Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit.

Sun, Jiabin; Rask, Carola; Olsson, Tomas; Holmgren, Jan; Czerkinsky, Cécil

doi:10.1073/pnas.93.14.7196

Cited by 173 publications

(132 citation statements)

References 32 publications

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“…administration of OVA/CTB conjugate effectively induces OVA-specific peripheral immunological tolerance, whether tested in normal BALB/c mice, OVA TCR Tg (DO11.10) mice, or in either BALB/c mice or Rag1 Ϫ/Ϫ mice transferred with OVA TCR Tg T cells. Consistent with our previous findings in other systems (17)(18)(19)(20)(21)(22), oral tolerance induction with Ag/CTB conjugate was superior to that induced with free Ag both in markedly increasing the efficacy of tolerization and in dramatically decreasing the effective amounts of Ag. The oral tolerance by i.g.…”

Section: Discussionsupporting

confidence: 91%

“…Oral administration of CT can in parallel with its adjuvant action prevent induction of oral tolerance to a coadministered Ag (17)(18)(19)33), although CT has also been reported (34) to promote the induction of T reg (Tr1 cells) in vitro. In this study, we found that coadministration of even very small amounts of CT together with the OVA/CTB conjugate effectively prevented the induction of CD25 ϩ CD4 ϩ suppressor T cells.…”

Section: Discussionmentioning

confidence: 99%

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Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

Sun

Raghavan

Sjöling

et al. 2006

The Journal of Immunology

103

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Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25+CD4+ regulatory T cells (Treg). We found that total Treg, KJ1–26+ Treg and CTLA-4+ Treg were all increased in Peyer’s patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF-β in serum. This could be abolished by coadministering cholera toxin or by treatment with anti-TGF-β mAb. CD25+ Treg, but also CD25−CD4+ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25+ Treg from OVA/CTB-treated mice, and treatment also markedly expanded CD25+Foxp3+ Treg. Furthermore, in Rag1−/− mice that had adoptively received highly purified Foxp3−CD25−CD4+ OT-II T cells OVA/CTB feeding efficiently induced CD25+ Treg cells, which expressed Foxp3 more strongly than naturally developing Treg and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25− T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF-β and in both the frequency and suppressive capacity of Foxp3+ and CTLA-4+ CD25+ Treg together with the generation of both Foxp3+ and Foxp3−CD25− CD4+ Treg.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

Sun

Raghavan

Sjöling

et al. 2006

The Journal of Immunology

103

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“…The present study demonstrates that feeding minute amounts of insulin conjugated to CTB can significantly reduce the incidence of diabetes even when given as a single dose and that protection tends to be more durable when using five consecutive doses of conjugate. Taken together, these findings are in keeping with our previous observations (24,25) indicating that CTB can serve as a powerful transmucosal delivery system for inducing peripheral tolerance.…”

Section: Discussionsupporting

confidence: 80%

“…More recently, oral administration of a myelin autoantigen conjugated to CTB has been shown to protect animals against experimentally induced allergic encephalomyelitis, even when given after disease induction (25). We now report that feeding adult female NOD mice with small doses of heterologous insulin conjugated to CTB (CTB-insulin) prevents beta cell infiltration by diabetogenic T cells and protects animals against spontaneous autoimmune diabetes.…”

mentioning

confidence: 87%

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Bergerot

Ploix

Petersen

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

220

182

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Mucosally induced immunological tolerance is an attractive strategy for preventing or treating illnesses resulting from untoward inf lammatory immune reactions against self-or non-self-antigens. Oral administration of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental autoimmune and allergic disorders. However, the approach often requires repeated feeding of large amounts of tolerogens over long periods and is only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune disease. We have recently shown that oral administration of microgram amounts of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune animals. We now report that feeding small amounts (2-20 g) of human insulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice. The protective effect could be transferred by T cells from CTBinsulin-treated animals and was associated with reduced lesions of insulitis. Furthermore, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells from congenic Thy-1,1 mice fed with CTB-insulin demonstrated a selective recruitment of Thy-1,1 donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration. These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.

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“…16 Cytokines have been blocked using antibodies such as anti-TNF 17 and tolerance has been restored by feeding MBP 18 and cholera toxin conjugated to MBP. 19 For reviews on cytokines in inflammatory brain lesions see references 20 and 21. Intranasal administration of mutated MBP-specific peptides 22,23 and oral administration of PLP peptides 24 have been pursued in order to restore tolerance to myelin antigens.…”

Section: Immunotherapies Of Eaementioning

confidence: 99%

Immuno- and genetic therapy in autoimmune diseases

et al. 2000

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Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immunoand gene therapy. Genes and Immunity (2000) 1, 295-307.

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Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit.

Abstract: Oral administration

Cited by 173 publications

References 32 publications

Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Immuno- and genetic therapy in autoimmune diseases

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