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Howard L. Weiner - One of the best experts on this subject based on the ideXlab platform.

  • History and mechanisms of oral tolerance.
    Seminars in immunology, 2017
    Co-Authors: Rafael Machado Rezende, Howard L. Weiner
    Abstract:

    Since its first description by Wells and Osbourne in 1911, oral tolerance has intrigued researchers due to its potential for therapeutic applications. Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Tolerance induction to commensal bacteria and dietary proteins represents the major immunological event taking place in the gut in physiological conditions. Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens: low doses of orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor Clonal Anergy/deletion. In this review, we highlight historical aspects and the mechanisms proposed for oral tolerance induction.

  • Clinical & Developmental Immunology, June–December 2006; 13(2–4): 143–157 Oral tolerance: Therapeutic implications for autoimmune diseases
    2013
    Co-Authors: Ana Maria Caetano Faria, Howard L. Weiner
    Abstract:

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor Clonal Anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy

  • Oral tolerance: therapeutic implications for autoimmune diseases.
    Clinical & developmental immunology, 2006
    Co-Authors: Ana Maria Caetano Faria, Howard L. Weiner
    Abstract:

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor Clonal Anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.

  • oral tolerance immune mechanisms and the generation of th3 type tgf beta secreting regulatory cells
    Microbes and Infection, 2001
    Co-Authors: Howard L. Weiner
    Abstract:

    Oral tolerance is a long recognized method to induce peripheral immune tolerance. Oral tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. Low doses of oral antigen induce active suppression, whereas high doses induce Clonal Anergy and deletion. Oral antigen preferentially generates a Th2(IL-4/IL-10)- or a Th3(TGF-beta)-type response. Th3-type cells are a unique T-cell subset which primarily secrete TGF-beta, provide help for IgA and have suppressive properties for Th1 and other immune cells. Th3-type cells appear distinct from the Th2 cells as CD4(+) TGF-beta-secreting cells with suppressive properties in the gut have been generated from IL-4-deficient animals. In vitro differentiation of Th3-type cells from Th0 precursors from TCR transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10 and anti-IL-12. Because regulatory T cells generated by oral antigen are triggered in an antigen-specific fashion but suppress in an antigen-nonspecific fashion, they mediate bystander suppression when they encounter the fed autoantigen at the target organ. Thus, mucosal tolerance can be used to treat inflammatory processes that are not autoimmune in nature. Mucosal antigen has also been used to treat animal models of stroke and of Alzheimer's disease. Induction of low-dose oral tolerance is enhanced by oral administration of IL-4 and IL-10. Coupling antigen to CTB or administration of Flt-3 ligand enhances oral tolerance. Anti-B7.2 but not anti-B7.1 blocks low-dose, but not high-dose oral tolerance. High-dose oral tolerance is blocked by anti-CTLA-4. CD25(+) CD4(+) regulatory T-cell function also appears to be related to TFG-beta.

  • induction and mechanism of action of transforming growth factor beta secreting th3 regulatory cells
    Immunological Reviews, 2001
    Co-Authors: Howard L. Weiner
    Abstract:

    Summary: Th3 CD4+ regulatory cells were identified during the course of investigating mechanisms associated with oral tolerance. Different mechanisms of tolerance are induced following oral antigen administration, including active suppression, Clonal Anergy and deletion. Low doses favor active suppression whereas high doses favor Anergy/deletion. Th3 regulatory cells form a unique T-cell subset which primarily secretes transforming growth factor (TGF)-β, provides help for IgA and has suppressive properties for both Th1 and Th2 cells. Th3 type cells are distinct from the Th2 cells, as CD4+ TGF-β-secreting cells with suppressive properties have been generated from interleukin (IL)-4-deficient animals. In vitro differentiation of Th3 cells from Th precursors from T-cell antigen receptor (TCR) transgenic mice is enhanced by culture with TGF-β, IL-4, IL-10, and anti-IL-12. Th3 CD4+ myelin basic protein regulatory clones are structurally identical to Th1 encephalitogenic clones in TCR usage, MHC restriction and epitope recognition, but produce TGF-β with various amounts of IL-4 and IL-10. Because Th3 regulatory cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific fashion, they mediate “bystander suppression” when they encounter the fed autoantigen at the target organ. In vivo induction of Th3 cells and low dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86 but not anti-CD80 blocks the induction of Th3 cells associated with low dose oral tolerance. Th3 regulatory cells have been described in other systems (e.g. recovery from experimental allergic encephalomyelitis) but may be preferentially generated following oral antigen administration due to the gut immunologic milieu that is rich in TGF-β and has a unique class of dendritic cells. CD4+CD25+ regulatory T-cell function also appears related to TGF-β.

Lee M. Nadler - One of the best experts on this subject based on the ideXlab platform.

  • R24 anti-GD3 ganglioside antibody can induce co-stimulation and prevent the induction of alloantigen-specific T cell Clonal Anergy
    European Journal of Immunology, 1996
    Co-Authors: Vassiliki A. Boussiotis, Lee M. Nadler, Alan N. Houghton, Nichole A. Pardo, Heather Collins, Jerome Ritz, Robert J. Soiffer
    Abstract:

    : R24 is a monoClonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell Clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in Anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell Clonal Anergy. Binding of GD3 by R24 also prevented Anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoClonal antibodies for the alpha and beta chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell Clonal response.

  • cd2 is involved in maintenance and reversal of human alloantigen specific Clonal Anergy
    Journal of Experimental Medicine, 1994
    Co-Authors: Vassiliki A. Boussiotis, Gary S Gray, Gordon J. Freeman, John G. Gribben, James D Griffin, Lee M. Nadler
    Abstract:

    Induction and maintenance of a state of T cell unresponsiveness to specific alloantigen would have significant implications for human organ transplantation. Using human histocompatibility leukocyte antigen DR7-specific helper T cell clones, we demonstrate that blockade of the B7 family of costimulatory molecules is sufficient to induce alloantigen-specific T cell Clonal Anergy. Anergized cells do not respond to alloantigen and a variety of costimulatory molecules, including B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule (LFA)-3. However, after culture in exogenous interleukin (IL)-2 for at least 7 d, anergized cells can respond to alloantigen in the presence of LFA-3. LFA-3 costimulation subsequently restores responsiveness to alloantigen in the presence of previously insufficient costimulatory signals. Expression of CD2R epitope is downregulated on anergic cells and is restored after 7 d of IL-2 culture. The loss of the CD2R is temporally associated with the inability of anergized cells to respond to LFA-3. These results suggest that in addition to blockade of B7 family members, inhibition of CD2 and, potentially, other costimulatory pathways that might reverse Anergy will be necessary to maintain prolonged alloantigen-specific tolerance.

  • Human T-cell Clonal Anergy is induced by antigen presentation in the absence of B7 costimulation.
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: Claude D. Gimmi, Gary S Gray, Gordon J. Freeman, John G. Gribben, Lee M. Nadler
    Abstract:

    Abstract The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigen-presenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs. In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIH 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell Clonal Anergy. These results demonstrate that it is possible to induce antigen-specific Clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.

Daniel L Mueller - One of the best experts on this subject based on the ideXlab platform.

  • Review E3 ubiquitin ligases and their control of T cell autoreactivity
    2005
    Co-Authors: Jody L Bonnevier, Ruan Zhang, Daniel L Mueller
    Abstract:

    A loss of T cell tolerance underlies the development of most autoimmune diseases. The design of therapeutic strategies to reinstitute immune tolerance, however, is hampered by uncertainty regarding the molecular mechanisms involved in the inactivation of potentially autoreactive T cells. Recently, E3 ubiquitin ligases have been shown to mediate the development of a durable state of unresponsiveness in T cells called Clonal Anergy. In this review, we will discuss the mechanisms used by E3 ligases to control the activation of T cells and prevent the development of autoimmunity

  • e3 ubiquitin ligases as t cell Anergy factors
    Nature Immunology, 2004
    Co-Authors: Daniel L Mueller
    Abstract:

    E3 ubiquitin ligases have emerged as key molecular regulators of immune cell function. Three families of proteins with ubiquitin ligase activity have been described (the HECT, RING and U-box proteins), and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. This review will discuss the relationship between the ubiquitination of select components of the antigen-sensing signaling apparatus in T cells and the development and maintenance of the Clonal Anergy state.

Mirandola, Sandra Regina - One of the best experts on this subject based on the ideXlab platform.

  • Efeito da imunoterapia com interferon beta na produção de citocinas pelos leucocitos de pacientes portadores de esclerose multipla
    [s.n.], 2018
    Co-Authors: Mirandola, Sandra Regina
    Abstract:

    Orientador: Leonilda Maria Barbosa dos SantosDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: O desenvolvimento da tolerância imunológica a antígenos próprios, é resultado de mecanismos que conduzem à supressão de clones de linfócitos específicos aos componentes da mielina, podendo ser um dos mecanismos envolvidos no desenvolvimento da tolerância aos neuro-antígenos. Entre os mecanismos mais estudados estão: deleção, anergia dos clones auto-reativos e os mecanismos regulatórios exercidos pelas citocinas. Evidências clínicas e experimentais sugerem que, anormalidades dos linfócitos T e das citocinas, produzidas pelas células TH1, estão envolvidos no desenvolvimento de doenças auto-imunes órgão-específicas como a Esclerose Múltipla. A Esclerose Múltipla (EM) é a mais importante doença desmielinizante que afeta o homem. Patologicamente é caracterizada pela inflamação e desmielinização de múltiplas áreas da substância branca do SNC, com posterior lesão do oligodendrócito, resultando clinicamente em disfunção neurológica. Embora seja uma doença órgão-específica, com resposta imunológica voltada ao SNC, estudos mostram alterações imunológicas nas células do sangue periférico. As células T auto-reativas, dos pacientes com EM, reconhecem componentes da mielina, como a proteína básica de mielina (MBP), contribuindo à patogenicidade da doença. Uma das abordagens terapêuticas não específica, utilizada no tratamento da Esclerose Múltipla é o Interferon Beta (IFNb). Nestas duas últimas décadas, alguns estudos foram concluídos, mostrando, de uma forma geral, que a administração do IFNb (tanto 1a como 1b) tem efeito benéfico no tratamento da EM na forma surto-remissão e mais recentemente os autores vem utilizando essa abordagem terapêutica também para as formas progressivas da doença (GOODKIN, 2000; NEUHAUS et al., 2003). O efeito terapêutico do interferon tipo I, o IFN beta em particular, mostrou exercer efeito benéfico aos pacientes tratados, diminuindo o número de exacerbações durante o primeiro ano de tratamento (FILLIPPINI et al., 2003), e em alguns casos tais efeitos benéficos duraram acima de 5 anos (MS group, 1995). O efeito terapêutico foi confirmado pela diminuição das lesões verificadas por MRI (PATY et al., 1993). Como a imunoterapia, com IFNb, tem mostrado efeitos benéficos aos pacientes portadores de Esclerose Múltipla (EM) na forma surto-remissão, resolvemos acompanhar o efeito da terapia com IFNb na produção de citocinas dos pacientes em tratamento ou não, assim como em indivíduos normais. Os resultados obtidos, mostraram um aumento significativo na produção das citocinas pro-inflamatórias, tais como TNFa e IFNg no plasma e cultura de leucócitos dos pacientes com EM não tratados. A administração do IFNb reduz, significativamente, os níveis das citocinas pró-inflamatórias, com simultâneo aumento na produção de IL10 e, mais discretamente, na produção de TGFb. Sugere-se então, que a polarização da produção das citocinas pró-inflamatórias participa da cascata de eventos, que leva à desmielinização e que, a administração in vivo de citocinas, como IFNb, pode mudar o curso da resposta inflamatóriaAbstract: Multiple Sclerosis (MS) is the most important demyelinating disease that affects man. Pathologically, it is characterized by the inflamation and demyelination of various areas of the brain, resulting in a clinically - diagnosed neurological dysfunction. Although it is organ-specific, with an immune response aimed at components of the central nervous system, studies have shown immunological alterations in peripheral blood cells. Autoreactive T cells to recognize myelin components such as myelin basic protein (MBP) and thus contribute to the pathogenesis of the disease. Immunotherapy with IFNb shows remarkable beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. Investigation was made of the effects of IFNb on proinflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as healthy controls. The development of tolerance to the body's own antigens is the result of mechanisms which lead to the supression of lymphocyte clones specific for myelin components. Among the best known of these mechanisms are the elimination of self-reacting clones. The suppression of the immune response may be one of the mechanisms involved in the development of tolerance to the neuro-antigens. Among the mechanisms which are most commonly studied are the elimination of the self reactive clones, Clonal Anergy and the immunoregulatory mechanisms exercised by the cytokines. Clinical and experimental evidence suggest that abnormalities of the T lymphocytes and of the cytokines produced by the TH1 cells are involved in the development of organ-specific auto-immune diseases such as Multiple Sclerosis. Results show a significant increase in the production of proinflammatory cytokine such as TNFa and IFNg in the plasma and in the supernatant of a leukocyte culture from MS patients with the untreated disease, whereas IFNb administration significantly reduces these levels, this was accompanied by a significant increase in the production of IL10 and a slight increase in that of TGFb. This reduction in proinflammatory cytokine production in the treated MS patient group accompanied by a simultaneous increase in the production of anti-inflammatory cytokines, suggests that the beneficial effects of IFNb immunotherapy results, at least in part from the modulation of cytokine patternsMestradoCiencias BiomedicasMestre em Ciências Médica

Sandra Regina Mirandola - One of the best experts on this subject based on the ideXlab platform.

  • Efeito da imunoterapia com interferon beta na produção de citocinas pelos leucocitos de pacientes portadores de esclerose multipla
    Universidade Estadual de Campinas . Faculdade de Ciências Médicas, 2004
    Co-Authors: Sandra Regina Mirandola
    Abstract:

    O desenvolvimento da tolerância imunológica a antígenos próprios, é resultado de mecanismos que conduzem à supressão de clones de linfócitos específicos aos componentes da mielina, podendo ser um dos mecanismos envolvidos no desenvolvimento da tolerância aos neuro-antígenos. Entre os mecanismos mais estudados estão: deleção, anergia dos clones auto-reativos e os mecanismos regulatórios exercidos pelas citocinas. Evidências clínicas e experimentais sugerem que, anormalidades dos linfócitos T e das citocinas, produzidas pelas células TH1, estão envolvidos no desenvolvimento de doenças auto-imunes órgão-específicas como a Esclerose Múltipla. A Esclerose Múltipla (EM) é a mais importante doença desmielinizante que afeta o homem. Patologicamente é caracterizada pela inflamação e desmielinização de múltiplas áreas da substância branca do SNC, com posterior lesão do oligodendrócito, resultando clinicamente em disfunção neurológica. Embora seja uma doença órgão-específica, com resposta imunológica voltada ao SNC, estudos mostram alterações imunológicas nas células do sangue periférico. As células T auto-reativas, dos pacientes com EM, reconhecem componentes da mielina, como a proteína básica de mielina (MBP), contribuindo à patogenicidade da doença. Uma das abordagens terapêuticas não específica, utilizada no tratamento da Esclerose Múltipla é o Interferon Beta (IFNb). Nestas duas últimas décadas, alguns estudos foram concluídos, mostrando, de uma forma geral, que a administração do IFNb (tanto 1a como 1b) tem efeito benéfico no tratamento da EM na forma surto-remissão e mais recentemente os autores vem utilizando essa abordagem terapêutica também para as formas progressivas da doença (GOODKIN, 2000; NEUHAUS et al., 2003). O efeito terapêutico do interferon tipo I, o IFN beta em particular, mostrou exercer efeito benéfico aos pacientes tratados, diminuindo o número de exacerbações durante o primeiro ano de tratamento (FILLIPPINI et al., 2003), e em alguns casos tais efeitos benéficos duraram acima de 5 anos (MS group, 1995). O efeito terapêutico foi confirmado pela diminuição das lesões verificadas por MRI (PATY et al., 1993). Como a imunoterapia, com IFNb, tem mostrado efeitos benéficos aos pacientes portadores de Esclerose Múltipla (EM) na forma surto-remissão, resolvemos acompanhar o efeito da terapia com IFNb na produção de citocinas dos pacientes em tratamento ou não, assim como em indivíduos normais. Os resultados obtidos, mostraram um aumento significativo na produção das citocinas pro-inflamatórias, tais como TNFa e IFNg no plasma e cultura de leucócitos dos pacientes com EM não tratados. A administração do IFNb reduz, significativamente, os níveis das citocinas pró-inflamatórias, com simultâneo aumento na produção de IL10 e, mais discretamente, na produção de TGFb. Sugere-se então, que a polarização da produção das citocinas pró-inflamatórias participa da cascata de eventos, que leva à desmielinização e que, a administração in vivo de citocinas, como IFNb, pode mudar o curso da resposta inflamatóriaMultiple Sclerosis (MS) is the most important demyelinating disease that affects man. Pathologically, it is characterized by the inflamation and demyelination of various areas of the brain, resulting in a clinically - diagnosed neurological dysfunction. Although it is organ-specific, with an immune response aimed at components of the central nervous system, studies have shown immunological alterations in peripheral blood cells. Autoreactive T cells to recognize myelin components such as myelin basic protein (MBP) and thus contribute to the pathogenesis of the disease. Immunotherapy with IFNb shows remarkable beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. Investigation was made of the effects of IFNb on proinflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as healthy controls. The development of tolerance to the body´s own antigens is the result of mechanisms which lead to the supression of lymphocyte clones specific for myelin components. Among the best known of these mechanisms are the elimination of self-reacting clones. The suppression of the immune response may be one of the mechanisms involved in the development of tolerance to the neuro-antigens. Among the mechanisms which are most commonly studied are the elimination of the self reactive clones, Clonal Anergy and the immunoregulatory mechanisms exercised by the cytokines. Clinical and experimental evidence suggest that abnormalities of the T lymphocytes and of the cytokines produced by the TH1 cells are involved in the development of organ-specific auto-immune diseases such as Multiple Sclerosis. Results show a significant increase in the production of proinflammatory cytokine such as TNFa and IFNg in the plasma and in the supernatant of a leukocyte culture from MS patients with the untreated disease, whereas IFNb administration significantly reduces these levels, this was accompanied by a significant increase in the production of IL10 and a slight increase in that of TGFb. This reduction in proinflammatory cytokine production in the treated MS patient group accompanied by a simultaneous increase in the production of anti-inflammatory cytokines, suggests that the beneficial effects of IFNb immunotherapy results, at least in part from the modulation of cytokine pattern