The laboratory of Ashutosh K. Mangalam, Ph.D., studies the role of genetic and environmental factors that contribute to the causes of multiple sclerosis (MS).
MS is a chronic inflammatory disease of the central nervous system that debilitates the lives of more than 1 million people worldwide. MS costs the U.S. economy billions of dollars a year in medical care expenses and indirect expenses, such as lost wages and productivity.
Dr. Mangalam's research utilizes novel humanized transgenic mice to dissect the complex mechanisms of inflammation and demyelination found in MS patients, with a long-term goal of finding more successful treatments that alleviate the complications and perhaps cure multiple sclerosis.
The lab has four major research interests:
- Understanding the role of CD8 T lymphocytes in the immunopathogenesis of MS
- Determining how genetic (HLA) and environmental factors, such as Epstein-Barr virus (EBV), smoking and vitamin D, predispose or protect an individual from developing MS
- Understanding the role of gut microbiota in MS
- Translating their results to develop novel therapeutic agents to treat MS
- Role of CD8 T cells in the disease process of inflammation and demyelination. Patients with MS have an increased number of CD8 T cells circulating in their blood, but the exact role of CD8 T cells in MS is not well understood. Dr. Mangalam and his team have recently shown that CD8+ T cells play both regulatory and pathogenic roles in their mouse model. Ongoing projects in this area include:
- Understanding how some regulatory CD8 T cells protect from disease development
- Understanding how other CD8 T cells can cause pathology in the central nervous system
- Integrating environmental and genetic risk factors in MS. Environmental factors, such as EBV, smoking and vitamin D, play important roles in the development of MS. The HLA transgenic mouse model used by Dr. Mangalam provides a novel and innovative tool to understand the interactions between genetic and environmental factors involved in inflammatory and demyelinating diseases such as MS. Ongoing projects in this area include:
- Understanding the mechanism by which a specific genetic risk factor (HLA-DR2) influences how environmental factors (EBV or smoking) affect the initiation, development and progression of MS
- Investigating the immune-modulatory role of vitamin D in an MS-susceptible mouse strain (HLA class II transgenic model)
- Human gut microbiota and MS. A healthy human gut harbors a large number of bacteria (100 trillion) that play an important role in host nutrition and development of the immune system. Alteration in microbiota composition is associated with various inflammatory and autoimmune diseases. Dr. Mangalam and his team want to know how gut bacteria influence how MS develops, asking questions such as:
- How does the fecal microbiome differ in MS patients and healthy controls?
- Can probiotic therapies prevent or alleviate the onset of MS?
- Are there correlations in the differences of the gastrointestinal microbial composition and immune system function that determine the onset of MS?
- Are MHC genes that are responsible for modulation of the immune system also responsible for regulating the composition of intestinal microbiota?
- Human commensal as a novel therapeutic agent for treating MS. In their constant search for new MS treatments, Dr. Mangalam and his colleagues have identified a new strain of human commensal organisms that appears to have potent systemic immunomodulatory effects. Preliminary data in mice suggest that giving this commensal as therapy reverses the neurologic signs of demyelination. Major ongoing projects in this area include:
- Preclinical testing of human commensal in an animal model for therapeutic efficacy
- Understanding the mechanism by which common human commensal can provide systemic immunomodulation in the context of a severe demyelinating disease
Significance to patient care
The research in Dr. Mangalam's lab will help in identifying genetic and environmental factors that predispose individuals to develop MS. Their work on CD8 T cells will help in the identification of good and bad CD8 T cells in MS patients, and a better understanding of these subsets could aid in designing novel therapies for MS patients.
Dr. Mangalam's gut microbiota analysis will help in understanding if disturbance in gut microbiota can be used as a predictive marker of MS and if its reorganization can be used as a novel therapeutic option.
Preclinical testing of their human commensal is ongoing. If successful, it can be easily translated to the clinic as a new adjunct treatment option for MS.