Objective. Our goal was to study the tolerance and efficacy of two B cell depletion strategies, including one with CD19-targeted chimeric antigen receptor (CAR) T cells, in a preclinical model mimicking the severe lung damages observed in systemic sclerosis. Methods. B cell depletion strategies were evaluated in the Fra-2 transgenic (Tg) mouse model. We considered a first group of 16 untreated mice, a second group of 15 mice receiving a single dose of anti-CD20 monoclonal antibody (mAb), and a third group of 8 mice receiving CD19-targeted CAR-T cells in combination with anti-CD20 monoclonal antibody. After six weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis, and pulmonary vascular remodeling were assessed. Results. CD19-targeted CAR-T cells infusion in combination with anti-CD20 mAb resulted in a deeper B cell depletion than anti-CD20 mAb alone in the peripheral blood and lesional lungs of Fra-2 Tg mice. CAR-T cell infusion worsened the clinical score and increased mortality in Fra-2 Tg mice. In line with the above findings, CAR-T cell infusion significantly increased lung collagen content, the histological fibrosis score, and right ventricular systolic pressure. CAR-T cells accumulated in lesional lungs and promoted T activation and inflammatory cytokine production. Treatment with anti-CD20 mAb in monotherapy had no impact on lung inflammation–driven fibrosis and pulmonary hypertension. Conclusion. B cell therapies failed to show efficacy in the Fra2 Tg mice. The exacerbated Fra-2 lung inflammatory burden stimulated accumulation and expansion of activated CD19-targeted CAR-T cells, secondarily inducing T cell activation and systemic inflammation, finally leading to disease worsening.
- Subjects
INFLAMMATION prevention; ANIMAL experimentation; SYSTEMIC scleroderma; CELL receptors; MONOCLONAL antibodies; TREATMENT effectiveness; T cells; PULMONARY fibrosis; ANTIGENS; MICE; VASCULAR remodeling
- Publication
Arthritis & Rheumatology, 2024, Vol 76, Issue 2, p268
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.42677