Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis

Wright, G. Payling; Notley, Clare A.; Xue, Shao-An; Bendle, Gavin; Holler, Angelika; Schumacher, Ton N.; Ehrenstein, Michael R.; Stauss, Hans J.

doi:10.1073/pnas.0907396106

Cited by 186 publications

(149 citation statements)

References 35 publications

(31 reference statements)

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“…Taken together, these data indicate that the observed protection is due to Tregs, and that Agspecific-treated Tregs (whether from treated NOD mice or treated NOD BDC2.5 mice) are more potent in vivo compared with untreated polyclonal Tregs. Because in this study we used a mimotope peptide (BDC2.5) instead of a bona fide islet Ag peptide such as insulin B [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] (39) or GAD65 524-543 (38), we tested whether, in our setting, natural islet Ag peptides would also be efficient at preventing the development of induced T1D. NOD mice were left untreated or treated for 3 d with either one of the following treatments: 1) rapamycin, IL-2/anti-IL-2 mAb complexes; 2) rapamycin, IL-2/anti-IL-2 mAb complexes, BDC2.5 peptide; 3) rapamycin, IL-2/anti-IL-2 mAb complexes, insulin B 9-23 peptide; and 4) rapamycin, IL-2/anti-IL-2 mAb complexes, GAD65 524-543 peptide.…”

Section: Combined Treatment Significantly Inhibits the Development Ofmentioning

confidence: 99%

“…Recently, Tregs have also been investigated in clinical trials to prevent/treat T1D, graft-versushost diseases, and organ transplant rejection (16). Notably, it is well established in several models that Ag-specific Tregs are more effective than polyclonal Tregs in immunosuppression in vitro and control of autoimmunity in vivo (e.g., T1D, arthritis, multiple sclerosis, arthritis, colitis) (17)(18)(19)(20)(21)(22)(23)(24); particularly, injection of small numbers of Ag-specific Tregs selectively expanded in vitro can reverse diabetes even after disease onset (17,18). However, whether Ag-specific Tregs can be expanded in vivo, whether these cells retain their immunosuppressive function following expansion, and the stability of their Foxp3 expression have not yet been elucidated.…”

mentioning

confidence: 99%

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Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Manirarora

Wei

2015

The Journal of Immunology

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Regulatory T cells (Treg) play a crucial role in the maintenance of self-tolerance. In this study, we sought to expand Ag-specific Tregs in vivo and investigate whether the expanded Tregs can prevent or delay the development of type 1 diabetes (T1D) in the NOD mouse model. NOD mice were treated with a combination of IL-2/anti–IL-2 Ab complex, islet Ag peptide, and rapamycin. After the combined treatment, CD4+CD25+Foxp3+ Tregs were significantly expanded in vivo, they expressed classical Treg markers, exerted enhanced suppressive functions in vitro, and protected against spontaneous development of T1D in NOD mice. Moreover, treated mice were almost completely protected from the adoptively transferred, aggressive form of T1D caused by in vitro–activated cytotoxic islet Ag-specific CD8 T cells. Protection from T1D was transferrable by Tregs and could be attributed to reduced islet infiltration of immune cells as well as the skewing of the immune response toward a Th2 cytokine profile. This new method of peripheral immune regulation could potentially contribute to development of novel immunotherapeutic strategies to prevent the development of T1D or to promote tolerance to islet transplants without using immunosuppressive drugs for long terms.

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Section: Combined Treatment Significantly Inhibits the Development Ofmentioning

confidence: 99%

mentioning

confidence: 99%

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Manirarora

Wei

2015

The Journal of Immunology

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“…Several studies have shown improvement of inflammation, e.g., that seen in murine antigeninduced arthritis, by transfusion of functional Tregs (86)(87)(88)(89). It has ignited some debates regarding the potential use in cellular therapy for RA.…”

Section: Regulatory T Cell-based Therapy In Ramentioning

confidence: 99%

Stem Cell-Based Cellular Therapy in Rheumatoid Arthritis

Haque¹,

Lei²,

Xiong³

et al. 2012

Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies

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“…Haque et al 123 provided an approach to generate functional Tregs, induced by iPSCs. 123 Adoptive cell transfer (ACT) of Tregs showed encouraging results in experimental settings for autoimmune diseases such as rheumatoid arthritis 124 and systemic lupus, 125 but had significant risk of teratoma formation as seen in case of ESCs.…”

Section: Induced Pluripotent Stem Cells (Ipscs)mentioning

confidence: 99%

Inflammatory Bowel Diseases: Current Therapeutic Approaches and Potential of Using Stem Cells

Srivastava¹

2017

JSRT

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Inflammatory bowel diseases (IBDs) are chronic and progressively deteriorating in nature without many promising curative treatments. Chronic inflammation of not well defined origins is considered to be the root cause of the problem which affects intestinal mucosa with or without transmural involvement. IBDs are divided in two main categories: Crohn's disease (CD) and ulcerative colitis (UC). While there is no long lasting cure for IBDs, current therapies can only reduce the causative inflammatory process with the hope to induce long-term remission. Treatment modalities for the IBDs are still evolving. The increased understanding of the underlying immunopathology has helped identify new targeted treatment options like immunosuppressive antibodies directed against signaling molecules. Use of stem cells, which are capable of modulating the immune system, can offer a long lasting relief to the patients suffering from the disease. The goal for stem cell-based therapy is to achieve long lasting cure, if not a permanent one. To achieve this, it would be desirable to obtain cell types, whether genetically modified or naturally occurring, having a high migratory ability in addition to homing ability into the afflicted parts of intestine. These cells should also have high in vivo survival potential, and then be able to regulate the immune reaction without provoking any response from the host's immune system and repair the injured tissue. Hematopoietic stem cells (HSC) and mesenchymal stromal cells (MSC) therapies are being investigated as a treatment for IBDs. MSC therapy is well tolerated and has minimal established side-effects compared to HSC therapy, which involves ablative chemotherapy. Several clinical studies using MSCs have been initiated and some early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, which can be resolved only by scientifically unveiling the mechanisms of therapeutic action of stem cells. In this review, we summarize current therapies for IBDs and recent advances in the field of stem cell therapy, which offer promise to become the next generation treatment of choice.

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Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis

Abstract: Regulatory T cells (Tregs

Cited by 186 publications

References 35 publications

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Stem Cell-Based Cellular Therapy in Rheumatoid Arthritis

Inflammatory Bowel Diseases: Current Therapeutic Approaches and Potential of Using Stem Cells

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