Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Crohn’s disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. “Humanized” mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.

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TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway

Mucosal Immunology ◽

10.1038/s41385-019-0168-y ◽

2019 ◽

Vol 12 (4) ◽

pp. 980-989 ◽

Cited By ~ 6

Author(s):

I. T. Chyuan ◽

H. F. Tsai ◽

C. S. Wu ◽

P. N. Hsu

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Bowel Disease ◽

Cell Activation ◽

Gut Inflammation ◽

Inflammatory Bowel ◽

Colitis Model

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

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8 ROLE OF THE HOST IMMUNE RESPONSE TO ENTERIC PROKARYOTIC VIRUSES IN INFLAMMATORY BOWEL DISEASE

Gastroenterology ◽

10.1053/j.gastro.2019.11.174 ◽

2020 ◽

Vol 158 (3) ◽

pp. S68-S69

Author(s):

Julia Angkeow ◽

Daniel Monaco ◽

Scott Handley ◽

H.B. Larman

Keyword(s):

Inflammatory Bowel Disease ◽

Immune Response ◽

Bowel Disease ◽

Host Immune Response ◽

Inflammatory Bowel

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New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches

Frontiers in Immunology ◽

10.3389/fimmu.2021.738762 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rosaely Casalegno Garduño ◽

Jan Däbritz

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Cd8 T Cells ◽

Bowel Disease ◽

Positive Outcome ◽

T Cell Subsets ◽

Therapeutic Approaches ◽

Therapeutic Value ◽

Inflammatory Bowel

CD8+ T cells are involved in the pathogenesis of inflammatory bowel disease (IBD), a complex multifactorial chronic disease. Here, we present an overview of the current research with the controversial findings of CD8+ T cell subsets and discuss some possible perspectives on their therapeutic value in IBD. Studies on the role of CD8+ T cells in IBD have contradictory outcomes, which might be related to the heterogeneity of the cells. Recent data suggest that cytotoxic CD8+ T cells (Tc1) and interleukin (IL) 17-producing CD8+ (Tc17) cells contribute to the pathogenesis of IBD. Moreover, subsets of regulatory CD8+ T cells are abundant at sites of inflammation and can exhibit pro-inflammatory features. Some subsets of tissue resident memory CD8+ T cells (Trm) might be immunosuppressant, whereas others might be pro-inflammatory. Lastly, exhausted T cells might indicate a positive outcome for patients. The function and plasticity of different subsets of CD8+ T cells in health and IBD remain to be further investigated in a challenging field due to the limited availability of mucosal samples and adequate controls.

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Role of miR-22 in intestinal mucosa tissues and peripheral blood CD4+ T cells of inflammatory bowel disease

Pathology - Research and Practice ◽

10.1016/j.prp.2018.04.009 ◽

2018 ◽

Vol 214 (8) ◽

pp. 1095-1104 ◽

Cited By ~ 6

Author(s):

Xu-Feng Pei ◽

Long-Lei Cao ◽

Fang Huang ◽

Xu Qiao ◽

Jie Yu ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Intestinal Mucosa ◽

Bowel Disease ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Inflammatory Bowel

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Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease

Mediators of Inflammation ◽

10.1155/2016/9890141 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Phillips-Farfán Bryan ◽

Carvajal Karla ◽

Medina-Torres Edgar Alejandro ◽

Espinosa-Padilla Sara Elva ◽

Fabrias Gemma ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Immune Response ◽

Immune System ◽

Gut Microbiota ◽

Bowel Disease ◽

Therapeutic Agents ◽

Intestinal Cells ◽

Intestinal Immunity ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly understood, immune system disturbances likely underlie its development. Sphingolipids (SLs) have been identified as important players and promising therapeutic targets to control inflammation in IBD. Interestingly, it seems that microorganisms of the normal gut microbiota and probiotics are involved in sphingolipid function. However, there is a great need to investigate the role of SLs as intermediates in the crosstalk between intestinal immunity and microorganisms. This review focuses on recent investigations that describe some mechanisms involved in the regulation of cytokine profiles by SLs. We also describe the importance of gut microbiota in providing signaling molecules that favor the communication between resident bacteria and intestinal cells. This, in turn, modulates the immune response in the bowel and likely in other peripheral organs. The potential of SLs and gut microbiota as targets or therapeutic agents for IBD is also discussed.

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CCR4-dependent regulatory T cell function in inflammatory bowel disease

Journal of Experimental Medicine ◽

10.1084/jem.20062076 ◽

2007 ◽

Vol 204 (6) ◽

pp. 1327-1334 ◽

Cited By ~ 82

Author(s):

Qian Yuan ◽

Shannon K. Bromley ◽

Terry K. Means ◽

Krister J. Jones ◽

Fumitaka Hayashi ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Adoptive Transfer ◽

Bowel Disease ◽

Transfer Model ◽

Time Points ◽

Suppressive Function ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the intestine. CD4+ T lymphocytes play an important role in both initiating and regulating intestinal inflammatory immune responses. CD4+CD25+CD45RBlow regulatory T (T reg) cells are capable of preventing the development of colitis in a mouse model of IBD. The precise mechanism of T reg cell–mediated prevention of colitis in this model is unclear, and the role of chemokine receptors in the trafficking and function of T reg cells in this model has not been determined. We examined the role of the chemokine receptor CCR4 in in vivo trafficking and suppressive function of T reg cells in a mouse adoptive transfer model of IBD. CCR4-deficient T reg cells failed to accumulate in the mesenteric lymph nodes (MLNs) at early time points (2–5 d) after adoptive transfer, resulting in a failure to suppress the generation of pathogenic T cells and the development of colitis. Moreover, although CCR4-deficent T cells had equivalent in vitro suppressive activity and accumulated in MLNs at later time points (42–56 d), they were unable to suppress colitis. Our study demonstrates that CCR4 plays an important role in T reg cell trafficking in LNs and that this is critical for T reg cell suppressive function in vivo.

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The Effectiveness of Probiotics in the Treatment of Inflammatory Bowel Disease (IBD)—A Critical Review

Nutrients ◽

10.3390/nu12071973 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1973

Author(s):

Dominika Jakubczyk ◽

Katarzyna Leszczyńska ◽

Sabina Górska

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Immune Response ◽

Bowel Disease ◽

Genetic Background ◽

Inflammatory State ◽

Inflammatory Bowel ◽

Potential Strategy ◽

Different Strains

Inflammatory bowel disease (IBD), which affects millions of people worldwide, includes two separate diseases: Crohn’s disease (CD) and ulcerative colitis (UC). Although the background (chronic inflammatory state) and some of the symptoms of CD and UC are similar, both diseases differ from each other. It is becoming clear that a combination of many factors, in particular genetic background, host immune response and microbial reduced diversity status are associated with IBD. One potential strategy to prevent/treat IBD is gut modulation by probiotics. Over the last twenty years, many publications have focused on the role of probiotics in the course of IBD. The review discusses the utility of different strains of probiotics, especially Bifidobacterium spp., in all factors potentially involved in the etiology of IBD. The probiotic modulatory properties among different study models (cell lines, animal models of colitis, clinical study) are discussed and probiotic usefulness is assessed in relation to the treatment, prevention, and remission of diseases.

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Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.3.g764 ◽

2001 ◽

Vol 281 (3) ◽

pp. G764-G778 ◽

Cited By ~ 101

Author(s):

Andrew Burich ◽

Robert Hershberg ◽

Kim Waggie ◽

Weiping Zeng ◽

Thea Brabb ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Bowel Disease ◽

Wild Type ◽

Immunodeficient Mice ◽

Inflammatory Bowel ◽

Rag 1

Inflammatory bowel disease (IBD) is thought to result from a dysregulated mucosal immune response to luminal microbial antigens, with T lymphocytes mediating the colonic pathology. Infection with Helicobacter spp has been reported to cause IBD in immunodeficient mice, some of which lack T lymphocytes. To further understand the role of T cells and microbial antigens in triggering IBD, we infected interleukin (IL)-10−/−, recombinase-activating gene (Rag)1−/−, T-cell receptor (TCR)-α−/−, TCR-β−/−, and wild-type mice with Helicobacter hepaticus or Helicobacter bilis and compared the histopathological IBD phenotype. IL-10−/−mice developed severe diffuse IBD with either H. bilis or H. hepaticus, whereas Rag1−/−, TCR-α−/−, TCR-β−/−, and wild-type mice showed different susceptibilities to Helicobacter spp infection. Proinflammatory cytokine mRNA expression was increased in the colons of Helicobacter-infected IL-10−/−and TCR-α−/−mice with IBD. These results confirm and extend the role of Helicobacter as a useful tool for investigating microbial-induced IBD and show the importance, but not strict dependence, of T cells in the development of bacterial-induced IBD.

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