Interleukin‐10‐Modulated Immature Dendritic Cells Control the Proinflammatory Environment in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a disabling, inflammatory, demyelinating disease of the central nervous system considered to be mediated by autoreactive T cells. Dendritic cells (DC), being professional antigen-presenting cells, play a pivotal role in the decision between T-cell activation and anergy. It has been suggested that mature DC (mDC) induce immunity, whereas immature DC (imDC) have the potential to induce tolerance. In this study, we investigated the effects of autologous imDC versus autologous mDC on lymphocytes with respect to the expression of functionally important cell-surface molecules and production of cytokines. Our aims were to investigate whether the maturation status of DC differs between MS and healthy controls (HC) and to explore whether the effects of DC on T-cell responses differ between MS and HC. DC were generated from adherent blood mononuclear cells from patients with MS and HC. imDC were obtained by culture with either granulocyte-macrophage colony-stimulating factor (GM-CSF) þ interleukin-4 (IL-4) or GM-CSF þ IL-4 þ IL-10. mDC were obtained by adding lipopolysaccharide to DC cultures. Upon coculture with autologous lymphocytes, mDC activated the autologous T cells as reflected by increased CD25 and cytotoxic T-lymphocyte antigen-4 expression on CD4 þ T cells together with the increased production of both T helper 1 (Th1) (IL-2 and interferon-g) and Th2 (IL-10 and IL-4) cytokines. Unmodulated naïve imDC induced the production of only IL-4. An exposure of imDC to IL-10 induced the production of IL-4 as well as IL-10 by autologous lymphocytes. We hypothesize that such imDC are important in controlling the proinflammatory environment in vivo in patients with MS.

A novel subset of helper T cells promotes immune responses by secreting GM-CSF

“…1,5,18,46 After antigen exposure, the early activation process is not equivalent for every T cell, as the cells are influenced by a variety of factors that further influence their response. [1][2][3][4][5][6][7] These factors include the types and doses of antigen, duration and site of exposure, cell type responsible for presentation, genetic factors, and the cytokine environment. As several of these factors come into play during an immune response, it is very unlikely that every T cell could experience the same schooling to create a perfectly coordinated response.…”

“…[1][2][3][4][5][6] Several types of immune cells, including dendritic cells (DCs), B cells, and NK cells, can influence the polarization of an immune response toward either a humoral or a cellular type, depending on the type of antigen, available cytokines, and the costimulatory environment. 5,[7][8][9] However, many of the molecules that drive a specific immune response have yet to be identified. 1,3,10 It is interesting that cytokines such as IL-18 can drive a type 1 helper T cell (Th1)-biased immune response in the absence of the classical cytokines.…”

Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

“…IL-10 may also induce T cell anergy and regulatory T cell production (Groux et al, 1996,Roncarolo et al, 2002. Immature dendritic cells exposed to IL-10 resist LPS-induced maturation (Adikari et al, 2004). IL-10 also stimulates certain aspects of immune function, including macrophage phagocytosis and B cell proliferation and antibody production (Beebe et al, 2002).…”

A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines

“…In this sense, TolDCs capable of modulating immune responses in an antigen-specific manner have become a promising therapeutic tool. TolDCs can be generated ex vivo from peripheral blood monocytes modulated by different approaches, including conditioning with pharmacological agents such as vitamin D3, dexamethasone (Dex) and rapamycin [8-10]; anti-inflammatory cytokines including IL-10 and TGF-β [5,11]; and genetic modifications such as IL-4 and IL-10 transduction [12,13]. …”