Targeting innate receptors with MIS416 reshapes Th responses and suppresses CNS disease in a mouse model of multiple sclerosis.
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.
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Madeleine
M
White
Innate Immunotherapeutics, Auckland, New Zealand.
Gill
G
Webster
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
David
D
O'Sullivan
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Sarrabeth
S
Stone
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand ; Malaghan Institute of Medical Research, Wellington, New Zealand.
Anne Camille
AC
La Flamme
D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000276:immunology
D007155:Immunologic Factors; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma