Modulatory preimplantation factor regulates post-infectious experimental autoimmune encephalomyelitis in therapeutic setting

Purpose: Preimplantation Factor (PIF) regulates inflammatory response in human systemic immune cells (1). Several autoimmune diseases including Multiple Sclerosis (MS) improve during pregnancy, where PIF may have a protective role. Synthetic PIF replicates native PIF action and regulatory features. PIF reverses chronic neuroinflammation while promoting neural repair in Experimental Allergic Encephalomyelitis (EAE) model (2). We examined if PIF modulates the novel experimental model of post-infectious EAE developed in our laboratory (3). Methods: SJL mice were infected with Mycobacterium Smegmatis expressing a recombinant chimeric protein MPT64-PLP139-151 (rMSp139) to induce EAE (1). Mice were monitored daily for EAE symptoms. By day 3 after infection, mice were treated daily (continuously or intermittently at disease peaks) with PIF or vehicle. We cultured Lymph node(LN) cells from SJL mice to analyze the levels of pro/anti-inflammatory cytokines and of transcription factors (Real Time PCR) and the shared T cell receptors specific for antigen (spectratyping). Brain slices from mice treated with FITC-labeled PIF were observed at confocal microscopy. Results: PIF administration reduces significantly disease load. Pro-inflammatory cytokines, FoxP3 expression and T cell repertoire are not modified by PIF treatment. Administration of fluorescent PIF shows that most of binding in the brain is limited to vessels wall and to scattered parenchimal elements. Discussion: PIF administration limited to acute episodes of EAE is as effective as prolonged administration and suspension of therapy does not result in rebound of the disease. Conclusion: These data support the hypothesis that PIF acts at the level of brain inflammation rather than during T cell priming, and propose it as a novel candidate anti-inflammatory agent in Multiple Sclerosis.