The application of gene therapy in autoimmune diseases

Seroogy, Christine M.; Fathman, C. Garrison

doi:10.1038/sj.gt.3301111

Cited by 23 publications

(16 citation statements)

References 34 publications

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“…However, most current therapeutic strategies for treatment of autoimmune disease (including TNF blockade) include potent and nonspecific immune suppression that may result in systemic toxicity and increased risk for infections and malignancies. Thus, local gene therapy using adoptive transfer of transduced antigen-specific CD4 + T cells expressing regulatory proteins may serve as a better long-term option for treating autoimmune diseases (26,27). Furthermore, localized delivery of a preselected amount of a regulatory protein to a specific site should ensure maximum therapeutic effect in the area of inflammation while minimizing the exposure of nontargeted organs to the gene products and markedly reducing the risk of undesirable systemic side effects.…”

Section: Discussionmentioning

confidence: 99%

Antigen-specific T cell–mediated gene therapy in collagen-induced arthritis

Nakajima¹,

Seroogy²,

Sandora³

et al. 2001

J. Clin. Invest.

176

116

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Section: Discussionmentioning

confidence: 99%

Antigen-specific T cell–mediated gene therapy in collagen-induced arthritis

Nakajima¹,

Seroogy²,

Sandora³

et al. 2001

J. Clin. Invest.

176

116

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“…Because Ag-specific therapies are directed against only one or a limited number of antigenic epitopes, they often lack the potency of Ag-nonspecific immunomodulatory agents. Among Ag-specific therapies, cellular immunotherapy with T lymphocytes may be particularly adept at linking specificity and potency (1). Adoptively transferred T cells can home to sites of inflammation and may persist for Ͼ1 year (2,3).…”

mentioning

confidence: 99%

IL-10-Dependent Suppression of Experimental Allergic Encephalomyelitis by Th2-Differentiated, Anti-TCR Redirected T Lymphocytes

Mekala

Alli

Geiger

2005

The Journal of Immunology

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We previously showed that transgenically expressed chimeric Ag-MHC-ζ receptors can Ag-specifically redirect T cells against other T cells. When the receptor’s extracellular Ag-MHC domain engages cognate TCR on an Ag-specific T cell, its cytoplasmic ζ-chain stimulates the chimeric receptor-modified T cell (RMTC). This induces effector functions such as cytolysis and cytokine release. RMTC expressing a myelin basic protein (MBP) 89–101-IAs-ζ receptor can be used therapeutically, Ag-specifically treating murine experimental allergic encephalomyelitis (EAE) mediated by MBP89-101-specific T cells. In initial studies, isolated CD8+ RMTC were therapeutically effective whereas CD4+ RMTC were not. We re-examine here the therapeutic potential of CD4+ RMTC. We demonstrate that Th2-differentiated, though not Th1-differentiated, CD4+ MBP89–101-IAs-ζ RMTC prevent actively induced or adoptively transferred EAE, and treat EAE even after antigenic diversification of the pathologic T cell response. The Th2 RMTC both Th2-deviate autoreactive T cells and suppress autoantigen-specific T cell proliferation. IL-10 is critical for the suppressive effects. Anti-IL-10R blocks RMTC-mediated modulation of EAE and suppression of autoantigen proliferation, as well as the induction of IL-10 production by autoreactive T cells. In contrast to IL-10, IL-4 is required for IL-4 production by, and hence Th2 deviation of autoreactive T cells, but not the therapeutic activity of the RMTC. These results therefore demonstrate a novel immunotherapeutic approach for the Ag-specific treatment of autoimmune disease with RMTC. They further identify an essential role for IL-10, rather than Th2-deviation itself, in the therapeutic effectiveness of these redirected Th2 T cells.

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“…In recent years, a variety of gene therapy strategies have been used in EAE. [14][15][16][17][18] One approach has been to genetically modify antigen-specific T cells to deliver immunoregulatory molecules. [45][46][47][48][49] Direct injection of naked DNA encoding anti-inflammatory cytokines has also been the focus of a significant number of EAE studies.…”

Section: Discussionmentioning

confidence: 99%

“…5,13 Development of therapies aimed at specifically deleting or tolerizing (anergizing) these cells, so they no longer respond to myelin antigen, is the ultimate goal of this and other studies. [14][15][16][17][18] Murine experimental autoimmune encephalomyelitis (EAE) is considered to be a powerful animal model for the study of both the immunological mechanisms of myelin destruction and for the testing of potential therapies for MS. [19][20][21] The disease can be induced by injection of genetically susceptible animals with myelin proteins and closely resembles the course, clinical manifestations and pathology of relapsing and remitting MS. In female SJL/J mice used in this study, the first attack is mediated by CD4 T cells specific for proteolipid protein (PLP) amino acids 139-151.…”

Section: Introductionmentioning

confidence: 99%

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Louie

Weiner

et al. 2005

Gene Ther

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With the ultimate goal of developing a novel treatment for multiple sclerosis (MS), we have developed a cell-based gene therapy protocol for the treatment of murine experimental autoimmune encephalomyelitis (EAE), a powerful animal model for MS. We have determined that transduced fibroblasts secreting encephalogenic epitopes, when injected into mice with EAE, cause a striking abrogation of disease. Both myelin basic protein (MBP) and proteolipid protein mini-gene constructs expressed in syngeneic fibroblast cells were capable of ameliorating ongoing EAE induced by MBP protein. These experiments are crucial since they suggest that not all encephalogenic epitopes need be secreted for the control of disease. We also demonstrate the success of this protocol when transduced syngeneic, and most importantly, allogeneic cells are sequestered within an implantable chamber. Furthermore, we find that through modifying antigen expression by changing the signal sequence of the mini-gene construct, we were able to significantly reduce the dose of cells required for treatment. These improvements to the minigene delivery system are critical for the eventual translation of our protocol to the clinic.

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The application of gene therapy in autoimmune diseases

Cited by 23 publications

References 34 publications

Antigen-specific T cell–mediated gene therapy in collagen-induced arthritis

Antigen-specific T cell–mediated gene therapy in collagen-induced arthritis

IL-10-Dependent Suppression of Experimental Allergic Encephalomyelitis by Th2-Differentiated, Anti-TCR Redirected T Lymphocytes

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

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