Faculty in the division made a wide-ranging set of fundamental and translational advances. These have provided strong insights into the functioning of the immune system in health and disease.
A collaboration among the Grimes, Singh, and Salomonis labs using the tools of systems and computational biology, led to the discovery of rare mixed-lineage intermediates that are precursors of monocytes and neutrophils in the bone marrow. They uncovering of these rare cells occurred using single-cell RNA-Seq methodology. They appear to manifest an unusual cellular state referred to as “dynamic instability” which poises the intermediates to give rise to one of two different stable cellular fates. Dynamic instability can propose to underlie binary cell fate choice in a variety of developmental systems.
The Hildeman laboratory has elucidated an important function for the methyl transferase Dnmt3a in the generation of CD8 T cell memory. Curiously, their findings demonstrate that loss of Dnmt3a increases the frequency of CD8 memory T cells that generate upon infection of mice with LCMV. This result is somewhat counterintuitive in that DNA methylation of control regions in the genome by de novo methyltransferases such as Dnmt3a promotes the generation of cellular memory. Uncovering the precise molecular mechanisms by which Dntm3a antagonizes memory CD8 T cell formation as well as its functions in other memory T and B cell responses is an exciting area of future exploration.
The Divanovic laboratory has demonstrated that thermoneutral housing provides a greatly improved, sex-independent, model of exacerbated non-alcoholic fatty liver disease (NAFLD) in mice. This translational advance represents a novel approach for analysis of cellular and molecular mechanisms underlying disease pathogenesis. NAFLD exacerbation at thermoneutrality conserved across multiple mouse strains, and associates with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways associated with the disease in humans. Notably, female mice, typically resistant to high fat diet (HFD)-induced obesity and NAFLD, developed full disease characteristics at thermoneutrality. These findings have important biomedical implications as NAFLD, which often leads to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide.
A longstanding and productive collaboration among the Jordan, Katz, and Hildeman labs has made considerable progress on its primary goal of controlling autoreactive T cells as a means of treating ongoing autoimmune disease. The use of p53 potentiation, with checkpoint abrogation (PPCA) therapy, demonstrates remarkable efficacy in mouse models of multiple sclerosis (MS) and type 1 diabetes (T1D). With T1D, the data shows that new onset diabetic NOD mice benefit from PPCA therapy with an increase in the remission period or outright reversal of T1D. As part of our center for transplant immunology, to both solid organ (heart, islet) transplant models, expanded use of this new therapeutic approach is showing signs of success.
Inter-Disciplinary Collaborations and Grants
Dr. Claire Chougnet, PhD, is leading an ARC proposal focused on inflammation and pre-term birth that has obtained an NIH UO1 award. This will enable the collaborative team to robustly advance the primate model for analysis of pre-term birth complications as well as gain fundamental insights into the development and functioning of the neonatal and infant immune systems.
Dr. David Hildeman, PhD, in collaborations with Dr. Steve Woodle, MD, from the University of Cincinnati College of Medicine, are focusing on targeting of allograft immune responses in kidney transplantation. Funding obtained from Novartis and Sanofi will allow exploration of lymphocyte responses and resistance mechanisms in patients on therapies.
Dr. Harinder Singh, PhD, in a collaboration with Dr. Woodle and Dr. Jim Driscoll, MD, PhD, both from University of Cincinnati College of Medicine, launched a collaborative effort to uncover genomic responses and molecular pathways that underlie resistance and rebound of plasma cells to proteasome inhibitor therapy. This therapeutic modality is being tested clinically to achieve desensitization in patients with pre-existing allo-reactive antibodies before organ transplantation.
Faculty Development, Promotion, and Recruitment
Dr. Mike Jordan, MD, promoted to a full professor based on his outstanding research accomplishments in elucidating the cellular and molecular bases of HLH as well as other genetically caused immune deficiencies.
Cincinnati Children's recruited John Hogenesch to a joint appointment in the Division of Immunobiology and research space in the Center for Systems Immunology (T5). John is an accomplished systems biologist with a focus on the circadian clock. He plans to collaborate with immunologists in exploring the actions of the circadian clock on immune responses.
Dr. Emily Miraldi, PhD, obtained a trustee award to advance her promising career in computational immunology.
National Institutes of Health (NIH
) awarded NIH T32 (2016-21) funding to Cincinnati Children's due to the tireless and superb efforts of Dr. Dave Hildeman, PhD
, as well as faculty mentors along with past and current PhD trainees. This is a first for the Immunology Graduate Program
at Cincinnati Children's. It is a highly competitive award that represents a superb return on a long term academic vision and investment in Immunology. The DFG
sponsored IRTG (2017-21) has been successfully renewed. The continuation of this international training program with Universities of Lubeck
in Germany is a superb testimonial to our faculty, and students, who gave compelling research presentations and testimonials at a site visit in Lubeck.