HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice
Regulatory T (Treg) cells are essential to maintain immune homeostasis in the intestine and Treg 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 Treg ce...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-02-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630204/full |
| _version_ | 1824037547970396160 |
|---|---|
| author | Rajeev K. Tyagi Justin Jacobse Justin Jacobse Jing Li Margret M. Allaman Kevin L. Otipoby Erik R. Sampson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel |
| author_facet | Rajeev K. Tyagi Justin Jacobse Justin Jacobse Jing Li Margret M. Allaman Kevin L. Otipoby Erik R. Sampson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel |
| author_sort | Rajeev K. Tyagi |
| collection | DOAJ |
| description | Regulatory T (Treg) cells are essential to maintain immune homeostasis in the intestine and Treg 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 Treg 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 Treg 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.PrkdcscidIl2rg-/- (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 Treg cells to treat IBD. |
| first_indexed | 2024-12-22T18:48:08Z |
| format | Article |
| id | doaj.art-9fde11171f8341ed846e55a297e925bf |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T18:48:08Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9fde11171f8341ed846e55a297e925bf2022-12-21T18:16:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.630204630204HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized MiceRajeev K. Tyagi0Justin Jacobse1Justin Jacobse2Jing Li3Margret M. Allaman4Kevin L. Otipoby5Erik R. Sampson6Keith T. Wilson7Keith T. Wilson8Keith T. Wilson9Keith T. Wilson10Keith T. Wilson11Keith T. Wilson12Jeremy A. Goettel13Jeremy A. Goettel14Jeremy A. Goettel15Jeremy A. Goettel16Jeremy A. Goettel17Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesWillem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United StatesDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesPandion Therapeutics, Immunology Department, Watertown, MA, United StatesPandion Therapeutics, Immunology Department, Watertown, MA, United StatesDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United StatesProgram in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United StatesVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United StatesCenter for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United StatesVeterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United StatesDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United StatesProgram in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United StatesVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United StatesCenter for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United StatesRegulatory T (Treg) cells are essential to maintain immune homeostasis in the intestine and Treg 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 Treg 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 Treg 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.PrkdcscidIl2rg-/- (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 Treg cells to treat IBD.https://www.frontiersin.org/articles/10.3389/fimmu.2021.630204/fullIBDIL-2humanizedcolitisTregs |
| spellingShingle | Rajeev K. Tyagi Justin Jacobse Justin Jacobse Jing Li Margret M. Allaman Kevin L. Otipoby Erik R. Sampson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Keith T. Wilson Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel Jeremy A. Goettel HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice Frontiers in Immunology IBD IL-2 humanized colitis Tregs |
| title | HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice |
| title_full | HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice |
| title_fullStr | HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice |
| title_full_unstemmed | HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice |
| title_short | HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice |
| title_sort | hla restriction of human treg cells is not required for therapeutic efficacy of low dose il 2 in humanized mice |
| topic | IBD IL-2 humanized colitis Tregs |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630204/full |
| work_keys_str_mv | AT rajeevktyagi hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT justinjacobse hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT justinjacobse hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jingli hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT margretmallaman hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT kevinlotipoby hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT erikrsampson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT keithtwilson hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jeremyagoettel hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jeremyagoettel hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jeremyagoettel hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jeremyagoettel hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice AT jeremyagoettel hlarestrictionofhumantregcellsisnotrequiredfortherapeuticefficacyoflowdoseil2inhumanizedmice |