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    Oral Communication

    Hemostatic Systems in Cancer, Inflammation and Immunity

    Mechanisms of Cardiovascular and Neurologic Diseases

    OC 49.2 - Pharmacological targeting of the contact pathway attenuates experimental autoimmune encephalomyelitis in mice

    Monday, June 26, 2023
    15:00 – 15:15 ET
    Room: 515
    Session Available As: On-Demand
    Background: Multiple sclerosis (MS) is a neurodegenerative, immune-mediated disease of the central nervous system (CNS) that affects over 2.2 million individuals annually. MS pathophysiology includes the formation of inflammatory lesions, axonal damage and demyelination, and blood brain barrier (BBB) disruption. Coagulation proteins, including factor (F) XII, can serve as important mediators of the adaptive immune response during neuroinflammation. Indeed, relapsing-remitting MS patients experiencing relapse have elevated levels of FXII in their plasma, and previous studies show that reducing FXII levels is protective in a murine model of MS, experimental autoimmune encephalomyelitis (EAE).

    Aims: Determine if pharmacological targeting of FXI, a major substrate of activated FXII (FXIIa), improves neurological function and attenuates CNS damage in the setting of EAE.

    Methods: EAE was induced in male mice using murine myelin oligodendrocyte glycoprotein peptides combined with heat-inactivated Mycobacterium tuberculosis and pertussis toxin. Upon onset of symptoms, mice were treated every other day intravenously with anti-FXI antibody, 14E11 (1mg/kg, n=9), or saline (n=7). Disease scores were recorded daily until euthanasia for ex vivo analyses of inflammation. Flow cytometry was used to quantify mononuclear cells in pooled brain samples and the activation of the macrophage subpopulation of splenocytes. Immunohistochemistry was used to assess axonal damage and fibrin(ogen) accumulation in the spinal cord in vehicle- and 14E11-treated mice (n=1/group).

    Results: Compared to vehicle control, 14E11 reduced the clinical severity of EAE. Pharmacological blockade of FXI also reduced BBB disruption, as measured by decreased axonal damage and fibrin(ogen) accumulation in the spinal cord. Compared to control, there appeared to be no effect of treatment on macrophage accumulation in the brain or activation of splenocytes.

    Conclusion(s): These data demonstrate that pharmacological inhibition of FXI reduces disease severity in mice with EAE. Thus, therapeutic agents targeting FXI and FXII may provide a useful approach for treating autoimmune and neurologic disorders, such as MS.

    Learning Objectives:

    • Upon completion, participant will be able to describe the role of coagulation factors, specifically FXI, in the pathogenesis of EAE.
    • Upon completion, participant will be able to evaluate the effectiveness of pharmacological targeting of FXI in reducing disease severity, axonal damage, and blood-brain barrier disruption in the setting of EAE.
    • Upon completion, participant will be able to identify the strengths and potential weakness of FXI-targeted interventions in the treatment of neuroinflammatory diseases, such as MS.