Shifting therapeutic attention in MS to osteopontin, type 1 and type 2 IFN

Abstract

It is widely debated whether MS is mediated solely by Th1, or solely by Th17, whether it might be mediated by both pathways, or perhaps by neither pathway. We must integrate the following four facts: first, MS lesions have a signature of IL-6-, IL-17-, osteopontin-and IFN-driven transcriptional activity. Second, MS is worsened with administration of IFN-c, the quintessential type 2 IFN and Th1 cytokine. Third, blockade of TNF-a worsened MS in clinical trials. Fourth, inhibiting the main driver of Th17, IL-23, failed to modulate relapsing-remitting MS (RRMS). Against this backdrop, standing outside the framework of the Th1 and Th17 pathways are the type 1 IFN, notably IFN-b, the most widely used approved therapy for RRMS. A paper in this issue of the European Journal of Immunology demonstrates that IFN-b suppresses production in CD4 1 T cells of both osteopontin and IL-17. In this commentary, the roles of these two molecules, i.e. osteopontin and IL-17, are discussed in relation to the pathogenesis of MS. Osteopontin may be more important than Th1 or Th17 in the pathogenesis of RRMS. Trials targeting this small integrin-binding protein ought to be pursued in RRMS. The notion that Th1 is the main driver of autoimmune tissue damage has largely been replaced by the notion that Th17 is critical for autoimmune-mediated tissue damage [5]. The central importance of IL-23, the key cytokine for Th17 development, has contributed greatly to the general enthusiasm for the notion that Th17 and in particular IL-17 is the key mediator of tissue damage in autoimmune disease [6].As a matter of fact there are actually three forms of EAE, one driven by Th1 [7], another by Th17 [7] and surprisingly a third type driven by Th2 that might be best called experimental allergic encephalomyelitis, as the disease was called in the 1940s through about 1980 [5,8]. Somehow EAE is now considered experimental autoimmune encephalomyelitis. Thus, tissue damage in EAE can be the result of any one of the three major lineages [5]. This is not widely appreciated when we read that Th17 is the major mediator of tissue damage in so many papers presently. Th17 is not the major mediator; it is merely one of the major mediators of tissue damage in EAE.The role of IL-17 itself is ever more controversial. Neither overexpression of IL-17A in T cells nor its complete loss had an Table 1.)Even with these clarifications from the EAE model, the facts in MS do not support, thus far, a major role for Th17 in relapsingremitting MS (RRMS). MS lesions have a signature of IL-6-, IL-17-, osteopontin-and IFN-driven transcriptional activity [11,12]. What do we know about these molecules in MS? IL-23 is the main driver of Th17 in man [13]. Despite widespread success in ameliorating EAE with various means of blocking IL-23, a clinical trial in MS with anti-IL-12p40 failed to show any effect in RRMS [14]. This raises a major question mark about the importance of Th17 in MS. Of course, IL-12p40 modulates both Th1 and Th17 [13]. The importance of Th1 in MS is widely recognized...

CCR2+CCR5+ T Cells Produce Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

“…Research on EAE demonstrated that both IFN-g-producing Th1 and IL-17-producing Th17 cells could cause inflammatory pathology in the CNS (9,10). Although characterization of pathogenic T cells in EAE has ignited a search for similar cells in humans, the identity of pathogenic T cells in MS has not been established (10).…”

“…In addition, increasing evidence suggest a pathogenic role for cytotoxic effector T cells in MS (14,15). Moreover, a recent clinical trial of anti-IL12p40 Ab to block IL-12/IL-23 signaling failed to modulate MS (16), making it difficult to portray a complete picture of MS (9).…”

Osteopontin and multiple sclerosis: An update

“…In EAE, decreased OPN production by IFNb treatment contributes to the reduced migratory activity of T cells. 39 Thus, although OPN might not be a specific marker for MS, targeting it might present a therapeutic approach to MS. 67,68 Further studies will be needed to validate this hypothesis.…”

The good and the bad of neuroinflammation in multiple sclerosis

“…Interestingly, it is one of the most abundant gene transcripts within acute MS lesions (Chabas et al, 2001) and is also elevated in plasma around the time of relapse (Steinman, 2009a). Studies showed that the VLA-4 integrin binds to OPN, thus increased levels of OPN within lesions could attract VLA-4-carrying cells (Steinman, 2009a).…”