Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis

Watanabe, Koichiro; Rao, Varada P.; Poutahidis, Theofilos; Rickman, Barry; Ohtani, Masahiro; Xu, Shilu; Rogers, Arlin B.; Ge, Zhongming; Horwitz, Bruce H.; Fujioka, Toshio; Erdman, Susan E.; Fox, James G.

doi:10.1128/iai.00542-08

Cited by 32 publications

(15 citation statements)

References 28 publications

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“…Recipients were acclimated for 7 days after injection and then DSS challenge was performed. 36,45 Macrophage isolation, coculture, and stimulation. Peritoneal macrophage cells were harvested and cultured using a standard protocol.…”

Section: Methodsmentioning

confidence: 99%

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

et al. 2016

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Integrin α4β7 controls lymphocyte trafficking into the gut and has essential roles in inflammatory bowel disease (IBD). The α4β7-blocking antibody vedolizumab is approved for IBD treatment; however, high dose of vedolizumab aggravates colitis in a small percentage of patients. Herein, we show that integrin β7 deficiency results in colonic regulatory T (Treg) cell depletion and exacerbates dextran sulfate sodium (DSS) colitis by evoking aberrant innate immunity. In DSS-treated β7-deficient mice, the loss of colonic Treg cells induces excessive macrophage infiltration in the colon via upregulation of colonic epithelial intercellular adhesion molecule 1 and increases proinflammatory cytokine expression, thereby exacerbating DSS-induced colitis. Moreover, reconstitution of the colonic Treg cell population in β7-deficient mice suppresses aberrant innate immune response in the colon and attenuates DSS colitis. Thus, integrin α4β7 is essential for suppression of DSS colitis as it regulates the colonic Treg cell population and innate immunity.

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Section: Methodsmentioning

confidence: 99%

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

et al. 2016

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“…Cryosections embedded in Tissue-Tek O.C.T (Skura Finetek, Torrance, CA), mounted on gelatin-coated slides were stained using an avidin-biotin immunoperoxidase method (Vector Laboratories, Burlingame, CA) (51,54). Renal tissues (nϭ5) were evaluated for presence of FoxP3 ϩ T cells using biotin-conjugated rat anti-mouse FoxP3 (eBioscience, San Diego, CA) mAbs.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Regulatory T-Cell Generation and Kidney Allograft Tolerance Induced by Mesenchymal Stem Cells Associated With Indoleamine 2,3-Dioxygenase Expression

Jiang²,

Arp³

et al. 2010

Transplantation

316

252

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“…1 Adoptively transferred T regs prevent the onset of colitis or treat established colitis in a number of murine models. [2][3][4][5][6][7] Open Access Scan to access more free content…”

Section: Introductionmentioning

confidence: 99%

Developing in vitro expanded CD45RA⁺regulatory T cells as an adoptive cell therapy for Crohn's disease

Canavan

Scottà

Vossenkämper

et al. 2015

Gut

176

141

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Background and aimThymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown.MethodsTo define the optimum population for Treg cell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA− Treg subsets were isolated from patients’ blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background.ResultsTregs can be expanded from the blood of patients with CD to potential target dose within 22–24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA− Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa.ConclusionsCD4+CD25+CD127loCD45RA+ Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials.

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Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis

Abstract: Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4؉ CD25

Cited by 32 publications

References 28 publications

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

Regulatory T-Cell Generation and Kidney Allograft Tolerance Induced by Mesenchymal Stem Cells Associated With Indoleamine 2,3-Dioxygenase Expression

Developing in vitro expanded CD45RA⁺regulatory T cells as an adoptive cell therapy for Crohn's disease

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Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis

Abstract: Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4؉ CD25

Cited by 32 publications

References 28 publications

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

Regulatory T-Cell Generation and Kidney Allograft Tolerance Induced by Mesenchymal Stem Cells Associated With Indoleamine 2,3-Dioxygenase Expression

Developing in vitro expanded CD45RA+regulatory T cells as an adoptive cell therapy for Crohn's disease

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Developing in vitro expanded CD45RA⁺regulatory T cells as an adoptive cell therapy for Crohn's disease