Abstract
Modification of the innate immune cell environment has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticulate immune response modifier that targets myeloid cells, activating cytosolic receptors NOD2 and TLR9, and has completed a phase 1b/2a trial for the treatment of secondary progressive multiple sclerosis. Using a mouse model of multiple sclerosis, we are investigating the pathways by which activation of TLR9 and NOD2 may modify the innate immune environment and the subsequent T cell-mediated autoimmune responses. We have found that MIS416 has profound effects on the Th subset balance by depressing antigen-specific Th1, Th17, and Th2 development. These effects coincided with an expansion of specific myeloid subpopulations and increased levels of MIS416-stimulated IFN-γ by splenocytes. Additionally, systemic IFN-γ serum levels were enhanced and correlated strongly with disease reduction, and the protective effect of MIS416 was abrogated in IFN-γ-deficient animals. Finally, treatment of secondary progressive MS patients with MIS416 similarly elevated the levels of IFN-γ and IFN-γ–associated proteins in the serum. Together, these studies demonstrate that administration of MIS416, which targets innate cells, reshapes autoimmune T cell responses and leads to a significant reduction in CNS inflammation and disease.
Highlights
Activation of innate pattern recognition receptors (PRR) has been implicated in both the pathogenesis as well as the regulation of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) [1,2,3,4]
Studies have shown that signaling through PRRs such as TLR2 or TLR4 is necessary for the induction of EAE as deficiency in these TLR or TLR-adaptor MyD88-mediated signaling inhibits EAE induction
In contrast to d0 MIS416 treatment, mice injected with MIS416 3 days prior to immunization (d-3) exhibited no difference in disease expression compared to untreated mice (Figure 2a; Table 1)
Summary
Activation of innate pattern recognition receptors (PRR) has been implicated in both the pathogenesis as well as the regulation of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) [1,2,3,4]. The role that NOD2 signaling may play in the induction or pathogenesis of MS is less clear [7], the association between bacterial infections and MS as well as the detection of antigen presenting cells containing peptidoglycan, a source of NOD2 ligand, in the brains of MS patients support a possible pathogenic role for this PRR in MS [8] In contrast to this pathogenic role, recent evidence points to the potential therapeutic application of PRR agonists as immunomodulatory agents to treat MS. The suppression of EAE by TLR3 activation has been attributed directly to the induction of endogenous IFN-b [10] and similar studies by O’Brien et al found that the protective TLR7 agonist, imiquimod, enhanced IFN-b production during EAE [9] In contrast to this mechanism, recent work has found that multiple low doses of a TLR7 agonist induced a tolerogenic state that was able to suppress CNS inflammation during EAE [11]. To determine how MIS416mediated NOD2 and TLR9 signaling may modulate immune responses during MS, we used the EAE mouse model of MS to determine the effect of MIS416 treatment on the development of T cell-mediated autoimmune responses
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