Intrathecal Fas Ligand Infusion Strengthens Immunoprivilege of Central Nervous System and Suppresses Experimental Autoimmune Encephalomyelitis

Abstract

Fas ligand (FasL) is an essential molecule strongly expressed in some immunoprivileged sites, but is expressed at very low levels in normal CNS. In this study, acute experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats with guinea pig myelin basic protein. Intrathecal infusion of recombinant FasL before EAE onset dose dependently suppressed acute EAE and alleviated pathological inflammation in lumbosacral spinal cord. This treatment greatly increased apoptosis in CNS inflammatory cells, but did not inhibit systemic immune response to myelin basic protein. Systemic administration of a similar dose of rFasL was ineffective. In vitro, encephalitogenic T cells were highly sensitive to rFasL-induced cell death, and activated macrophages were also susceptible. In addition, in vitro rFasL treatment potentiated the immunosuppressive property of rat cerebrospinal fluid. We conclude that intrathecal infusion of rFasL eliminated the initial wave of infiltrating T cells and macrophages, and therefore blocked the later recruitment of inflammatory cells into CNS. Although Fas receptor expression was observed on spinal cord neurons, astrocytes, and oligodendrocytes, no damage to these cells or to the myelin structure was detected after rFasL infusion.

Role of soluble Fas ligand in autoimmune diseases

“…Some studies suggested that change of sFasL in serum mignt be involved in many processes and progress of diseases. The serum level of sFasL was high in patients with large granule lymphocyte leukemia and NK like lymphoma, SLE, RA and EAE [9][10][11] . sFasL was upregulated on the tumor surface upon drug incubation in chemosensitive tumor cells.…”

Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

“…The severity of inflammation in the lumbosacral, thoracic, and cervical spinal cord was each graded on a scale of 0 -4 as detailed previously (10), and the total inflammation score was obtained by adding these three scores. Luxol fast blue staining and immunostaining were performed following the established protocols (11). Anti-HO-1 and anti-BVR Abs were purchased from StressGen Biotechnologies.…”

Oligodendrocyte cell death in pathogenesis of multiple sclerosis: Protection of oligodendrocytes from apoptosis by complement

“…Interestingly, recovery from EAE may depend on the expression of FasL and apoptosis of infiltrating lymphocytes [35][36]. Intrathecal administration of FasL in mice with EAE also suppresses inflammation and disease activity [37] by enhancing the death of infiltrative lymphocytes. Together these data suggest that OLGs are susceptible to FasLmediated, caspase-induced apoptotic death and that FasL plays distinct roles during the initiation and recovery phases of EAE.…”