Recovery from Acute Experimental Autoimmune Encephalomyelitis (EAE) Characterized by Endothelial Cell Unresponsiveness to Cytokines and Pericyte Activation

Abstract

Experimental allergic encephalomyelitis (EAE) is an antigen-driven T-cell-mediated autoimmune disease in animals that closely resembles the human disease multiple sclerosis (MS). In rats, EAE is characterized by an acute clinical phase followed by recovery (1). The mechanism by which animals recover from the paralytic disease is unknown. It is thought that cytokine-mediated regulation by T-suppressor cells plays an important role (2–4). Transforming growth factor beta-1 (TGFβ-1), is a naturally occurring immunoregulatory protein (5) which has emerged as a leading candidate in immunoregulation of EAE (6–14). The mechanisms by which TGFβ1 ameliorates the incidence and severity of EAE is not well understood, but a primary effect on macrophage and/or T-cell-mediated immune function or on the blood brain barrier (BBB) has been suggested (6,9,13–18) In a previous study, we have reported that TGF131 inhibits interferon gamma (IFNγ)-mediated activation of rat central nervous system (CNS) microvessel endothelial cells (EC) and that TGFβ1 pretreated EC are unresponsive to subsequent stimulation (19). In the present study, we examine in culture, CNS microvessels from Lewis rats through induction, clinically apparent disease, and in the recovery phase of EAE for the expression of EC activation antigens and for sensitivity to further activation with IFNγ. Expression of activation antigens is sequential and precedes appearance of clinical symptoms. Results further indicate that recovery from EAE is, in part, characterized by EC unresponsiveness to IFNγ, and vascular pericyte reactivity.