A role for natural killer cells in the immunopathogenesis of multiple sclerosis

Kastrukoff, Lorne F.; Morgan, Norma; Zecchini, Daniel; White, Richard Allen; Petkau, A. John; Satoh, Jun‐ichi; Paty, Donald W.

doi:10.1016/s0165-5728(98)00014-9

Cited by 93 publications

(70 citation statements)

References 46 publications

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“…The functional activity of NK cells is variable and is generally lower in MS patients than in healthy individuals [110] . Periods of reduced NK cell numbers in the blood was associated with a higher relapse tendency after.…”

Section: Cd56mentioning

confidence: 99%

Multiple sclerosis and the role of immune cells

Høglund

Maghazachi

2014

WJEM

132

101

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Multiple sclerosis (MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.

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Section: Cd56mentioning

confidence: 99%

Multiple sclerosis and the role of immune cells

Høglund

Maghazachi

2014

WJEM

132

101

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“…Recent studies indicate that the CD56 dim NK cell subset can also be a source of proinflammatory cytokines (12,13). Alterations in peripheral blood NK cell subset numbers and functions have been linked to disease activity in MS (14,15). Treatment of MS patients with daclizumab (IL-2Ra mAb therapy) leads to expansion of the IL-10-producing CD56 bright *Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; subset of NK cells, which may act to regulate the proliferation of potentially autoreactive T lymphocytes, a suggested mechanism for the efficacy of this drug (16,17).…”

mentioning

confidence: 99%

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

Johnson

Evans

Durafourt

et al. 2011

The Journal of Immunology

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FTY720 (fingolimod) treatment of multiple sclerosis (MS) results in lymphopenia due to increased recruitment into and decreased egress from secondary lymphoid organs of CCR7+ lymphocytes. Although absolute numbers of NK lymphocytes were reported as being unaltered in FTY720-treated MS patients (MS-FTY), such analyses did not detect a change in a minor subset. Because expression of CCR7 has been described on CD56bright NK cells, a minority population of NK cells, we investigated the effect of FTY720 treatment on the phenotype and function of human NK cells in the peripheral circulation of MS patients. MS-FTY patients displayed a decreased proportion of peripheral CD56brightCD62L+CCR7+ NK cells compared with untreated MS and healthy donors. In vitro treatment with FTY720-P increased migration of untreated donor NK cells to CXCL12 while reducing the response to CX3CL1 with similar migration responses seen in NK cells from MS-FTY patients. FTY720-P inhibited sphingosine 1-phosphate–directed migration of CD56bright and CD56dim NK cells subsets from untreated healthy donors. IL-12– and IL-15–stimulated NK cells from MS-FTY patients displayed similar capacity to produce IFN-γ, TNF, IL-10, and MIP-1α cytokines/chemokines compared with NK cells from untreated healthy donors and displayed comparable levels of degranulation in response to K562 tumor cells compared with untreated donors. Subset alterations and function of NK cell populations will need to be considered as part of assessing overall immunosurveillance capacity of patients with MS who will receive sustained FTY720 therapy.

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“…It is highly probable, that these cells represent a subpopulation of CD56 bright NK cells. Functional deficiencies in NK cells, especially in their secretion of IFN-γ, which is mainly secreted by CD56 bright NK cells, have been associated with MS and other autoimmune diseases by many studies performed in the past 30 years [69][70][71]. It is likely that CD56 bright NK cells work together with other regulatory cell populations, such as FoxP3+ T-regs or Tr1 regulatory cells, to maintain immune tolerance under physiological conditions.…”

Section: Moa Of Daclizumab On the Human Immune Systemmentioning

confidence: 99%

Daclizumab Therapy for Multiple Sclerosis

Bielekova

2013

Neurotherapeutics

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Daclizumab is a humanized monoclonal antibody of IgG1 subtype that binds to the Tac epitope on the interleukin-2 (IL-2) receptor α-chain (CD25), thus, effectively blocking the formation of the high-affinity IL-2 receptor. Because the high-affinity IL-2 receptor signaling promotes expansion of activated T cells in vitro, daclizumab was designed as a therapy that selectively inhibits T-cell activation. Assuming the previous statement, daclizumab received regulatory approval as add-on therapy to standard immunosuppressive regimen for the prevention of acute allograft rejection in renal transplantation. Based on its putative mechanism of action (MOA), daclizumab represented an ideal therapy for T-cell-mediated autoimmune diseases and was subsequently tested in inflammatory uveitis and multiple sclerosis (MS). In both of these diseases, daclizumab therapy significantly inhibited target organ inflammation. Mechanistic studies in MS demonstrated that the MOA of daclizumab is surprisingly broad and that the drug exerts unexpected effects on multiple components of the innate immune system. Specifically, daclizumab dramatically expands and activates immunoregulatory CD56 bright NK cells, which gain access to the intrathecal compartment in MS and can kill autologous activated T cells. Daclizumab also blocks trans-presentation of IL-2 by mature dendritic cells to primed T cells, resulting in profound inhibition of antigen-specific T cells. Finally, daclizumab modulates the development of innate lymphoid cells. In conclusion, daclizumab therapy, which is currently in phase III testing for inflammatory MS, has a unique MOA that does not limit migration of immune cells into the intrathecal compartment, but rather provides multifactorial immunomodulatory effects with resultant inhibition of MS-related inflammation.

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A role for natural killer cells in the immunopathogenesis of multiple sclerosis

Cited by 93 publications

References 46 publications

Multiple sclerosis and the role of immune cells

Multiple sclerosis and the role of immune cells

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

Daclizumab Therapy for Multiple Sclerosis

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