Northwestern/UChicago work on multiple sclerosis [MS]
Stephen Miller and Brian Popko have a new theory on the origins of multiple sclerosis:
The current prevailing theory [of multiple sclerosis [MS]] is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign. These confused immune cells enter the brain and begin their mistaken attack on myelin, thus initiating MS.
New inside-out discovery
But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The inside-out hypothesis suggests that when myelin falls apart, the products of its degradation are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full-scale attack on myelin, initiating MS.
An estimated 400,000 people in the U.S. and 2.5 million worldwide have MS. Of those with long-standing disease, 50 to 60 percent have progressive MS.
link: http://www.northwestern.edu/newscenter/stories/2015/12/how-multiple-sclerosis-can-be-triggered-by-brain-cell-death.html#sthash.99VZUBHB.dpuf
http://www.nature.com/neuro/journal/v19/n1/full/nn.4193.html
***As background:
T cells in multiple sclerosis and experimental autoimmune encephalomyelitis
Clin Exp Immunol. 2010 Oct; 162(1): 1–11.
MS is a chronic, progressive inflammatory disorder of the brain and spinal cord. The inflammatory plaque, whether determined histopathologically or using magnetic resonance imaging (MRI), is the pathological hallmark of MS [1]. Studies demonstrating the presence of inflammatory cells and their products in the brain lesions of MS patients, in addition to reports from animal models, has led to the generally accepted hypothesis that disease is mediated by pathogenic T cell responses against myelin antigens, followed by a broader neurodegenerative process [2]. The autoreactive T cells migrate across the blood–brain barrier (BBB) and mediate damage against the central neurones and their myelin sheaths, in particular, but also their axons. The key morphological feature of MS is primary demyelination of nerve axons leading to signal conduction block or conduction slowing at the site of demyelination.
(...)
The overwhelming evidence of a role for T cells in the pathogenesis of EAE and MS makes them an attractive target for therapeutic intervention. Indeed, the two most commonly used drugs used to treat MS, IFN-β and glatiramir acetate, can increase Treg cells and IL-10 and thereby suppress proinflammatory T cell cytokines, although they probably also act on other cell types. More deliberate strategies to manipulate T cells involve either targeting inflammatory T cells or their effector functions, or boosting the function of Treg cells. The anti-VLA-4 antibody natalizumab, which inhibits the entry of T cells into the CNS, is relatively effective compared to other licensed drugs.
link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990924/
***As to Alemtuzumab
epletion is followed by lymphocyte repopulation, which begins within weeks. B-lymphocyte counts typically return to baseline by 6 months post-treatment, whereas in clinical trials, mean T-cell counts approached normal (but not baseline) levels by 12 months post-treatment [Kovarova et al. 2012; Kasper et al. 2013]. CD4+ T-cell repopulation is particularly delayed. In a long-term follow-up of 37 patients who had received alemtuzumab treatment in the 1990s for MS, median recovery time to normal levels was 8.4 months for B cells, 20 months for CD8+ T cells and 12 years for CD4+ T cells [Hill-Cawthorne et al. 2012]. It should be noted that many of these patients received a single treatment course of 100 mg over 5 infusion days, which is higher than the approved dose (60 mg over 5 days for the initial course, and 36 mg over 3 days for subsequent courses). T-lymphocyte repopulation is accomplished through proliferation of mature lymphocytes that escaped depletion (i.e. ‘homeostatic’ proliferation) as well as new production from precursors in the thymus [Cox et al. 2005; Jones et al. 2013].
Despite profound depletion of circulating lymphocytes, animal studies have shown that lymphocyte numbers in primary and secondary lymphoid organs are maintained [Hu et al. 2009]. Other aspects of the immune system are also unaffected by alemtuzumab, including innate immune cells, some T-cell subsets (tissue-resident effector memory T cells), plasma cells and serum immunoglobulin levels [Coles et al. 1999b; Clark et al. 2012; Turner et al. 2013].
***
Also http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386803/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286943/
***For a review of monoclonal antibody treatements of MS, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643868/
including as to rituximab:
Rituximab is a chimeric, IgG1, CD20-directed mAb approved for the treatment of patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (in combination with methotrexate) and granulomatosis with polyangiitis and microscopic polyangiitis (in combination with glucocorticoids) [Genentech, 2013]. In a randomized, double-blind, placebo-controlled phase II trial of patients with RRMS [Hauser et al. 2008], rituximab significantly reduced total and new Gd-enhancing lesions and the proportion of patients with relapse compared with placebo after 24 and 48 weeks; however, rituximab is not approved for the treatment of MS and is no longer in clinical development for this indication. However, offlabel use of rituximab for MS occurs in clinical practice in several countries.
Rituximab targets CD20 expressed on pre-B and mature B cells, depleting these cells in the circulation and CNS [Naismith et al. 2010]. Although MS was traditionally considered a T-cell mediated disease, accumulating evidence suggests that B cells play a role. As addon therapy, rituximab decreased the number of Gd-enhancing lesions in a phase II trial of patients with an inadequate response to standard injectable DMTs [Naismith et al. 2010]. In study patients with primary progressive MS, rituximab slowed increases in T2 hyperintense lesion volume but did not prolong time to confirmed disease progression compared with placebo [Hawker et al. 2009]; however, a subgroup analysis found that disease progression was slowed in patients younger than 51 years of age with ⩾1 Gd-enhancing lesion [Hawker et al. 2009].
***Separately
Mult Scler. 2007 Mar;13(2):149-55. Epub 2007 Jan 29.
Increased CD8+ central memory T cells in patients with multiple sclerosis.
Liu GZ1, Fang LB, Hjelmström P, Gao XG.
Abstract
A T-cell-mediated autoimmune process against central nervous system myelin is believed to underlie the pathogenesis of multiple sclerosis (MS). Formation of immunological memory is based on the differentiation of naïve T cells to memory T cells after exposure to antigens and specific cytokines. The aim of this study was to analyse peripheral blood mononuclear cells in patients with MS for different T-cell subsets including naïve and memory T cells. Flow cytometry and enzyme-linked immunosorbent assay were used to analyse memory T-cell subsets and plasma concentration of interleukin-15 (IL-15) in peripheral blood of MS patients, patients with other neurological disorders and healthy controls. MS patients had a skewed distribution of T cells with an increased level of CD8+/CCR7+/CD45RA - central memory T cells (TCM) compared to healthy controls. In addition, MS patients showed significantly higher levels of plasma IL-15 than healthy controls did. Upregulated CD8+ TCM in MS patients may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. This derangement may be important for maintaining chronic inflammation in MS.
link: http://www.ncbi.nlm.nih.gov/pubmed/17439879
The current prevailing theory [of multiple sclerosis [MS]] is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign. These confused immune cells enter the brain and begin their mistaken attack on myelin, thus initiating MS.
New inside-out discovery
But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The inside-out hypothesis suggests that when myelin falls apart, the products of its degradation are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full-scale attack on myelin, initiating MS.
An estimated 400,000 people in the U.S. and 2.5 million worldwide have MS. Of those with long-standing disease, 50 to 60 percent have progressive MS.
link: http://www.northwestern.edu/newscenter/stories/2015/12/how-multiple-sclerosis-can-be-triggered-by-brain-cell-death.html#sthash.99VZUBHB.dpuf
http://www.nature.com/neuro/journal/v19/n1/full/nn.4193.html
***As background:
T cells in multiple sclerosis and experimental autoimmune encephalomyelitis
Clin Exp Immunol. 2010 Oct; 162(1): 1–11.
MS is a chronic, progressive inflammatory disorder of the brain and spinal cord. The inflammatory plaque, whether determined histopathologically or using magnetic resonance imaging (MRI), is the pathological hallmark of MS [1]. Studies demonstrating the presence of inflammatory cells and their products in the brain lesions of MS patients, in addition to reports from animal models, has led to the generally accepted hypothesis that disease is mediated by pathogenic T cell responses against myelin antigens, followed by a broader neurodegenerative process [2]. The autoreactive T cells migrate across the blood–brain barrier (BBB) and mediate damage against the central neurones and their myelin sheaths, in particular, but also their axons. The key morphological feature of MS is primary demyelination of nerve axons leading to signal conduction block or conduction slowing at the site of demyelination.
(...)
The overwhelming evidence of a role for T cells in the pathogenesis of EAE and MS makes them an attractive target for therapeutic intervention. Indeed, the two most commonly used drugs used to treat MS, IFN-β and glatiramir acetate, can increase Treg cells and IL-10 and thereby suppress proinflammatory T cell cytokines, although they probably also act on other cell types. More deliberate strategies to manipulate T cells involve either targeting inflammatory T cells or their effector functions, or boosting the function of Treg cells. The anti-VLA-4 antibody natalizumab, which inhibits the entry of T cells into the CNS, is relatively effective compared to other licensed drugs.
link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990924/
***As to Alemtuzumab
epletion is followed by lymphocyte repopulation, which begins within weeks. B-lymphocyte counts typically return to baseline by 6 months post-treatment, whereas in clinical trials, mean T-cell counts approached normal (but not baseline) levels by 12 months post-treatment [Kovarova et al. 2012; Kasper et al. 2013]. CD4+ T-cell repopulation is particularly delayed. In a long-term follow-up of 37 patients who had received alemtuzumab treatment in the 1990s for MS, median recovery time to normal levels was 8.4 months for B cells, 20 months for CD8+ T cells and 12 years for CD4+ T cells [Hill-Cawthorne et al. 2012]. It should be noted that many of these patients received a single treatment course of 100 mg over 5 infusion days, which is higher than the approved dose (60 mg over 5 days for the initial course, and 36 mg over 3 days for subsequent courses). T-lymphocyte repopulation is accomplished through proliferation of mature lymphocytes that escaped depletion (i.e. ‘homeostatic’ proliferation) as well as new production from precursors in the thymus [Cox et al. 2005; Jones et al. 2013].
Despite profound depletion of circulating lymphocytes, animal studies have shown that lymphocyte numbers in primary and secondary lymphoid organs are maintained [Hu et al. 2009]. Other aspects of the immune system are also unaffected by alemtuzumab, including innate immune cells, some T-cell subsets (tissue-resident effector memory T cells), plasma cells and serum immunoglobulin levels [Coles et al. 1999b; Clark et al. 2012; Turner et al. 2013].
***
Also http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386803/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286943/
***For a review of monoclonal antibody treatements of MS, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643868/
including as to rituximab:
Rituximab is a chimeric, IgG1, CD20-directed mAb approved for the treatment of patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (in combination with methotrexate) and granulomatosis with polyangiitis and microscopic polyangiitis (in combination with glucocorticoids) [Genentech, 2013]. In a randomized, double-blind, placebo-controlled phase II trial of patients with RRMS [Hauser et al. 2008], rituximab significantly reduced total and new Gd-enhancing lesions and the proportion of patients with relapse compared with placebo after 24 and 48 weeks; however, rituximab is not approved for the treatment of MS and is no longer in clinical development for this indication. However, offlabel use of rituximab for MS occurs in clinical practice in several countries.
Rituximab targets CD20 expressed on pre-B and mature B cells, depleting these cells in the circulation and CNS [Naismith et al. 2010]. Although MS was traditionally considered a T-cell mediated disease, accumulating evidence suggests that B cells play a role. As addon therapy, rituximab decreased the number of Gd-enhancing lesions in a phase II trial of patients with an inadequate response to standard injectable DMTs [Naismith et al. 2010]. In study patients with primary progressive MS, rituximab slowed increases in T2 hyperintense lesion volume but did not prolong time to confirmed disease progression compared with placebo [Hawker et al. 2009]; however, a subgroup analysis found that disease progression was slowed in patients younger than 51 years of age with ⩾1 Gd-enhancing lesion [Hawker et al. 2009].
***Separately
Mult Scler. 2007 Mar;13(2):149-55. Epub 2007 Jan 29.
Increased CD8+ central memory T cells in patients with multiple sclerosis.
Liu GZ1, Fang LB, Hjelmström P, Gao XG.
Abstract
A T-cell-mediated autoimmune process against central nervous system myelin is believed to underlie the pathogenesis of multiple sclerosis (MS). Formation of immunological memory is based on the differentiation of naïve T cells to memory T cells after exposure to antigens and specific cytokines. The aim of this study was to analyse peripheral blood mononuclear cells in patients with MS for different T-cell subsets including naïve and memory T cells. Flow cytometry and enzyme-linked immunosorbent assay were used to analyse memory T-cell subsets and plasma concentration of interleukin-15 (IL-15) in peripheral blood of MS patients, patients with other neurological disorders and healthy controls. MS patients had a skewed distribution of T cells with an increased level of CD8+/CCR7+/CD45RA - central memory T cells (TCM) compared to healthy controls. In addition, MS patients showed significantly higher levels of plasma IL-15 than healthy controls did. Upregulated CD8+ TCM in MS patients may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. This derangement may be important for maintaining chronic inflammation in MS.
link: http://www.ncbi.nlm.nih.gov/pubmed/17439879
posted by Lawrence B. Ebert at 10:29 AM
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