The focus of our research program is to investigate cellular and molecular mechanisms involved in the regulation of inflammation. Inflammation is a component of virtually every disease and if not controlled can lead to severe tissue damage. The primary disease model utilized in the laboratory is the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). MS is an autoimmune disorder of the central nervous system (CNS) and is characterized by focal areas of inflammation. In past studies, we have extensively utilized EAE to study negative immune regulatory mechanisms that keep inflammation in check within the CNS. Our current studies have expanded to mouse models of contact dermatitis (contact hypersensitivity) and inflammatory bowel disease (DSS-colitis).

B cell regulation of autoimmunity was first demonstrated by us in the EAE model, whereby B cell deficient (BCD) mice were unable to recover from the clinical signs of EAE.

Thus, our findings indicate that BD_L play an essential role in Treg homeostasis whereby they maintain Treg numbers at a sufficient level to dampen inflammation. Current studies are investigating the development, phenotype and localization of this novel subset of regulatory B cells. These studies are being advanced using single cell RNA sequencing (scRNAseq), which we are utilizing to further define the BD_L subset in mouse and humans.

BD_L-based Adoptive Cell Therapy (ACT)

The ultimate goal of our research is to develop a BD_L-based universal ACT for the treatment of autoimmunity and other inflammatory disorders. To accomplish this goal, Dr. Dittel was recently awarded an NIH Director’s Transformational Research Award. The strategy is to develop a mouse prototype that escapes rejection by the immune system while potently increasing Treg cell numbers to achieve attenuation of EAE. Using knowledge gained from the mouse, a human BD_L-based ACT will be generated and tested in humanized mouse models.

MPO is a myeloid-lineage restricted enzyme that utilizes H2O2 to generate hypochlorous acid that has strong antibacterial properties. In sterile inflammation, such as MS, MPO and MPO-derived oxidants are thought to be pathogenic promoting inflammation and causing tissue damage. In particular, MPO has been implicated in vascular permeability. In MS, the opening of the blood-brain barrier (BBB) is considered detrimental. The presence of MPO within inflammatory lesions in MS patients along with our studies in the EAE model, suggests that it plays a pathogenic role in MS. Using a novel inhibitor of MPO, we have found that its inhibition during EAE rapidly attenuates disease severity that is associated with sealing of the BBB. Current studies in the lab are focused on the pathogenic role of MPO in inflammation with an emphasis on vascular permeability. In addition to EAE, these studies also utilize the contact hypersensitivity and DSS-colitis models in which permeability is also considered pathogenic. The goal of this research is to undercover the mechanism whereby MPO induces vascular and epithelial permeability and to determine whether MPO is a viable therapeutic target for the treatment of inflammatory diseases.

It is now clear that interactions between the immune system and microbiome have consequences for human health. In past studies, we utilized microbiome analysis to study microbial dysbiosis in the gut in IL-10-deficient mice. In current studies, we are utilizing this knowledge and expertise to determine how

Post-doc opportunities are available to work on BD_L focused projects. To express interest please contact Dr. Dittel at bdittel@versiti.org