T cell vaccination in multiple sclerosis relapsing–remitting nonresponders patients

Achiron, Anat; Lavie, Gad; Kishner, Irena; Stern, Yael; Sarova-Pinhàs, I; Ben-Aharon, T; Barak, Yoram; Raz, H; Lavie, Mor; Barliya, Tilda; Faibel, Meir; Cohen, Irun R.; Mandel, Mathilda

doi:10.1016/j.clim.2004.06.004

Cited by 43 publications

(41 citation statements)

References 20 publications

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“…The mechanism of this CD8 ϩ antiidiotypic T cell regulation is relatively well characterized and is found to involve components of target T cell receptor in the context of MHC class I molecules (3)(4)(5)(6). However, it remains to be determined whether depletion of circulating autoreactive T cells alone would be sufficient to induce or account for clinical improvements seen in some of MS patients treated with T cell vaccination (3,5,15,(20)(21)(22)(23). In this regard, it is insightful that Cohen and colleagues (7,12) and other investigators showed in experimental autoimmune encephalomyelitis experiments that only activated, but not resting, encephalitogenic T cells could induce full protection through T cell vaccination.…”

Section: Reactivity Patterns and The Recognition Of Il-2 Receptor-dermentioning

confidence: 99%

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Hong

Zang²,

Nie³

et al. 2006

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

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Immunization with irradiated autologous T cells (T cell vaccination (3,6,8). CD8 ϩ antiidiotypic T cell response is thought to contribute directly to depletion of circulating autoreactive T cells (3,5,9). It was also evident in a number of studies that in addition to CD8 ϩ antiidiotypic T cells, T cell vaccination induces CD4 ϩ regulatory T cell responses in both experimental autoimmune encephalomyelitis and human MS (7, 10). CD4 ϩ regulatory T cell responses may represent an important immune regulatory component relevant to clinical effects of T cell vaccination (7, 9, 11). However, the nature and functional properties of these CD4 ϩ regulatory T cells are poorly understood. It has been suggested that CD4 ϩ regulatory T cell responses may be induced through interaction with certain T cell markers loosely and collectively called ''ergotopes'' (7, 11, 12). There have been some indications that T cell activation molecules such as IL-2 receptor and heat-shock protein 60 may be among candidate ergotopes (11)(12)(13)(14). It has been a topic of great interest to characterize the nature and functional properties of human CD4 ϩ regulatory T cell responses induced by T cell vaccination in clinical trials because the findings would have direct implication in the understanding of the potential therapeutic role of T cell vaccination in human autoimmune conditions. This study was undertaken to characterize CD4 ϩ regulatory T cell responses in patients with MS that received immunization through multiple s.c. injections with irradiated autologous myelin basic protein (MBP)-reactive T cell lines in a previous clinical trial (15). Substantial CD4 ϩ regulatory T cell responses were observed in all MS patients after three immunizations, which correlated with clinical improvement in some of the patients, with respect to disability score, rate of relapse, and brain lesions by magnetic resonance imaging (15). A panel of CD4 ϩ regulatory T cell lines was raised against autologous MBP-reactive T cells originally used for immunization. We first determined whether CD4 ϩ regulatory T cell responses induced by T cell vaccination represented heterogeneous populations of distinctive functional and phenotypic patterns. Experiments were designed to define whether a proportion of the resulting CD4 ϩ regulatory T cell lines expanded from the CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cell pool, a hypothesis proposed in this study. Attempts were made to further address whether human CD4 ϩ regulatory T cells induced by T cell vaccination shared the features of antiergotypic T cells seen in experimental animal models in recognition of candidate ergotopes. The findings described here support the important role of CD4 ϩ regulatory T cell responses in T cell vaccination, which may have therapeutic relevance in MS. Results CD4 ؉ Regulatory T Cell Responses Induced by T Cell Vaccination inPatients with MS. Blood specimens were obtained from MS patients that received multiple s.c. injections of irradiated autologous MBPreactive T cells in a previous clinical tri...

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Section: Reactivity Patterns and The Recognition Of Il-2 Receptor-dermentioning

confidence: 99%

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Hong

Zang²,

Nie³

et al. 2006

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

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“…T cell vaccination (TCV) was developed and successfully applied in several animal models of AIDs [16]. Based on the positive results in animals, TCV was tested in humans, mostly in MS and RA by several groups in Europe [28], the US [27], and Israel [1], with positive results (lowering the attack rate and lesion burden by MRI [73,74]). TCR peptide vaccination was also tried in human MS [11].…”

Section: The Selectivity Of Treatmentmentioning

confidence: 99%

Treatment of autoimmune disease: time for a paradigm shift?

Mor

2007

Arch. Immunol. Ther. Exp.

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Current treatment of human autoimmune diseases (AIDs) was developed empirically and relies mostly on non-selective suppression of the immune system. Traditional non-selective immunosuppressants such as corticosteroids, cyclophosphamide, and methotrexate and more novel means such as monoclonal antibodies to CD3, CD4, or CD25 do not discriminate between pathogenic and beneficial T cells. Importantly, the severe side effects seen with current therapies are related to the fact that these treatments not only suppress the pathogenic disease-inducing cells, but also cells influential in combating infections and killing malignant cells. Severe infections and malignancies are the inevitable result of non-selective immune suppression. Many of the novel forms of therapy of AID were developed in experimental animals, and their translation to the human disease was associated with the revelation of unexpected and sometimes catastrophic side effects. These surprises underscore the major differences between the relative simplicity of the experimental model and the complexity of the human disease. How can this current state of treatment of AID be improved? Which principles should guide us in the design of new treatments? This review attempts to offer a new look at these questions.

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“…Immunizing animal models with synthetic peptides corresponding to CDR3 [228] or CDR2 [229] segment of TCR of the T-cells which are activated against myelin basic protein (MBP) conferred resistant to the following induction of EAE and promoted recovery from the disease [232]. This approach has also been used in pilot clinical trials to immunize MS patients with either attenuated autologous MBP-reactive T-cells [233][234][235] or synthetic peptides [236,237]. Results of these and similar studies show a significant reduction in the population of disease-associated T-cells and indicate a protective effect against the disease, yet further evidence need to be achieved to prove the safety and efficacy of this approach in treating affected patients.…”

Section: N O T F O R D I S T R I B U T I O Nmentioning

confidence: 99%

Autoimmunity and Apoptosis - Therapeutic Implications

Rashedi

Panigrahi²,

Ezzati³

et al. 2007

CMC

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Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T-and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions.

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T cell vaccination in multiple sclerosis relapsing–remitting nonresponders patients

Cited by 43 publications

References 20 publications

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Treatment of autoimmune disease: time for a paradigm shift?

Autoimmunity and Apoptosis - Therapeutic Implications

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T cell vaccination in multiple sclerosis relapsing–remitting nonresponders patients

Cited by 43 publications

References 20 publications

CD4+regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

CD4+regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Treatment of autoimmune disease: time for a paradigm shift?

Autoimmunity and Apoptosis - Therapeutic Implications

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CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis