Concordance and contradiction concerning cytokines and chemokines in experimental demyelinating disease

Abstract

Experimental autoimmune encephalomyelitis (EAE) has served as a model for human demyelinating diseases, including multiple sclerosis. EAE is mediated by CD4+ T lymphocytes of the TH1 subset. These T cells produce inflammatory cytokines and chemokines that are associated with pathogenicity. The disease is downregulated by other T cells, presumably of the TH2 subset that secrete a different pattern of cytokines which modulate the activity of the pathogenic TH1 cells. Ongoing studies should provide insight into how the interactions of T-cell subsets impact on the pathogenesis of autoimmune demyelinating diseases.

Cyclopentenone prostaglandins PGA2 and 15-deoxy-?12,14 PGJ2 suppress activation of murine microglia and astrocytes: Implications for multiple sclerosis

“…The current study also shows that both 15d‐PGJ 2 and PGA 2 are effective in downregulating the expression of the β chemokine MCP‐1 by microglia. MCP‐1 is primarily chemoattractant for T cells and monocytes (Smeltz and Swanborg, 1998; Kennedy and Karpus, 1999); however, MCP‐1 is chemoattractant for dendritic cells, natural killer cells, and microglia as well (Mahad and Ransohoff, 2003). MCP‐1 has been implicated in MS based on its localization to astrocytes in active lesions, cerebrospinal fluid, and serum of affected patients (McManus et al, 1998; Simpson et al, 1998; Sorensen et al, 1999; Van Der Voorn et al, 1999; Franciotta et al, 2001).…”

Immunotherapy for Alzheimers Disease: Potential Problems and Possible Solutions

“…In MS, brain lesions are usually found in white matter areas, and are commonly accompanied by disruptions in the BBB. Based on an animal model of MS, experimental autoimmune encephalomyelitis (EAE), the Th1 lymphocyte subset and the associated cytokines, INF-γ , TNF-α/β, IL12, IL23, and chemokines have been proposed as factors in the pathogenesis of MS [14,76]. The accuracy of the EAE model of MS remains controversial, however, inflammation in EAE resembles the inflammation observed in the AN-1792 clinical trial.…”

“…In both EAE and the AN-1792 trial, a self-antigen was combined with a powerful Th1 polarizing adjuvant to break tolerance and provoke an immune response. In the case of EAE, there is clear evidence that the CD4 + Th1 subset of lymphocytes specific to myelin, produce inflammatory cytokines (IFNγ , IL12) and chemokines associated with pathogenesis [76,77]. During the inflammatory phase of EAE, T lymphocytes and natural killer cells (NK) express INF-γ , which induces MHC gene expression and activates adhesion molecules on cerebrovascular endothelial cells that directly affect the permeability of the BBB and promote cellular trafficking into the brain [78].…”

“…INFγ also induces TNFα, which causes an up regulation of CD40 on microglia and macrophages [79,80], and the clinical course of EAE and inflammation are controlled by the expression of CD40 in the CNS [81]. Interestingly, cytokines associated with the Th2 subset are produced during the remission phase of EAE [76], and the Th2 cytokines, IL4, TGF-β and IL10, have been shown to attenuate the activity of Th1 response and to inhibit autoimmune disease [14,77,78,[82][83][84]. Because the available evidence implicates anti-Aβ antibodies in the clearance of Aβ from the brain, and the fact that Th2 lymphokines primarily function in support of the production of antibodies, this would appear to be a preferred pathway to activate Aβ-immunotherapy.…”

Nasal administration of transforming growth factor-β1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis

“…The mechanism underlying downregulation of in¯ammatory reaction is not well understood, although a role for Th2 cytokines, especially IL-4 and IL-10, has been demonstrated. 38 A greater understanding of the inhibitory mechanism of EAE by nasal administration of TGF-b1 may lead to an effective therapeutic strategy in MS.…”