PMID- 33717161 OWN - NLM STAT- MEDLINE DCOM- 20210920 LR - 20210920 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice. PG - 630204 LID - 10.3389/fimmu.2021.630204 [doi] LID - 630204 AB - Regulatory T (T(reg)) cells are essential to maintain immune homeostasis in the intestine and T(reg) cell dysfunction is associated with several inflammatory and autoimmune disorders including inflammatory bowel disease (IBD). Efforts using low-dose (LD) interleukin-2 (IL-2) to expand autologous T(reg) cells show therapeutic efficacy for several inflammatory conditions. Whether LD IL-2 is an effective strategy for treating patients with IBD is unknown. Recently, we demonstrated that LD IL-2 was protective against experimental colitis in immune humanized mice in which human CD4(+) T cells were restricted to human leukocyte antigen (HLA). Whether HLA restriction is required for human T(reg) cells to ameliorate colitis following LD IL-2 therapy has not been demonstrated. Here, we show that treatment with LD IL-2 reduced 2,4,6-trinitrobenzensulfonic acid (TNBS) colitis severity in NOD.Prkdc(scid)Il2rg(-/-) (NSG) mice reconstituted with human CD34(+) hematopoietic stem cells. These data demonstrate the utility of standard immune humanized NSG mice as a pre-clinical model system to evaluate therapeutics targeting human T(reg) cells to treat IBD. CI - Copyright (c) 2021 Tyagi, Jacobse, Li, Allaman, Otipoby, Sampson, Wilson and Goettel. FAU - Tyagi, Rajeev K AU - Tyagi RK AD - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. FAU - Jacobse, Justin AU - Jacobse J AD - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands. FAU - Li, Jing AU - Li J AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States. FAU - Allaman, Margret M AU - Allaman MM AD - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. FAU - Otipoby, Kevin L AU - Otipoby KL AD - Pandion Therapeutics, Immunology Department, Watertown, MA, United States. FAU - Sampson, Erik R AU - Sampson ER AD - Pandion Therapeutics, Immunology Department, Watertown, MA, United States. FAU - Wilson, Keith T AU - Wilson KT AD - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States. AD - Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States. FAU - Goettel, Jeremy A AU - Goettel JA AD - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States. AD - Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States. AD - Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States. LA - eng GR - I01 CX002171/CX/CSRD VA/United States GR - K01 DK106311/DK/NIDDK NIH HHS/United States GR - P30 DK058404/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210224 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA Antigens) RN - 0 (Interleukin-2) RN - 8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid) SB - IM MH - Animals MH - HLA Antigens/*immunology MH - Humans MH - Inflammatory Bowel Diseases/*drug therapy/immunology MH - Interleukin-2/pharmacology/*therapeutic use MH - Mice MH - Mice, Inbred NOD MH - T-Lymphocyte Subsets/drug effects MH - T-Lymphocytes, Regulatory/*drug effects/immunology MH - Trinitrobenzenesulfonic Acid/pharmacology PMC - PMC7945590 OTO - NOTNLM OT - IBD OT - IL-2 OT - Tregs OT - colitis OT - humanized COIS- ES and KO are employed by Pandion Therapeutics. The authors declare that financial support for some of the humanized murine studies was provided by Pandion Therapeutics. The funder was, in part, involved in study design and procurement of mice. The data collection and analysis was not a part of the funding provided. The authors shared the results of the study with Pandion and shared the manuscript draft for critiques prior to submission. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/03/16 06:00 MHDA- 2021/09/21 06:00 PMCR- 2021/01/01 CRDT- 2021/03/15 06:58 PHST- 2020/11/16 00:00 [received] PHST- 2021/01/15 00:00 [accepted] PHST- 2021/03/15 06:58 [entrez] PHST- 2021/03/16 06:00 [pubmed] PHST- 2021/09/21 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.630204 [doi] PST - epublish SO - Front Immunol. 2021 Feb 24;12:630204. doi: 10.3389/fimmu.2021.630204. eCollection 2021.