MHC-Restricted Depletion of Human Myelin Basic Protein-Reactive T Cells by T Cell Vaccination

Zhang, Jingwu; Medaer, Robert; Stinissen, Piet; Hafler, David A.; Raus, Jef

doi:10.1126/science.7690157

Cited by 278 publications

(185 citation statements)

References 22 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%

“…Furthermore, although the cell culture-based, split-well method used in this study has been proven useful in comparing the frequency of CD4 ϩ myelin-reactive T cells between individual samples when used consistently (6,15,16,28,38), it is problematic to calculate the actual precursor frequency of CD8 ϩ CTLs in this study. Consequently, direct comparison of specific CD8 ϩ T cell wells/cultures was made between MS patients and controls to discern differences in the CD8 ϩ T cell responses to the selected peptides of MBP.…”

Section: Figurementioning

confidence: 99%

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

Zang

Rivera

et al. 2004

The Journal of Immunology

118

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%

Section: Figurementioning

confidence: 99%

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

Zang

Rivera

et al. 2004

The Journal of Immunology

118

105

View full text Add to dashboard Cite

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“…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).…”

Section: Immunization With Irradiated Autologous T Cells (T Cell Vaccmentioning

confidence: 99%

“…nation) has been demonstrated to induce regulatory immune responses in autoimmune conditions of both human and experimental animal models, which are attributed to the suppression of disease activities (1)(2)(3). At least two types of regulatory T cell responses have been identified, which include antiidiotypic and so-called antiergotypic T cell responses (2)(3)(4)(5)(6)(7).…”

Section: Mmunization With Inactivated Autoreactive T Cells (T Cell mentioning

confidence: 99%

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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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Vaccination with autoreactive T cell clones in multiple sclerosis: overview of immunological and clinical data

Stinissen¹,

Zhang²,

Medaer³

et al. 1996

J. Neurosci. Res.

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MHC-Restricted Depletion of Human Myelin Basic Protein-Reactive T Cells by T Cell Vaccination

Cited by 278 publications

References 22 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

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

Vaccination with autoreactive T cell clones in multiple sclerosis: overview of immunological and clinical data

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MHC-Restricted Depletion of Human Myelin Basic Protein-Reactive T Cells by T Cell Vaccination

Cited by 278 publications

References 22 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

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

Vaccination with autoreactive T cell clones in multiple sclerosis: overview of immunological and clinical data

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Product

Resources

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