T-cell vaccination in multiple sclerosis

T cells that are autoreactive against myelin antigens play a pivotal role in the pathogenesis of multiple sclerosis (MS). The concept of T cell vaccination (TCV) has been developed to generate an immune response against these autoreactive pathogenic T cells. Immunologic data accumulated so far demonstrates depletion of T cells reactive against immunodominant myelin peptides after immunization in the animal model of experimental autoimmune encephalomyelitis, as well as in vaccinated MS patients. Clinical trials have confirmed the safety and efficacy of TCV in a small number of immunized MS patients. TCV resulted in reduced relapse rates and slowed the progression of neurological disability and MRI brain lesion load. Recently, there have been several double-blind, placebo-controlled studies initiated to evaluate the role of TCV in MS. Specifically, it is important to examine the effect of early TCV, given after the first episode suggestive of the disease, in order to prevent the process of epitope spreading.     

T-cell vaccination for autoimmune diseases: immunologic lessons and clinical experience in multiple sclerosis

Autoreactive T-cells are regulated under the normal conditions and play an important role in autoimmune pathologies when they are dysregulated as a result of genetic, environmental and other unknown factors associated with various autoimmune diseases. The immune regulation of autoreactive T-cells may be regained by activating the regulatory network, such as the idiotype anti-idiotypic network. Immunization with inactivated autoreactive T-cells (T-cell vaccination) can be used as a powerful means of activating the idiotype anti-idiotypic network to deplete specific subsets of autoreactive T-cells potentially involved in autoimmune conditions. It induces regulatory immune responses that closely resemble the in vivo situation, where the immune system is challenged by clonal activation and expansion of given T-cell populations in various autoimmune diseases. Recent clinical trials in multiple sclerosis have begun to reveal the role of T-cell vaccination in the understanding of in vivo regulation of autoreactive T-cells and in the development of effective therapeutic strategies for multiple sclerosis and other autoimmune conditions. In this article, we will review the recent advances in T-cell vaccination in relationship to the regulatory mechanism induced by T-cell vaccination and the potential of T-cell vaccination as a treatment for T-cell-mediated autoimmune diseases. Current issues and thoughts related to the preparation of T-cell vaccine, the relevant sources of autoimmune T-cells and epitope spreading are also discussed.     

T-cell vaccination in multiple sclerosis: immunoregulatory mechanism and prospects for therapy

Vaccination with inactivated autoreactive T cells (T-cell vaccination) was originally developed to study immune regulation in experimental autoimmune conditions. During the last two decades, research in this area has led to the new understanding of cellular and molecular mechanisms whereby autoreactive T cells are regulated in vivo and the development of new therapeutic strategies using synthetic peptides and plasmid or viral DNA vectors. Recently T-cell vaccination has been advanced to human trials in patients with multiple sclerosis. These early clinical studies were designed to test the potential treatment efficacy of T-cell vaccination and have shown some promising results. In this article, new insights in the understanding of the regulatory mechanism induced by T-cell vaccination and the results of the clinical trials are reviewed. In particular, issues related to the improvement of the current T-cell vaccination protocol are discussed in relationship to the concept of immune regulation and clinical considerations.     

T-cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-cell vaccination

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-cell vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-cell vaccination has been tested for MS in several clinical trials. This review summarizes these clinical trials and updates our current knowledge on the induction of regulatory immune networks by T cell vaccination.     

Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy

Fingolimod, also known as FTY720, has recently been approved by the regulatory authorities in the US, EU, Australia, Russia, among others, for the treatment of relapsing-remitting multiple sclerosis. Fingolimod therefore represents the first oral drug for the treatment of this autoimmune disease of the central nervous system. Fingolimod modulates sphingosine-1 phosphate receptors and has unique immunoregulatory properties. Mechanistic studies from animal models have shown that fingolimod prevents immune cells from exiting from the lymphoid tissue and reaching the inflammatory tissue. Indeed, two phase III studies that laid the basis for fingolimod's approval demonstrated that fingolimod efficiently improves the relapse rate compared to both placebo and one of the standard MS medications. In this review, we will summarize the immunological profile of fingolimod, discuss the possible direct neurobiological effects that have been suggested recently and present the clinical data regarding the efficacy and safety profiles of this promising new drug.     

Immune responses to polyclonal T-cell vaccination in patients with progressive multiple sclerosis

The overall objective of disease management in autoimmune diseases is to suppress chronic inflammation and prevent organ damage. Therapies often revolve around five drug classes: non-steroidal anti-inflammatory drugs (NSAIDS), anti-malarials, steroids, immunosuppressants, and bio-therapies. However, none of these is a ‘cure’ and each displays a potential for adverse events. In particular, while all of them suppress harmful autoimmune responses, they also impact on useful protective immune responses. T-Cell receptor (TCR) immunogenicity provides a rationale for T-cell vaccinations to induce anti-idiotypic immune responses with the purpose of down-regulating functionality of idiotype-bearing self-reactive T-cells. To explore this, in this study, 39 patients with progressive (chronic) multiple sclerosis (MS) were multiply immunized with autological polyclonal T-cell vaccines (TCVs). None of the TCV-treated patients experienced any significant side-effects during the entire follow-up period (2 years). T-Cell vaccination had no significant effects on T-cell sub-population contents in the blood of MS patients after 2 years of immunotherapy initiation. However, a substantial reduction in the frequency of CD4^+?and CD8^+?memory T-cells able to produce interferon (IFN)-γ following activation were noted in the blood of TCV-treated patients. Moreover, significant and sustained reduction in plasma IFNγ levels and concomitant increases in interleukin (IL)-4 levels were documented in these samples. The TCV-treated subjects, however, exhibited no significant changes in plasma IL-17 and IL-18. More importantly was a significant decline in proliferative T-cell responses to myelin antigens in the TCV-treated patients, indicating attenuation of myelin-specific T-cell activity. Collectively, the results suggest that polyclonal T-cell vaccination is safe to use, able to induce measurable, long-lasting, anti-inflammatory immune effects in patients with advanced MS.     

T-cell autoimmunity in multiple sclerosis

Autoreactive T cells are crucial in the immunopathogenesis of multiple sclerosis. As discussed at a recent meeting, research in this area has provided the basis for innovative immunotherapies.     

Glatiramer acetate: mechanisms of action in multiple sclerosis

Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four amino acids resembling myelin basic protein (MBP). GA has been shown to be effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. It was tested in several clinical studies and approved for the immunomodulatory treatment of relapsing-type MS in 1996. Glatiramer acetate demonstrates a strong promiscuous binding to major histocompatibility complex molecules and inhibits the T cell response to several myelin antigens. In addition, it was shown to act as a T cell receptor antagonist for the 82-100 MBP epitope. Glatiramer acetate treatment causes in vivo changes of the frequency, cytokine secretion pattern and effector function of GA-specific T cells. It was shown to induce GA-specific regulatory CD4(+) and CD8(+) T cells and a TH1-TH2 shift with consecutively increased secretion of antiinflammatory cytokines. GA-specific TH2 cells are able to migrate across the blood-brain barrier and cause in situ bystander suppression of autoaggressive TH1 T cells. In addition glatiramer acetate was demonstrated to influence antigen presenting cells (APC) such as monocytes and dendritic cells. Furthermore secretion of neurotrophic factors with potential neuroprotective effects was shown.     

T-cell subsets in multiple sclerosis: Lack of correlation between helper and suppressor T cells and the clinical state

Peripheral blood T-lymphocyte subsets were investigated in a group of 26 multiple sclerosis (MS) patients of different clinical categories and compared to those of 15 normal controls and 7 other patients with known immunoregulatory disorders. In addition 17 well-documented acute relapses in 11 MS patients were also studied, some of whom were tested serially prior to, during, and after the acute attack. Using three different commercial preparations of monoclonal antibodies directed against human T3, T4, and T8 lymphocyte markers, none of the MS patients irrespective of disease category exhibited any changes in the absolute numbers of T-cell subsets or ratios thereof; this was true during either quiescent or active stages of the disease. In contrast, several patients with known immunoregulatory disorders exhibited clear changes in T4/T8 ratios. Factors such as type of patient studied, sampling error, and methods of isolation of mononuclear cells, as well as source of monoclonal antibody, failed to explain the lack of change in T-cell subsets in these patients. Thus, our data fail to confirm the previous reports of a decrease in the absolute numbers of T8 cells or the increase in the T4/T8 ratios in active or quiescent MS patients. These negative findings underscore the need for further studies relating these markers to meaningful functional properties of these cells and their interaction with the relevant target organs.     

Hepatitis B vaccination and the risk of multiple sclerosis

BACKGROUND: Reports of multiple sclerosis developing after hepatitis B vaccination have led to the concern that this vaccine might be a cause of multiple sclerosis in previously healthy subjects. METHODS: We conducted a nested case-control study in two large cohorts of nurses in the United States, those in the Nurses' Health Study (which has followed 121,700 women since 1976) and those in the Nurses' Health Study II (which has followed 116,671 women since 1989). For each woman with multiple sclerosis, we selected as controls five healthy women and one woman with breast cancer. Information about hepatitis B vaccination was obtained by means of a mailed questionnaire and was confirmed by means of vaccination certificates. The analyses included 192 women with multiple sclerosis and 645 matched controls and were conducted with the use of conditional logistic regression. RESULTS: The multivariate relative risk of multiple sclerosis associated with exposure to the hepatitis B vaccine at any time before the onset of the disease was 0.9 (95 percent confidence interval, 0.5 to 1.6). The relative risk associated with hepatitis B vaccination within two years before the onset of the disease was 0.7 (95 percent confidence interval, 0.3 to 1.8). The results were similar in analyses restricted to women with multiple sclerosis that began after the introduction of the recombinant hepatitis B vaccine. There was also no association between the number of doses of vaccine received and the risk of multiple sclerosis. CONCLUSIONS: These results indicate no association between hepatitis B vaccination and the development of multiple sclerosis.     

T cell vaccination in multiple sclerosis: a preliminary report.

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system. Inoculation of attenuated T cell clones recognizing immunodominant regions of myelin autoantigens can protect animals from the induction of experimental autoimmune diseases. In this phase one trial, we investigated whether inoculations with attenuated T cell clones are feasible in humans for eventual trials with autoreactive clones and whether there are any associated immunologic effects. A total of seven inoculations with attenuated, autologous T cell clones isolated from the cerebrospinal fluid in four subjects with progressive MS was performed. No untoward side effects were observed. Immunologic studies suggested that the inoculation of autologous activated T cell clones followed by partial, short-term, immunosuppression as evidenced by a decrease of subsequent responses to stimulation via the CD2 pathway and increases in the autologous mixed lymphocyte response. We conclude that the use of attenuated autoreactive T cell clones appears feasible for further clinical trials in humans with autoimmune diseases.     

T cell vaccination in multiple sclerosis relapsing-remitting nonresponders patients

Myelin autoreactive T cells are involved in the pathogenesis of multiple sclerosis (MS) and lead to propagation of the disease. We evaluated the efficacy of T cell vaccination (TCV) therapy for patients with aggressive relapsing-remitting MS who failed to respond to immunomodulatory treatments. Twenty nonresponders relapsing-remitting MS patients were immunized with autologous attenuated T cell lines after activation with synthetic myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptides. Each patient received three vaccinations in 6- to 8-week intervals. Annual relapse rate decreased from 2.6 to 1.1, P = 0.026. Neurological disability stabilized as compared with the 2- and 1-year pretreatment progression rates. Significant reduction in the number and volume of active lesions, as well as reduction in T2 lesion burden, was demonstrated by quantitative MRI analysis. No serious adverse events were observed. Our findings suggest that TCV has beneficial clinical effects in MS patients who, in spite of immunomodulatory treatments, continue to deteriorate. TCV could serve as a potential alternative therapy for this subgroup of nonresponders patients.     

Catalytic autoantibodies in multiple sclerosis: Pathogenetic and clinical aspects

The significance of catalytic autoantibodies abzymes in the pathogenesis of multiple sclerosis was evaluated in patients with different disease patterns and severity of disability.__________This revised version was published online in July 2005 with the addition of the issue titleTranslated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 1, pp. 98–101, January, 2005     

T-cell regulation by CD46 and its relevance in multiple sclerosis

CD46 is a complement regulatory molecule expressed on every cell type, except for erythrocytes. While initially described as a regulator of complement activity, it later became a ‘magnet for pathogens’, binding to several viruses and bacteria. More recently, an alternative role for such complement molecules has emerged: they do regulate T-cell immunity, affecting T-cell proliferation and differentiation. In particular, CD46 stimulation induces Tr1 cells, regulatory T cells characterized by massive production of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. Hence, CD46 is likely to control inflammation. Indeed, data from CD46 transgenic mice highlight a role for CD46 in inflammation, with antagonist roles depending on the cytoplasmic tail being expressed. Furthermore, recent data have shown that CD46 is defective in multiple sclerosis, IL-10 production being severely impaired in these patients. This lack of IL-10 production probably participates in the inflammation observed in patients with multiple sclerosis. This review will summarize the data on CD46 and T cells, and how CD46 is likely involved in multiple sclerosis.     

T-cell response dynamics in animal models of multiple sclerosis: implications for immunotherapies

Multiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a complex immune nature and varied clinical presentation. Current therapies for MS are limited by toxicity and efficacy, so interest has now turned to specifically modulating autoreactive T-cell responses. Murine MS models, such as experimental autoimmune encephalomyelitis (EAE), have proved invaluable for understanding the immune components of MS and for designing and testing potential immunotherapies. Here, we review the current knowledge of the mechanisms of induction and progression of EAE and MS and the immunotherapies that have resulted from studies of the EAE model.     

MSCT多模式重组诊断脊髓分裂畸形的临床应用

目的总结多层螺旋CT在诊断脊髓分裂畸形中的临床应用。方法 13例脊髓分裂畸形的病人均进行全脊椎CT扫描,后分别进行图像后处理,方法包括多平面重组(MPR)、容积再现(VR)、最大密度投影(MIP)、曲面重组(CPR),比较各种图像后处理方法在判断椎管内骨嵴的形态、范围、伴发椎体畸形以及相应脊髓改变等方面的各自优势。结果 13例病人中PangⅠ型8例(61.5%),PangⅡ型5例(31.5%)。VR像对于6例椎管内骨性分隔及伴发椎体畸形的形态显示较好,立体感强;但2例纤维性分隔及所有病人脊髓的改变几乎不能显示。MIP对骨骼和脊髓的异常均能显示,但4例脊椎侧弯的病例难以显示脊椎全貌。CPR像对4例脊柱侧弯的病人可显示脊椎全貌,但脊髓改变在2例侧弯程度较重的病人中难以清晰显示。结论 CT诊断脊髓分裂畸形准确、可靠,多种图像后处理方法结合使用可最大限度的对病变节段的椎体、脊髓状况做出判断,有利于临床治疗方案的确定。