Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes

Vandenbark, Arthur A.; Vainiene, M.; Ariail, K.; Miller, Stephen D.; Offner, Halina

doi:10.1002/(sici)1097-4547(19960815)45:4<430::aid-jnr12>3.0.co;2-4

Cited by 32 publications

(22 citation statements)

References 25 publications

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“…We and others (5,13) have previously demonstrated the exquisite ability of ECDI Ag-coupled (Ag-SP) cells to restore self tolerance and prevent disease progression during EAE. Not surprisingly, costimulatory signals appear to play a dogmatic role in the regulation of Ag-SP tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

“…One hallmark of the ECDI-Ag-coupled-cell tolerance regimen is its exquisite Ag specificity when used in both preventative and treatment modes in relapsing-remitting EAE (5,12,13,36). In light of the potential contribution of indirect tolerance to Ag-SP in our model system, we revisited the specificity of Ag-SP tolerance under conditions favoring indirect tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Ag-SP induces T cell tolerance leading to prevention and treatment of many animal models of autoimmune and inflammatory diseases (5)(6)(7)(8)(9) and promotes survival of allogeneic transplant (10). In EAE, Ag-SP therapy induces long-lasting Ag-specific tolerance in both the actively induced and adoptive transfer models of EAE, regardless of whether the treatment is administered at times before or following disease initiation (5,(11)(12)(13). In light of its ability to selectively induce long-lasting Ag-specific tolerance in CD4 ϩ T cells in the absence of any negative side effects, Ag-SP tolerance possess significant therapeutic potential for the future treatment of both MS and other autoimmune diseases.…”

mentioning

confidence: 99%

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Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

Turley

Miller

2007

The Journal of Immunology

116

142

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MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4+ T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have previously reported that i.v. treatment with Ag-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SPs) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SPs coupled with peptide can directly present peptide:MHC II complexes to target CD4+ T cells in the absence of costimulation to induce anergy. However, Ag-SPs coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SPs and target CD4+ T cells. Thus, we investigated whether MHC II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during autoimmune disease. Using MHC-deficient, allogeneic, and/or syngeneic donor Ag-SPs, we show that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. Interestingly, we found that ECDI treatment induces apoptosis of the donor cell population which promotes uptake and reprocessing of donor cell peptides by host APCs resulting in the apparent MHC II-independent induction of tolerance. However, syngeneic donor cells are more efficient at inducing tolerance, suggesting that Ag-SPs induce functional Ag-SP tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and effective treatment of autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

Turley

Miller

2007

The Journal of Immunology

116

142

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“…Enrichment in Tregs has been observed after antigen immunotherapy in patients with RA and T1D (160)(161)(162)(163). Administration of antigen-coupled ethylene carbodiimide-fixed cells (as well as, more recently, antigen-coated beads) has been extremely effective at restoring tolerance in NOD mice and EAE (164)(165)(166)(167). Additionally, a recent phase I clinical trial in MS showed that this approach reduced myelin-specific autoreactive T cell responses in humans (168).…”

Section: Stability Of Tregsmentioning

confidence: 99%

T cells in the control of organ-specific autoimmunity

Bluestone¹,

Bour-Jordan²,

Cheng³

et al. 2015

J. Clin. Invest.

135

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“…Induction of tolerance using antigen-coupled ethylene carbodiimide (ECDI)-fixed cells is a potent strategy that has been used successfully to prevent and reverse disease using insulincoupled cells in NOD mice and MBP-and PLP-coupled cells in EAE (Vandenbark et al 1996;Fife et al 2006). In EAE, ECDI-fixed cells coupled to myelin peptides were significantly safer and more effective at curbing disease than soluble peptides (Smith et al 2005).…”

Section: Cellular Therapies To Restore Tolerance In Autoimmune Diseasesmentioning

confidence: 76%

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

Bluestone

Bour-Jordan

2012

Cold Spring Harbor Perspectives in Biology

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Autoimmune diseases reflect a breakdown in self-tolerance that results from defects in thymic deletion of potentially autoreactive T cells (central tolerance) and in T-cell intrinsic and extrinsic mechanisms that normally control potentially autoreactive T cells in the periphery ( peripheral tolerance). The mechanisms leading to autoimmune diseases are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in pathogenic inflammatory responses in peripheral tissues driven by self-antigen-specific T cells. In this article, we describe the different checkpoints of tolerance that are defective in autoimmune diseases as well as specific events in the autoimmune response which represent therapeutic opportunities to restore long-term tolerance in autoimmune diseases. We present evidence for the role of different pathways in animal models and the therapeutic strategies targeting these pathways in clinical trials in autoimmune diseases.

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Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes

Cited by 32 publications

References 25 publications

Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

T cells in the control of organ-specific autoimmunity

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

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