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Published on: March 26, 2015
Fc multimers effectively treat murine models of multiple sclerosis
Jin Wang1, Kellie Brown1, Caroline Danehy2
1Dept. of Microbiology Immunology and Biochemistry, UTHSC, Memphis, TN, United States.
Abstract:
Multiple Sclerosis (MS) is a chronic neurodegenerative disease with limited therapeutic options. Recombinant Fc multimers (rFc), designed to mirror many of the anti-inflammatory activities of Intravenous Immunoglobulin (IVIG), have been shown to effectively treat numerous immune-mediated diseases in rodents. In this study we used the experimental autoimmune encephalomyelitis (EAE) murine model of MS to test the efficacy of a rFc, M019, that consists of multimers of the Fc portion of IgG2, in inhibiting disease severity. We show that M019 effectively reduced clinical symptoms when given either pre- or post-symptom onset compared to vehicle treated EAE induced mice. M019 was effective in reducing symptoms in both SJL model of relapsing remitting MS as well as the B6 model of chronic disease. M019 binds to FcγR bearing-monocytes both in vivo and in vitro and prevented immune cell infiltration into the CNS of treated mice. The lack of T cell infiltration into the spinal cord was not due to a decrease in T cell priming; there was an equivalent frequency of Th17 cells in the spleens of M019 and vehicle treated EAE induced mice. Surprisingly, there was an increase in chemokines in the sera but not in the CNS of M019 treated mice compared to vehicle treated animals. We postulate that M019 interacts with a FcγR rich monocyte intermediary to prevent T cell migration into the CNS and demyelination.
Insights
Recombinant Fc multimers (rFc) like M019 show promise for treating Multiple Sclerosis (MS). M019 effectively reduced disease symptoms in mouse models by preventing immune cell entry into the central nervous system.
Area of Science:
- Neuroimmunology
- Immunotherapy
Background:
- Multiple Sclerosis (MS) is a chronic neurodegenerative condition with limited treatment options.
- Recombinant Fc multimers (rFc) mimic Intravenous Immunoglobulin (IVIG) anti-inflammatory effects and show efficacy in immune-mediated diseases.
- The experimental autoimmune encephalomyelitis (EAE) mouse model is used to study MS pathogenesis and test therapies.
Purpose of the Study:
- To evaluate the efficacy of a novel rFc, M019 (multimers of IgG2 Fc portion), in treating MS using the EAE mouse model.
- To investigate the mechanism of action of M019 in reducing disease severity and immune cell infiltration.
Main Methods:
- Administration of M019 pre- or post-symptom onset in EAE induced mice (SJL and B6 models).
- Assessment of clinical disease severity and immune cell infiltration into the central nervous system (CNS).
- Analysis of T cell priming and chemokine levels in serum and CNS.
Main Results:
- M019 significantly reduced clinical symptoms in both relapsing-remitting and chronic EAE models.
- M019 prevented immune cell infiltration into the CNS without decreasing T cell priming.
- Increased serum chemokines were observed, but not in the CNS, in M019 treated mice.
Conclusions:
- M019 demonstrates therapeutic potential for Multiple Sclerosis by reducing disease severity.
- The mechanism involves M019 interacting with FcγR-bearing monocytes to prevent T cell migration into the CNS.
- This study provides a basis for developing rFc-based therapies for MS and other neuroinflammatory diseases.
