Targeting Innate Receptors with MIS416 Reshapes Th Responses and Suppresses CNS Disease in a Mouse Model of Multiple Sclerosis

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.

Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific

“…There was an intermediate reduction in the spleen, an untreated site – likely due to non-specific, systemic effects of Rapa. Supporting this hypothesis, recent literature demonstrates that systemic treatments with modulatory or suppressive drugs can cause differential impacts on inflammatory responses in different tissues – findings that also illustrate the utility of having a tool to directly probe how signals in one tissue impact the course, efficiency, and durability of tolerance (White et al, 2014). One further rationale for co-delivery of tolerogenic signals (e.g., Rapa) with self-antigen is to mitigate the risk of exacerbating disease with a therapy containing disease-relevant antigen during active autoimmunity (Maldonado et al, 2015).…”

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

“…MIS416 has been suggested to modulate T-cell-mediated autoimmune responses in EAE by simultaneously activating innate Toll-like receptor 9 and nucleotide-binding oligomerization domain-containing protein 2 [96]. The restricted uptake of MIS416 by phagocytic cells has been suggested to lead to targeted modulation of the innate immune system [97]. MIS416 was initially used in patients with SPMS outside of a formal clinical trial setting under compassionate use legislation in New Zealand.…”

“…MIS416 was initially used in patients with SPMS outside of a formal clinical trial setting under compassionate use legislation in New Zealand. Recently, in a phase Ib/IIa clinical trial, MIS416 was shown to suppress the development of proinflammatory T helper (Th)1, Th2, and Th17 cells in EAE, and to i ncrease the serum level s of IFN-γ and IFN-γ-associated proteins in 19 patients with SPMS [97]. A phase IIb trial is underway to further investigate the effect of MIS416 in progressive forms of MS (NCT02228213) [98].…”

A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

“…In experimental animal models, the partial blockade of sodium channels showed neuroprotective properties [87,88,89]. …”