Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

Steinman, Lawrence

doi:10.1016/j.nurt.2007.07.007

Cited by 23 publications

(16 citation statements)

References 30 publications

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“…Functional T cell studies looking at T cell lines and clones have focused almost entirely on myelin epitope presentation through HLA-DR and, in particular, by the DRA1*0101/DRB1*1501 pair (33,34), although there have been occasional reports of HLA-DQ6-restricted T cells clones from MS patients, including cells specific for MBP 85-99 (35,36). Lack of clarity as to which MHCII peptide specificities are relevant to pathogenesis has relevance to many areas of endeavor in MS research, from analysis and immune-specific targeting of pathogenic TCRs (37) to peptide immunotherapies (38) and programs tracking patients' responses during disease (39). Although most MS genetics studies in North European Caucasian populations suggest HLA-DRB1*1501 as the genetic risk factor in MS (40 -44), other genetic studies in unique populations suggest that HLA-DQ alleles may also be a risk factor.…”

Section: Discussionmentioning

confidence: 99%

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice

Kaushansky

Altmann

Ascough

et al. 2009

The Journal of Immunology

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The susceptibility to multiple sclerosis (MS), a chronic neurological autoimmune disease that primarily targets CNS myelin, has long been associated with HLA class-II genes. Although several other HLA and non-HLA disease predisposing alleles have been identified, alleles of the HLA-DR15 haplotype (DRB1*1501, DRB5*0101, and DQB1*0602) remain the strongest susceptibility factor. Many studies have suggested that the HLA-DRB1*1501 allele determines MS-associated susceptibility. However, due to strong linkage disequilibrium within the HLA class II region, it has been difficult to unequivocally determine the relative roles of the DRB1*1501 and DQB1*0602 products. In this study we use HLA class-II transgenic mice to illuminate the relative contributions of the DRB1*1501 and DQB1*0602 alleles or their combination to susceptibility toward a new “humanized” MS-like disease induced by myelin-associated oligodendrocytic basic protein (MOBP). Although many immunological studies have focused overwhelmingly on the role of the HLA-DRB1*1501 product in MS, we show that HLA-DRB1*1501 transgenics are refractory to MOBP disease induction, whereas the HLA-DQB1*0602 transgenics are susceptible via T cells reactive against MOBP15–36 and MOBP55–77 encephalitogenic epitopes. Although both transgenics react against these epitopes, the MOBP15–36- and MOBP55–77-reactive T cells are of Th2-type in HLA-DRB1*1501 transgenics and are pathogenic Th1/Th17 cells in the HLA-DQB1*0602 transgenic mice. This new humanized model of MS further implicates autoimmunity against MOBP in MS pathogenesis, provides the first evidence of pathogenic HLA-DQ-associated anti-myelin autoimmunity, and is the first to offer a rationale for HLA-DQB1*0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for MS.

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Section: Discussionmentioning

confidence: 99%

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice

Kaushansky

Altmann

Ascough

et al. 2009

The Journal of Immunology

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“…Other infectious agents may also serve to trigger cross-reactivity with myelin components 124,126. One advantage of the adaptive immune response in MS lies in the ability to harness the specificity of T cell responses 122. As such, very discrete immunologic targets of therapy may be available for treating MS, including vaccines 9 and antigen presenting cell (APC)-mediated delivery of antigens 39 designed to induce antigenspecific tolerance.…”

Section: The Role Of T Lymphocytes In Multiple Sclerosismentioning

confidence: 99%

The Immunopathophysiology of Multiple Sclerosis

Alvarez

2011

Neurologic Clinics

136

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OverviewThe etiology of multiple sclerosis (MS) remains elusive. However, clues to its pathogenesis have traditionally been derived from the basic pathologic characterization of central nervous system (CNS) tissues of MS patients. While ongoing debate lingers over the autoimmune nature of MS, it is well established that the immune system directly participates in the destruction of myelin and nervous cells. Understanding the mechanisms of immunemediated destruction of CNS components in MS promises to not only promote effective design of MS therapeutics, but also provides a broader understanding of immune-mediated diseases affecting the CNS. This review will explore the principle features of the immuno-pathology of MS, in particular of relapsing-remitting MS (RR-MS). Herein, emerging concepts in the pathogenesis of MS in the context of known features of pathology have been highlighted. These include the characterization of cytokine networks promoting inflammatory damage of the CNS, B cell involvement, and inflammatory damage of axons and neurons. An effort has been made to preferentially focus on MS rather than animal models of the disease, such as experimental autoimmune encephalomyelitis (EAE). For a more comprehensive examination of data derived from studies on animal models, readers are referred to other outstanding reviews 52,53 . From human studies alone, it is clear that the past 5-10 years have been highly productive in advancing the understanding of the pathogenesis of MS. For both the general neurologist and MS specialist, fundamental appreciation of the immunopathology of MS should lead to a broader understanding of the disease course and the emerging MS therapeutics that are now more than ever tailored to the intricacies of the immune system. Pathologic characterization of MS lesionsPlaques of inflammatory demyelination within the CNS are the pathologic hallmark of MS 29,32,47 . Myelin destruction is an essential element of the plaque. Yet the MS plaque is not simply a static entity of myelin loss in isolation; rather, lesions are comprised of a wide variation of immunologic and pathologic features. These features have been categorized in an effort to understand the neural-immune mechanisms underlying MS. Constructing a

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“…However, for diseases in which the antigens are known or good candidate antigens are available (such as myasthenia gravis 30, Graves’ disease 31, pemphigus vulgaris 32, type I diabetes 33, multiple sclerosis 34 and various types of uveitis22,35–37), antigen-specific therapy would seem to be the ideal approach. As experimental strategies for the induction of antigen-specific tolerance improve, feasibility of antigen-specific regulation comes within reach.…”

Section: Autoimmunitymentioning

confidence: 99%

Immunotherapy of autoimmunity and cancer: the penalty for success

Caspi

2008

Nat Rev Immunol

153

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Advances in our understanding of autoimmunity and tumour immunity have led to improvements in immunotherapy for these diseases. Ironically, effective tumour immunity requires the induction of the same responses that underlie autoimmunity, whereas autoimmunity is driven by dysregulation of the same mechanisms that are involved in host defence and immune surveillance. Therefore, as we manipulate the immune system to treat cancer or autoimmunity, we inevitably unbalance the vital mechanisms that regulate self tolerance and antimicrobial resistance. This Science and Society article aims to dissect the conundrum that is inherent to the concept of immunotherapy and highlights the need for new and more specific therapeutic approaches.The development of cancer and autoimmunity can be seen as a failure of the immune system to control tumour cell growth and to regulate autoreactive responses, respectively. The ability to reprogramme the immune system so that it will maintain homeostasis without the need for continuous treatment is the holy grail of therapies for these diseases. Conventional therapies for autoimmunity and cancer rely primarily on broad-spectrum suppressive regimens. The serious side effects of prolonged chemotherapy for the treatment of cancer or the harsh immuno-suppressive regimens for the treatment of autoimmune disease are well-known and have driven the continuing quest for more specific and less toxic therapies.The immune system is finely balanced to distinguish foreign from self antigens. The process of thymic (central) tolerance eliminates high-affinity self-antigen-specific T cells, as well as those that fail to recognize self antigens entirely, and spares T cells that recognize self antigens with intermediate affinity. Because the naive immune repertoire is positively selected on self antigens, self recognition is hard-wired in the system and this blurs the boundaries between autoimmunity and immunity. Normally, peripheral tolerance keeps potentially autoreactive lymphocytes in check because recirculating lymphocytes are exposed to tissue antigens under non-inflammatory conditions, which results in a tolerant, anergic state. Similarly, autoimmunity and host anti-microbial immunity are inextricably linked, as effector responses that cause inflammatory tissue damage are the same ones that mediate effective host defence. Therefore, immunotherapeutic regimens that target common pathways of the immune system inevitably elicit both desirable and undesirable consequences. Strategies to eliminate cancer cells by breaking tolerance to self antigens can result in autoimmunity; conversely, suppressing immune function to inhibit autoimmune responses can compromise resistance to infection and allow for the development of malignancy 1-5 .Approaches to therapy, both in cancer and in autoimmunity, can broadly be divided into the antigen-specific and the antigen-non-specific (BOX 1). Each has its advantages and its drawbacks, which affect the choice of therapy. Box 1 Antigen-specific versus antigen-non-spe...

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Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

Cited by 23 publications

References 30 publications

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice

The Immunopathophysiology of Multiple Sclerosis

Immunotherapy of autoimmunity and cancer: the penalty for success

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Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

Cited by 23 publications

References 30 publications

HLA-DQB1*0602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice

HLA-DQB1*0602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice

The Immunopathophysiology of Multiple Sclerosis

Immunotherapy of autoimmunity and cancer: the penalty for success

Contact Info

Product

Resources

About

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice

HLA-DQB10602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB11501;DQB1*0602) Transgenic Mice