Bonnie Dittel Laboratory Versiti Blood Research Institute
Research Interests | Immunobiology
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.
B Cell IgD Low (BDL) Regulatory B Cells
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.
Figure 1: An illustration of EAE disease in B cell deficient (BCD) mice. BCD mice (green dotted line) do not recover from the signs of EAE like their wild-type (WT (solid blue line)) counterparts. When BCD mice are adoptively transferred BDL (red line) prior to EAE induction, the mice undergo recovery similar to WT mice.
In our subsequent studies, we discovered a new regulatory subset of B cells termed B Cell IgD Low (BDL), named due to their low level of IgD expression. We found that adoptive transfer of BDL into BCD promoted recovery from EAE. Specifically, BDL negatively regulate the severity of EAE inducing CD4 Foxp3 T regulatory cells (Treg) expansion in a GITRL-dependent manner.
Figure 2: BDL induce Treg proliferation in a GITRL-dependent manner. BDL depicted in green including their cell surface phenotype engage CD4+Foxp3+ T regulatory (Treg) (blue) via GITRL, which binds to its receptor GITR on Treg thereby promoting their proliferation and expansion.
Thus, our findings indicate that BDL 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 BDL subset in mouse and humans.
BDL-based Adoptive Cell Therapy (ACT)
The ultimate goal of our research is to develop a BDL-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 BDL-based ACT will be generated and tested in humanized mouse models.
Figure 3: Strategy to generate a BDL-based universal adoptive cell therapy (ACT). To prevent allorecognition and rejection, expression of MHC class I and II molecules will be eliminated. To prevent NK killing of the MHC class II- cells, HLA-G will be expressed. To maintain survival of the ACT, an IgM+ parent cell will be selected. Overexpression of GITRL will promote Treg expansion. Redundant suicide mechanisms will be introduced to control the number of the BDL ACT after administration to patients.
Post-doc opportunities are available to work on BDL focused projects. To express interest please contact Dr. Dittel at email@example.com
Neuroscience Research Center Imagine More, Medical College of Wisconsin
RG-1901-33315, National Multiple Sclerosis Society
R01AI160244-01, NIAID- NIH Director’s Transformative Research Award