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Published on: February 17, 2022
Targeting ECM-producing cells with CAR-T therapy alleviates fibrosis in chronic kidney disease
Songbo Zhao1, Rongkun Li1, Yuan Xia2
1Department of Pharmacology, The Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
Abstract:
Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, clinical interventions and therapies targeting kidney fibrosis remain conceptual and practical challenges due to the complex origin, functional heterogeneity, and regulation of scar-forming cells. Here, we define fibroblasts, pericytes, and myofibroblasts as the major extracellular matrix (ECM)-producing cells in the kidney, highlighting their primary contribution to kidney fibrosis. We then identify platelet-derived growth factor receptor β (PDGFRβ) as a potential targeting surface antigen for anti-fibrotic chimeric antigen receptor (CAR)-T against CKD. In multiple mouse CKD models, both adoptive transfer and CD5-lipid nanoparticle (LNP)-mediated in vivo generation of PDGFRβ CAR-T cells significantly ameliorate fibrosis-associated pathologies, including kidney, myocardial interstitial, and perivascular fibrosis without notable toxicity, evoking an integrated therapeutic strategy for multi-organ fibrosis in mice with CKD and its cardiovascular complications. The anti-fibrotic effects are also demonstrated in the human kidney organoid CKD, further strongly supporting the therapeutic potential for the treatment of patients with CKD.
Insights
Targeting platelet-derived growth factor receptor β (PDGFRβ) with chimeric antigen receptor (CAR)-T cells shows promise for treating kidney fibrosis in chronic kidney disease (CKD). This approach effectively reduces fibrosis in mouse models and human kidney organoids.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Kidney fibrosis is a key feature of chronic kidney disease (CKD), presenting significant therapeutic challenges due to complex cellular origins.
- Fibroblasts, pericytes, and myofibroblasts are identified as major extracellular matrix-producing cells driving kidney fibrosis.
Purpose of the Study:
- To identify a viable therapeutic target for kidney fibrosis.
- To evaluate the efficacy of platelet-derived growth factor receptor β (PDGFRβ)-targeted chimeric antigen receptor (CAR)-T cells in preclinical models of CKD.
Main Methods:
- Identification of PDGFRβ as a surface antigen on kidney scar-forming cells.
- Generation and adoptive transfer of PDGFRβ CAR-T cells in mouse models of CKD.
- Assessment of anti-fibrotic effects in vivo and in human kidney organoids.
Main Results:
- PDGFRβ CAR-T cell therapy significantly ameliorated kidney fibrosis and associated pathologies in multiple mouse CKD models.
- Therapy demonstrated efficacy against myocardial interstitial and perivascular fibrosis without significant toxicity.
- Anti-fibrotic effects were confirmed in human kidney organoid models of CKD.
Conclusions:
- PDGFRβ is a promising therapeutic target for treating kidney fibrosis in CKD.
- PDGFRβ CAR-T cell therapy offers a potential strategy for managing CKD and its cardiovascular complications.
- This approach holds therapeutic potential for patients with chronic kidney disease.
