Correlation of immunological studies and disease progression in chronic progressive multiple sclerosis

Trotter, John L.; Clifford, David B.; McInnis, J E; Griffeth, R C; Bruns, Kathy A.; Perlmutter, Martin; Anderson, Charles B.; Collins, Kelly G.; Banks, Gordon; Hicks, Barbara

doi:10.1002/ana.410250211

Cited by 60 publications

(27 citation statements)

References 29 publications

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“…Production of IL-2 in RR MS decreases during exacerbations and normalizes on remission [26}. In contrast, production of IL-2 by peripheral blood lymphocytes is increased in CP MS [24,261, for which reason a decreased in vitro proliferative response to exogenous IL-2 might have been expected in CP MS. This was not found perhaps because a high dose of IL-2 (200 units/ml) was employed.…”

Section: Discussionmentioning

confidence: 98%

Increased lymphocyte beta‐adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28− suppressor cell

Karaszewski

Reder

Anlar

et al. 1991

Annals of Neurology

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Beta-adrenergic receptor density on T cells from healthy humans is greatest on suppressor cells (CD8+, CD28-) and the effect of catecholamines, secreted by the sympathetic nervous system, predominates on this subset. The sympathetic skin response, a measure of sympathetic nervous system function, is absent in most patients with chronic progressive multiple sclerosis (MS). We measured beta-adrenergic receptor density on suppressor cells, cytotoxic cells, and monocytes from patients with chronic progressive MS and healthy control subjects. Control receptor density on suppressor cells was 2.8 +/- 0.3 fmol/10(6) cells versus a density of 5.1 +/- 0.7 fmol/10(6) cells for patients. Cytotoxic cell (CD8+, CD28+) receptor density was 1.4 +/- 0.4 fmol/10(6) cells in control subjects and 0.9 +/- 0.3 fmol/10(6) cells in the patients. Monocytes displayed beta-adrenergic receptor densities of 2.6 +/- 0.4 fmol/10(6) cells in normal individuals and 2.7 +/- 0.4 fmol/10(6) cells in the patient group. CD8 lymphocyte beta-adrenergic receptor densities in patients with relapsing-remitting and those with stable MS were not different from control values, yet were significantly less than the values for patients with chronic progressive MS. We find that mononuclear cells from healthy control subjects and patients with chronic progressive MS proliferate in response to 200 units/ml of recombinant human interleukin-2 (IL-2) similarly. However, IL-2 treatment increased beta-adrenergic receptor density on normal mononuclear cells, but failed to increase it on mononuclear cells from patients with chronic progressive MS.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 98%

Increased lymphocyte beta‐adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28− suppressor cell

Karaszewski

Reder

Anlar

et al. 1991

Annals of Neurology

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“…The possibility that infectious agents, particularly viruses, are involved [3], [4] remains controversial [5], [6], [7] and the evidence suggests that if an infectious agent is involved, it alone may not be sufficient to initiate the observed pathology [5], [6], [7]. There are several lines of evidence implicating the cytokine, interleukin-2 (IL-2) in the pathology of MS [8], [9], [10], [11]. Patients with MS have elevated levels of IL-2 in their cerebrospinal fluid (CSF) and sera and IL-2-deficient mice are more resistant to experimental autoimmune encephalitis (EAE) than their heterozygote and wild-type counterparts [12].…”

Section: Introductionmentioning

confidence: 99%

IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

et al. 2011

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To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS.

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“…everal lines of evidence implicate interleukin-2 (IL-2) in the pathology of multiple sclerosis (MS) (1)(2)(3)(4). Patients with MS have elevated levels of IL-2 in their sera and cerebrospinal fluid (CSF) (1)(2)(3)(4).…”

mentioning

confidence: 99%

“…Patients with MS have elevated levels of IL-2 in their sera and cerebrospinal fluid (CSF) (1)(2)(3)(4). The soluble IL-2 receptor (sIL-2R) is also elevated in the sera and CSF of patients with MS (3,(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Mott

Zandian

Allen

et al. 2013

J Virol

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We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination. Several lines of evidence implicate interleukin-2 (IL-2) in the pathology of multiple sclerosis (MS) (1-4). Patients with MS have elevated levels of IL-2 in their sera and cerebrospinal fluid (CSF) (1-4). The soluble IL-2 receptor (sIL-2R) is also elevated in the sera and CSF of patients with MS (3, 5-10). These clinical findings of elevated IL-2 levels (and lower than normal IL-4 levels) in the sera of MS patients suggest a possible link between IL-2 and the onset of MS. Furthermore, supernatants harvested from T lymphocytes of MS patients cause damage to myelin and glial cells in vitro (11,12), suggesting that the MS T lymphocytes produce demyelination factors and are activated in vivo.In order to investigate the role of cytokines in demyelination in a viral model of MS, we had constructed a panel of recombinant herpes simplex virus 1 (HSV-1) isolates that constitutively express murine cytokines, including IL-2 (13), IL-4, gamma interferon (IFN-␥), . Using these viruses, we have shown that infection of different strains of mice with a recombinant HSV-1 strain constitutively expressing IL-2 (HSV-IL-2), but not HSV-IL-4, HSV-IFN-␥, HSV-IL-12p35, or HSV-IL12p40, results in demyelination of the optic nerves (ONs), the spinal cords (SCs), and the brains of the infected mice, as determined by histologic examination of tissues obtained at necropsy (17,18). In addition, the HSV-IL-2-infected mice developed optic neuropathy, as determined by changes in the visual evoked cortical potentials (VECPs) (18). Using knockout mice, depletion, and transfer studies, we found that both CD8 ϩ and CD4 ϩ T cells contributed to HSV-IL-2-induced central nervous system (CNS) demyelination, with CD8 ϩ T cells being the primary inducers (19). We have also found that infection of mice with a recombinant HSV-1 isolate expressing IL-12p...

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Correlation of immunological studies and disease progression in chronic progressive multiple sclerosis

Cited by 60 publications

References 29 publications

Increased lymphocyte beta‐adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28− suppressor cell

Increased lymphocyte beta‐adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28− suppressor cell

IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

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