Cell Therapy of Refractory Crohn’s Disease

Knyazev, Oleg; Парфенов, А И; Щербаков, П. Л.; Ручкина, И Н; Konoplyannikov, A. G.

doi:10.1007/s10517-013-2297-8

Cited by 15 publications

(7 citation statements)

References 17 publications

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“…Both hematopoietic and mesenchymal stem cells (MSCs) have shown good results when they induced a long-lasting clinical remission in severe cases of CD. 115 …”

Section: Signaling Pathways Mediated By Cytokinesmentioning

confidence: 99%

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Manuc¹,

Manuc²,

Diculescu³

2016

CEG

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Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn’s disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral nutrition, and granulocyte colony-stimulating factors.

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“…Both hematopoietic and mesenchymal stem cells (MSCs) have shown good results when they induced a long-lasting clinical remission in severe cases of CD. 115 …”

Section: Signaling Pathways Mediated By Cytokinesmentioning

confidence: 99%

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Manuc¹,

Manuc²,

Diculescu³

2016

CEG

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“…Over the past decade, the immunomodulatory functions of MSCs have triggered great interest in their application toward treating various immune disorders, including graft‐versus‐host disease (GVHD), transplanted organ rejection, and autoimmune diseases . While previous large‐scale clinical trials using MSCs therapy had inconclusive results , it is possible that these results are due to the varied cytokine environments MSCs encounter in vivo.…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo Induced Regulatory Human/Murine Mesenchymal Stem Cells as Immune Modulators

et al. 2015

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Over the past decade there has been a growing interest in using mesenchymal stem cells (MSCs) as an immune-regulatory agent for prevention and treatment of various immune disorders including graft-versus-host disease (GVHD), transplanted organ rejection, and autoimmune diseases. However, the high diversity in the results from clinical trials using MSCs for such disorders emphasizes the need for MSCs to be "professionalized" ex vivo to a more defined regulatory phenotype before administering to patients. To this aim, we have established an ex vivo immunomodulatory triple combination treatment (TCT) for MSCs, using IFNc, TGFb, and kynurenine. We show that pretreated MSCs acquire an immunomodulatory phenotype, have improved regulatory functions, and upregulate the expression of inducible nitric oxide synthase, indoleamine 2,3-dioxygenase, cyclooxygenase-2 (COX2), heme oxygenase 1, leukemia inhibitory factor (LIF), and programmed death ligand 1. We define the pathway of kynurenine induced aryl hydrocarbon receptor activation in MSCs and how it contributes to the upregulation of COX2 expression and IL-6 downregulation. The combination of reduced IL-6 secretion with enhanced LIF expression leads to the inhibition of Th17 differentiation in coculture of TCT MSCs and lymphocytes. To test the immunomodulatory function of TCT MSCs in vivo, we used the cells as GVHD prophylaxis in a GVHD mouse model. TCT MSCs administration significantly decreased GVHD score and improved mouse survival. Importantly, single administration could attenuate disease symptoms for more than 3 weeks. Based on these results, we suggest considering TCT MSCs as an improved cell therapy for systemic diseases with an underlying inflammatory and immunologic etiology.

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“…It has been shown that MSCs also exhibited potential roles for anti-inflammatory functions [ 40 ]. Thus, MSCs have been employed as therapeutic strategies for various immune disorders including graft-versus-host disease (GVHD) [ 41 – 43 ], organ transplantation [ 44 – 47 ], autoimmune diseases [ 48 – 52 ] and inflammatory bowel disease [ 53 , 54 ]. Indeed, MSCs interact with T cells to reduce their pro-inflammatory cytokine production [ 36 , 55 ], while increasing their production of anti-inflammatory cytokines, including IL-4 and IL-10 [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

Aso

Tsuruhara

Takagaki³

et al. 2016

PLoS ONE

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It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice.

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Cell Therapy of Refractory Crohn’s Disease

Cited by 15 publications

References 17 publications

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Ex Vivo Induced Regulatory Human/Murine Mesenchymal Stem Cells as Immune Modulators

Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

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Cell Therapy of Refractory Crohn’s Disease

Cited by 15 publications

References 17 publications

Recent insights into the molecular pathogenesis of Crohn&#39;s disease: a review of emerging therapeutic targets

Recent insights into the molecular pathogenesis of Crohn&#39;s disease: a review of emerging therapeutic targets

Ex Vivo Induced Regulatory Human/Murine Mesenchymal Stem Cells as Immune Modulators

Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

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Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets