Blood-brain barrier-crossing IL-4 for treatment of neuroinflammatory disease 4663

Abstract Description Excessive or chronic inflammatory processes play major roles in neurological disorders such as multiple sclerosis (MS), Alzheimer’s Disease (AD), stroke, and traumatic brain injury. Cytokine therapies that reduce neuroinflammation show great promise. However, therapeutic options that act on central nervous system (CNS) cell populations are lacking, partly because the blood-brain barrier (BBB) prevents most blood molecules from reaching the CNS. We engineered IL-4 molecules that bind to transferrin receptor and transcytose across the BBB to the CNS, where they strongly polarize microglia to an IL-4-associated alternative activation state associated with reduced inflammation and tissue repair. Interestingly, across multiple experiments, only IL-4 variants with FcRn-mediated recycling capacity (i.e., those containing an Fc region or serum albumin fusion) can suppress the onset of experimental autoimmune encephalomyelitis (EAE). This finding may be important for the further evaluation of BBB-crossing therapies for neuroinflammatory disorders, and for the understanding of the inflammatory component of MS pathology. Funding Sources Supported by the University of Chicago Medical Scientist Training Program and Chicago Immunoengineering Innovation Center. Topic Categories Therapeutic Approaches to Autoimmunity (THER)