Using chimeric antigen receptor (CAR) T Cells to autoimmune systemic sclerosis (SSc) 4232

Description Macrophages (MØs) are implicated in the pathogenesis of systemic sclerosis (SSc), an inflammatory and fibrotic autoimmune disease. Our prior work has shown that MØs from SSc patients secrete elevated levels of TGF-b and CCL2, have high surface CD206, and induce SSc fibroblast activation. Thus, we hypothesized that targeting SSc MØs for elimination would result in decreased fibrosis. To test this, we designed a novel therapeutic approach using chimeric antigen receptor (CAR) T cells. To determine how targeted elimination of CD206high MØs alters dermal fibrosis, we used the bleomycin (BLM) mouse model. C57BL/6 mice were injected subcutaneously daily with BLM for 21 days. MØ-targeting anti-CD206 CAR T cells, control CAR T cells or vehicle were injected intradermally at Day 0 (n = 6 mice/treatment group). Animals were euthanized at day 21 and skin was processed for histology and stained by H&E. RNA was extracted and analyzed by qRT-PCR and microarray, and dermal thickness was measured using Image J (10 measurements/mouse). Local administration of anti-CD206 CAR T cells led to significant reductions in dermal thickness and inhibition of type I interferon, IL-6/STAT3, and TNF/NFkB signaling pathways, which are associated with disease progression. Our results provide proof-of-concept to support therapeutic targeting of pro-fibrotic MØs in SSc patients. Ongoing studies are focused on determining the effect of systemic anti-CD206 CAR T cell treatment on dermal and lung fibrosis.