Effect of Natalizumab on Circulating CD4+ T-Cells in Multiple Sclerosis

Abstract

In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent transmigration of circulating immune-cells across the vascular endothelium into the CNS. Recent studies suggested that natalizumab treated MS patients have an increased T-cell pool in the blood compartment which may be selectively enriched in activated T-cells. Proposed causes are sequestration of activated T-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T-cells in general or myelin-reactive T-cells in particular showed signs of increased immune activation. Furthermore we examined the effects of natalizumab on CD4+ T-cell responses to myelin in vitro. Natalizumab-treated MS patients had significantly increased numbers of effector-memory T-cells in the blood. In T-cells from natalizumab-treated MS patients, the expression of TNF-α mRNA was increased whereas the expression of fourteen other effector cytokines or transcription factors was unchanged. Natalizumab-treated MS patients had significantly decreased expression of the co-stimulatory molecule CD134 on CD4+CD26HIGH T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26HIGHCD4+ T-cells in vitro. Otherwise CD4+ T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased the effector memory T-cell pool but not the activation state of T-cells in the blood compartment. Myelin-reactive T-cells were not selectively increased in natalizumab treated MS.

OX40, OX40L and Autoimmunity: a Comprehensive Review

“…Coeliac disease OX40-positive lymphocytes present in disease but not control duodenal biopsies [27]; peripheral OX40 expression not affected [152] Rheumatoid arthritis Increased OX40-positivity on lymphocytes in synovial fluid from inflamed joints [26,153,123,154,110] OX40L expression on sublining layer of sinovium from inflamed joints [123,155] Reduced sOX40 [110] Increased sOX40L with correlation with autoantibody status [110] Inflammatory myositis OX40 expression present in inflammatory myopathies but not controls [156,157] OX40L seen on T cells, B cells, macrophages and myeloid dendritic cells in inflammatory myopathies but not controls [156] Uveitis Multiple OX40-positive infiltrating lymphocytes from ciliary bodes of eyes enucleated for uveitis [139] Type 1 Diabetes Mellitus Increased proportion of CD4+ cells positive in peripheral blood of newly diagnosed paediatric cases [106] Systemic sclerosis Elevated serum sOX40 concentrations in comparison with SLE and healthy controls [109] Graves' Thyroiditis Increased OX40-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112,158,159] Increased OX40L-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112] Elevations of sOX40L [48] Multiple sclerosis Reduction in OX40+CD26+ peripheral CD4+ T cells correlating with clinical response after treatment with natalizumab [104] OX40 expressed in MS brain and cord sections [126] Neuromyelitis optica Increased OX40 positivity of pathological brain specimens [126] Sjögren syndrome Increased OX40 expression on peripheral T cells [160] Increased OX40L expression on peripheral B cells and monocytes [160] Myasthenia gravis Increased thymic OX40 staining around germinal centres [161] OX40L present in myasthenia gravis thyroid but not control [161] Increased OX40-staining on peripheral CD4+ T cells [105] Granul...…”

“…in SLE [97][98][99][100][101][102][103]. Disease-ameliorating interventions can reduce proportions of circulating lymphocytes expressing OX40 such as natalizumab in multiple sclerosis or may correlate with other measures of severity: in myasthenia gravis there is a correlation with acetylcholine receptor antibody titer [104,105].…”

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

“…Natalizumab treatment of RRMS patients resulted in decreased cerebral microglial activation [Maoz et al 2014], and reductions in cortical microglial activation following a year of natalizumab therapy were associated with stabilization of physical disability [Politis et al 2013]. Finally, inhibition of VLA-4 on dendritic cells may decrease the capacity of these and other cells to efficiently present antigen and activate T cells [Börnsen et al 2012;de Andres et al 2012;del Pilar Martin et al 2008]. These effects on CNS macrophage infiltration, microglial and/or blood-derived macrophage activation and dendritic-cell function may be directly, and more likely indirectly, beneficial in SPMS by decreasing the number of inflammatory cells in the perivascular and subarachnoid spaces.…”

Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

“…Furthermore, it is also possible that the inefficient viral control is consequence of the effects of NTZ in the immune system. NTZ was showed to disturb the balance between cytokines, up regulating some pro inflammatory cytokines 38 and decreasing the expression of the co-stimulatory molecule CD134 on CD4(+)CD26(HIGH) T-cells 39 . Also, Perkins and coworkers reported that patients receiving Natalizumab who developed PML do not present JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production 40 .…”