Research Advances

Outstanding faculty members in the division lead vigorous, externally funded research programs that seek to understand the regulation, development, and function of innate and adaptive immunity in both health and disease. Faculty employ cutting-edge research tools at the cellular, molecular, and genetic levels to understand mechanisms underlying immune-mediated diseases. Armed with this knowledge, our faculty identify novel translational insights that enable the development of new preventive and therapeutic strategies for both childhood and adult diseases.

The Alenghat lab published a seminal study in the journal Nature this year (Microbiota-derived metabolite promotes HDAC3 activity in the gut). Along with collaborators Lee Denson, MD, and David Haslam, MD, the Alenghat lab discovered that the intestinal microbiota generates inositol trisphosphate (IP3) and that this metabolite can activate an epigenetic-modifying protein histone deacetylase 3 (HDAC3) in epithelial cells of the intestine. While short chain fatty acids from commensal bacteria instead inhibit HDACs, the studies highlighted HDAC3 as a sensor of metabolites that can balance mucosal responses to distinct microbial cues. The research team also used gnotobiotic approaches and models of intestinal damage and inflammation to demonstrate the enhancement of epithelial repair by IP3 and phytate, a dietary product that bacteria break down to produce IP3. They saw similar epithelial growth with IP3 when treating intestinal organoids generated from intestinal tissue of patients with inflammatory bowel disease. Thus, HDAC3 represents an integrating enzyme that can coordinate healthy intestinal dynamics by sensing distinct microbial signals generated in response to changes in diet or the microbiota.

The Hildeman and Chougnet labs collaborated with colleagues at Cincinnati Children's and the University of Lubeck as part of the International Research Training Grant on a study published in Science Advances this year (IL-10–producing Tfh cells accumulate with age and link inflammation with age-related immune suppression). Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. The group discovered that a novel population of immune suppressive, anti-inflammatory T cells produces high levels of IL-10 and accumulates with age in both mice and humans. Maintaining high levels of systemic IL-10 in aged mice requires these CD4+ T cells. They also showed the functional importance of such increase, as blockade of IL-10 signaling in aged mice restores their vaccine-driven germinal center B cell responses similar to levels observed in young mice. Notably, they showed that the source of suppressive IL-10 came not from FoxP3+ regulatory T cells (Treg), but from cells bearing markers of T follicular helper (Tfh) cells, a cell type normally critical for antibody production. Thus, these data show that age-related decreased vaccine responsiveness is reversible through blockade of IL-10, a concept they will test in non-human primates with the support of a Falk Institute Catalyst Award.

The Tilburgs lab and colleagues published a landmark paper in Cell this year (Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts). This paper describes how human dNK, a key lymphocyte found at the maternal-fetal interface of the placenta during pregnancy, contribute to clearance of bacterial infection. Human dNK expressed high levels of the antimicrobial peptide granulysin (GNLY) and selectively transfer it via nanotubes to extravillous trophoblasts to kill intracellular listeria monocytogenes (Lm). The transfer of GNLY occurred independent of other cytotoxic granule proteins including granzymes and perforin, and selectively killed Lm bacteria without causing trophoblast cell death. Thus, transfer of GNLY allows dNK to protect against infection while leaving maternal-fetal interface and tolerance intact.

Translational Breakthroughs

The Herr lab collaborates with Khurana Hershey’s lab to study the impact of staphylococcal bacteria on the pathogenesis of pediatric atopic dermatitis (AD). In 2021, they published a paper in Allergy (Biofilm propensity of Staphylococcus aureus skin isolates is associated with increased atopic dermatitis severity and barrier dysfunction in the MPAACH pediatric cohort), showing that staphylococcal biofilm propensity, not simply skin colonization, associates with increased AD severity and diminished barrier function in the MPAACH pediatric AD cohort. Previously, based on many years of basic research, the Herr lab developed a novel antimicrobial platform to combat staphylococcal biofilms. This research laid the groundwork for a phase 1b clinical trial by Hoth Therapeutics starting in Australia in 2021 using a topical drug formulation based on Herr’s anti-biofilm technology, identified as BioLexa lotion. The preliminary results from the phase 1b trial healthy subject cohort showed toleration of BioLexa, with no serious adverse events and no drug-related, treatment-emergent adverse events observed. Recruitment for the next cohort will start in the fall of 2021 to investigate preliminary efficacy of BioLexa in patients with mild to moderate AD.

The Jordan lab collaborated with the Marsh and Wong labs at Cincinnati Children's to publish a translational paper in Blood (T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis | American Society of Hematology). HLH is a disorder of damaging immune activation which experimental studies suggest cause by excessive activation of T cells. Sepsis is also a disorder of damaging immune activation, but the thought is the cause is activation of innate immune cells (neutrophils, monocytes, etc.) in responses to bacterial infections in most cases. Patients with HLH can become sick very rapidly and may look very similar to those with sepsis (at least initially), so distinguishing HLH from sepsis is a common clinical problem. Thus, these two disorders appear to involve two different arms of the immune system. The group found that a key differentiating factor between the two diseases was characterization of HLH by a very prominent population of activated, interferon gamma producing CD8+ T cells, while these cells were lacking in sepsis. Their study revealed a simple profile assessed within hours that is >95% sensitive and specific for distinguishing these two states. Also, much of what knowledge about HLH derives from experimental mouse models of the disease, which demonstrate a central role for activated T cells. Their patient-derived findings are a key validation of these experimental studies, further demonstrating the power of basic scientific studies to define human diseases.

Faculty Awards and Promotions

Congratulations to Claire Chougnet, PhD, who became the inaugural Margaret K. Hostetter Endowed Chair awardee in June 2021. Chougnet was the first hire of the Division of Immunobiology (at the time Molecular Immunology) at the end of 2001. She is the recipient of continuous funding by the NIH since 2005, with publication of >135 peer-reviewed articles (with more than 800 citations of her work in 2020).

Congratulations to Chougnet, who also received the 2020 Cincinnati Children's Senior Mentorship Award.

Congratulations to Andrew Herr, PhD, and Jonathan Katz, PhD, both elected as fellows of the graduate school, given their tremendous contributions to the Immunology Graduate Program.

Congratulations to Katz for his election to Sigma Xi, Scientific Research Honor Society.

Congratulations to Emily Miraldi, PhD, who received the Charlotte R. Schmidlapp Women Scholar Recognition of Excellence Award.

Congratulations to Ian Lewkowich, PhD, on his promotion to associate professor with tenure.

Congratulations to Herr on his promotion to full professor.