Faculty Spotlight

The medical school was recently awarded two grants from the National Institutes of Health (NIH) that will fund important research in the Center for Immunobiology focused on B cells and the antibodies they produce.  

A research project led by WMed researchers Nichol Holodick, PhD, Tom Rothstein, MD, PhD, and Momoko Yoshimoto, MD, PhD, titled “The Role of Biological Sex in the Self-renewal of B1 Cells into Old Age in Mice and Humans,” is being supported by a five-year, $3.8 million R01 grant from the NIH.  

A separate research project led by Dr. Rothstein, “Intermingling of Circulating B Cells and Cerebral Spinal Fluid B Cells with Advancing Age,” is being supported by a two-year, $418,000 R21 grant from the NIH.  

The R01 award marks the first time Drs. Holodick, Rothstein, and Yoshimoto are leading a research project together as co-principal investigators.  

Dr. Yoshimoto’s research path is motivated by her prior clinical experience as a pediatric hematology/oncologist in Japan and her ongoing study of the development of various hematopoietic stem/progenitor cells in the mouse embryo. Drs. Holodick and Rothstein, meanwhile, have spent more than a decade researching and examining B cells to understand more about their immune response in the human body.  

“Dr. Yoshimoto widens our developmental understanding,” Dr. Holodick explained.  

“And by doing so we can connect the origin and the function together,” Dr. Yoshimoto added. “That’s a very cool thing.”  

Dr. Holodick, an associate professor in the Department of Investigative Medicine, has shown B-1 cells and the natural antibody protection they afford deteriorates with advancing age in males but remains highly effective in females. Dr. Yoshimoto, a professor in the Department of Investigative Medicine, has shown that most B-1 cells originate from fetal progenitor cells, even in old mice. Dr. Rothstein, who serves as director of the Center for Immunobiology, and is professor and chair of the Department of Investigative Medicine, has shown that in humans, as in mice, B-1 cells decline with advancing age.   

This research has raised an intriguing hypothesis that females can better maintain fetal-derived B-1 cells and thus produce more protective natural antibodies. As such, the combination of immunological and hematological approaches by Drs. Holodick, Rothstein, and Yoshimoto synergize and create an attractive new research direction. This latest NIH-funded research project will offer the opportunity to explore possible reasons for this sex-associated disparity.  

“What we want to know is, particularly in old people, are the B-1 cells proliferating? Are they dividing? Or maybe they’ve never divided but are maintained long term in a 'ready' state,” Dr. Rothstein explained.  

The three projects making up this research grant are designed to fill this gap in knowledge by determining how biological sex influences long-term persistence of mouse B-1 cells generated during different phases of life; examining sex-specific regulation of mouse B-1 cell functions with increasing age; and evaluating the role of sex in specifying human B-1 cell function in older, as opposed to younger, individuals.  

“There are potentially a lot of therapeutic uses for these B-1 cell antibodies in the years to come” Dr. Rothstein said. “If we can show what’s happening to them, that may tell us what to do about them.  Maybe we don’t have to give antibodies to a patient, maybe we just have to give them a little hormone or a little tweak to activate and maintain the B-1 cells.  The work will tell us how to design the therapy.”  

Importantly, the most exciting aspect of this NIH R01 proposal is that the work combines animal studies and human studies.  

Drs. Holodick, Rothstein, and Yoshimoto are hopeful the knowledge gained from this research will help provide meaningful insight toward enhancing B-1 cell function into old age for all, male and female alike.  

Separately, the R21 grant from the NIH will allow Dr. Rothstein to explore whether B cells in the peripheral blood gain entry to the brain in older individuals, a possible explanation for the neuroinflammation that initiates and exacerbates neurodegenerative illnesses like Alzheimer’s Disease.  

In previous work, Dr. Rothstein and his team compared B cells in the peripheral blood and in the cerebral spinal fluid of the same individuals and found no similarity in their antibodies. This was consistent with the general notion that the brain is a privileged site, according to Dr. Rothstein.  

“Notably, that work was done with young volunteers, but it is older humans, a group we did not study, that are at risk of disease,” Dr. Rothstein said in his research project abstract. “Our new project will support a fresh look at this issue, by examining old, as well as young, volunteers” to determine whether, in older individuals, B cells typically gain entry to the brain.  

“Translocation of autoreactive B cells to the brain in older individuals would likely increase the risk for, or be directly responsible for, neurodegenerative illnesses,” Dr. Rothstein said. “If so, therapies already devised to affect B cells in autoimmune disorders may represent a new approach to preventing and/or treating Alzheimer’s Disease.”  

Dr. Rothstein said the medical school’s success in securing these latest NIH grants is a direct result of the strong research environment that’s been cultivated at the institution.  

“We’ve created an environment where cutting-edge, advanced scientific work can be done competitive to anywhere else in the country,” Dr. Rothstein said. “We were very successful in recruiting the very best investigators. We have the scientists who can do, and who currently do, the most advanced and competitive work.”