c-kit Differentially Regulates EAE Susceptibility in Male and Female SJL Mice

It is well established that there are sex-based differences in susceptibility to multiple sclerosis. Not only are women three times as likely to develop MS as men, they are also more likely to present at a younger age and exhibit a relapsing-remitting course. In contrast, men are generally diagnosed later in life and most often exhibit a primary- progressive course of disease. The basis for this sex-determined bias is not fully understood but it is postulated that more robust immune responsiveness in females, sex-linked genetic effects and influences of sex hormones on events that regulate disease progression contribute. Certain female hormones expressed at high levels during pregnancy protect by decreasing inflammatory processes. Later onset of disease in male patients corresponds with a decline in testosterone with age and treatment with testosterone in male patients provides therapeutic benefits. In animal models, testosterone is also protective as shown by increased susceptibility to disease in castrated males and the decreased disease in testosterone-treated females. Using a mouse model of multiple sclerosis, our proposed studies will define the cell types that influence protection from disease in males. We have defined a protein (c-kit) expressed on immune cells and well as nerve progenitor cells, that when absent, causes males, but not females, to revert from protection to severe disease. The experiments in this proposal will define how this molecule exerts its selective protective effects in males. Remarkably, drugs that modulate the activity of c-kit are already currently in use in other clinical settings for treatment of certain tumors. In animals these drugs have been shown to exert neuroprotective effects in models of stroke and CNS injury. Thus, it is important to clarify the role of these molecules so the possible treatment of MS with such well-studied drugs is not overlooked. We anticipate that our investigations will provide new insights into the pathologic mechanisms that underlie both disease in both males and females and lead to improved therapies.