Analysis of TOB1 deficiency in mice

Tob1 -/- mice show exacerbated EAE

In previously published work, we found that patients at an early stage of MS, known as clinically isolated syndrome (CIS), who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene. The current study had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs. We now found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease. Subsequent experiments revealed that the absence of Tob1 in just CD4+ T cells was sufficient to explain the observed EAE phenotype in Tob1 deficient mice. We demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. We found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.

Tob1 -/- mice show exacerbated EAE.
Personalized Treatments for MS Patients

We also propose the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination. The research is significant for humans, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.