Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial

Vandenbark, Arthur A.; Chou, Yuan K.; Whitham, Ruth H.; Mass, Michele; Buenafe, Abigail C.; Liefeld, Diane; Kavanagh, Daniel G.; Cooper, Shelley; Hashim, George A.; Offner, Halina; Bourdette, Dennis

doi:10.1038/nm1096-1109

Cited by 166 publications

(120 citation statements)

References 47 publications

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“…The distinct role of these CD8 ϩ CTLs is of particular relevance to MS where demyelination represents the most significant CNS pathology associated with neurologic deficits. There is evidence in the literature on the CD4 ϩ T cell responses to candidate myelin Ags in MS and the preliminary therapeutic attempts to suppress or eliminate CD4 ϩ myelin-reactive T cells (28,29). In contrast, the frequency, the functional properties, and the potential role of CD8 ϩ T cells recognizing myelin Ags in MS are virtually unknown.…”

Section: Discussionmentioning

confidence: 99%

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Zang

Rivera

et al. 2004

The Journal of Immunology

121

105

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Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8+ T cell responses and their functional properties in patients with MS. There were significantly increased CD8+ T cell responses to 9-mer MBP peptides, in particular MBP111–119 and MBP87–95 peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8+ T cell lines were of the Th1 phenotype, producing TNF-α and IFN-γ and belonged to a CD45RA−/CD45RO+ memory T cell subset. Further characterization indicated that the CD8+ T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP111–119) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8+ T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8+ CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.

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Section: Discussionmentioning

confidence: 99%

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Zang

Rivera

et al. 2004

The Journal of Immunology

121

105

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“…All animals were examined once a day and the disease activity index (DAI) was assessed as described previously. 27,28 Briefly, the DAI combines scores for weight loss, stool consistency, and bleeding. Scores were defined as follows: stool consistency was graded 0 for no diarrhea, 2 for loose stool that did not stick to the anus, and 4 for liquid stool that did stick to the anus.…”

Section: Induction and Assessment Of Dss-induced Colitismentioning

confidence: 99%

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

Bento

Marcon

Dutra

et al. 2011

The American Journal of Pathology

213

145

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Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-␥ (PPAR␥) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-␤-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the antiinflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPAR␥. Oral treatment with BCP reduced disease activity, colonic macro-and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-␣, IL-1␤, interferon-␥, and keratinocyte-derived chemokine. Inflammatory bowel diseases (IBDs) are a group of chronic diseases that affect the gastrointestinal tract and have been mainly subdivided as ulcerative colitis and Crohn's disease. 1 The IBDs are characterized by a strong leukocyte activation and infiltration into the intestinal tissues, the release of proinflammatory cytokines 2 and enzymes, and the formation of reactive oxygen species. All of these events can induce an extensive and unbalanced activation of the mucosal immune system, driven by the commensal flora. 3 Recent evidence suggests a role for the cannabinoid system in IBD regulation. Cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed in normal human colon 4,5 and are up-regulated in IBD colonic tissue. In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis. 5 It is thought that CB1 activation results in a decrease of intestinal hypermotility and hypersecretion, whereas the activation of CB2 results in the inhibition of proinflammatory mediators. In addition, both CB2 and CB1 knockout mice are more susceptible to the development of experimental colitis, and the activation of these receptors is extremely important for the abrogation of intestinal inflammation. 6 The role of CB2, however, is directly involved with innate immune system, because CB2 is primarily expressed in immune cells, such as macrophages, CD4 ϩ and CD8 ϩ T cells, monocytes, and polymorphonuclear neutro-

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“…Therapeutic vaccination using peptides from the specific autoantigen-recognizing CDR region of myelin-reactive T cells is another concept that has been tested in a doubleblind proof-of-concept trial in 23 patiens [135]. Further studies have resulted in the development of a vaccine containing 3 CDR2 peptides (Neurovax; Immune Response BioPharma, Atlantic City, NJ, USA) that has been in the focus of an open-label study in 27 patients with MS [136].…”

Section: Autologous T-cell Therapymentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial

Cited by 166 publications

References 47 publications

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

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