Allogeneic cord blood regulatory T cells can resolve lung inflammation |
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| Institution: | 1. Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA;2. Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA;3. Cellenkos Inc, Houston, Texas, USA;4. Division of Hematology/Oncology, Department of Medicine, New York–Presbyterian Hospital, Columbia University Irving Medical Center, New York, New York, USA;5. Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, University of Toronto, Toronto, Canada;1. Departments of Obstetrics & Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Center of Growth, Metabolism and Aging, College of Life Sciences, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, Sichuan, China;2. Department of Forensic Genetics, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China;3. Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, Sichuan, China;4. Division of Immunology, Sichuan Cunde Therapeutics, Chengdu 610093, Sichuan, China;1. Gastroenterology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Policlinico G.B. Rossi and University of Verona, Verona, Italy;2. Division of Surgery and Cell Therapy Unit, Institute for Health Research, Jiménez Díaz Foundation University Hospital, Madrid, Spain;3. Laboratory of Advanced Cellular Therapies, Hematology Unit, Vicenza Hospital, Vicenza, Italy;1. College of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China;2. Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China;1. Pediatrics, University of California, San Francisco, San Francisco, California, USA;2. Crispr Therapeutics AG, Boston, Massachusetts, USA;3. ISCT Immune-Gene Therapy Committee, ISCT, Vancouver, California, USA |
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| Abstract: | Background aimsCD4+CD25+CD127lo regulatory T cells (Tregs) are responsible for maintaining immune homeostasis. Tregs can be rendered defective and deficient as a result of the immune imbalance seen in lung injury, and such dysfunction can play a major role in continued tissue inflammation. The authors hypothesized that adoptive therapy with healthy allogeneic umbilical cord blood (UCB)-derived Tregs may be able to resolve inflammation.ResultsEx vivo-expanded UCB Tregs exhibited a unique phenotype with co-expression of CD45RA+CD45RO+ >80% and lung homing markers, including CD49d. UCB Tregs did not turn pathogenic when exposed to IL-6. Co-culture with increasing doses of dexamethasone led to a synergistic increase in UCB Treg-induced apoptosis of conventional T cells (Tcons), which translated into significantly higher suppression of proliferating Tcons, especially at a lower Treg:Tcon ratio. Multiple injections of UCB Tregs led to their preferential accumulation in lung tissue in an immune injury xenogenic model. A significant decrease in lung resident cytotoxic CD8+ T cells (P = 0.0218) correlated with a sustained decrease in their systemic distribution compared with controls (P < 0.0001) (n = 7 per arm) as well as a decrease in circulating human soluble CD40 ligand level (P = 0.031). Tissue architecture was preserved in the treatment arm, and a significant decrease in CD3+ and CD8+ burden was evident in immunohistochemistry analysis.ConclusionsUCB Treg adoptive therapy is a promising therapeutic strategy for treatment of lung injury. |
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