Research Advances

Outstanding faculty in the Division of Immunobiology use cutting-edge research tools at the cellular, molecular and genetic levels to further 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 diseases affecting children. Our faculty made some ground-breaking discoveries, published over the last year, that led to additional grant funding and when translated to the clinic, will impact child health.

During the past year, research in the Pasare lab revealed a very important mechanism by which effector memory CD4 T cells initiate innate inflammation to drive cytokine storms and autoimmune pathology. Microbial recognition by the pattern recognition receptors of the innate immune system results in transcriptional induction of pro-inflammatory gene program that is critical for host protection. The PRR induced inflammatory cytokines play an important role in mobilization of innate immune responses as well as activation of adaptive immunity. However, many of the same innate inflammatory cytokines are also drivers of pathology in T cell-mediated autoimmune diseases and during T cell-targeted cancer immunotherapies. Although blocking individual cytokines can mitigate some pathology, the upstream mechanisms governing overabundant innate inflammatory cytokine production in T cell drive pathology are less clear. Publication of work from the Pasare laboratory in Science Immunology (Effector memory CD4+ T cells induce damaging innate inflammation and autoimmune pathology by engaging CD40 and TNFR on myeloid cells) reveals a very important mechanism by which effector memory T cell initiate innate inflammation to drive cytokine storms and autoimmune pathology. Specifically, work from the laboratory led to the discovery that cognate interactions between effector memory CD4 T cells and myeloid cells leads to induction of an inflammatory transcriptional profile in the innate immune system that is reminiscent of, yet entirely independent of, classical pattern recognition receptor activation. The lab identified two critical signaling nodes engaged by effector memory CD4 T cells to mobilize a broad pro-inflammatory program in myeloid cells. Effector memory CD4 T cells express TNF and CD40L that rapidly engage TNFR and CD40 on antigen presenting dendritic cells to drive inflammatory cytokine production. Interfering with these signaling nodes in multiple models of T cell-driven inflammation completely rescued the cytokine storms and toxicity as well as autoimmune pathology, suggesting that T cell instruction of the innate immune system is a primary driver of sterile inflammation and immunopathology. While these pathways might have evolved as a mechanism of host protection during reinfection by virulent pathogens, they contribute to destructive inflammation and pathology during T cell-driven diseases. This work has important therapeutic implications for mitigating pathology in autoimmune diseases and combating T cell-driven cytokine storms. Cincinnati Children’s applied for a patent to cover methods for treating diseases by blocking TNF and CD40.

The Divanovic lab made an important discovery on the mechanisms driving obesity, an unabated public health problem that affects over half a billion people worldwide. Obesity stems from an imbalance between energy intake, energy expenditure, and energy turnover (lipolysis, lipogenesis). Persistent energy imbalance leads to the pathological expansion of adipose tissue (AT) that contributes to the propagation of obesity-associated low-grade inflammation. This maladaptive obesity-associated inflammation underlies the pathogenesis of obesity-associated metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular disease and diverse cancers. In an article published in Nature Communications (A BAFF/APRIL axis regulates obesogenic diet-driven weight gain), the Divanovic lab demonstrated a critical role of BAFF and APRIL in regulating weight gain. They showed that multiple transgenic mouse lines with increased BAFF expression were associated with protection from weight gain. Mechanistically, both BAFF and APRIL were sufficient to induce upregulation of lipid metabolism pathways in subcutaneous white adipocytes and to augment white adipose tissue (WAT) lipolysis as well as to to enhance brown adipocyte respiration and EE. Notably, lack of both BAFF and APRIL promoted increase in obesity in mice. Lastly, conservation of BAFF/APRIL effects in human adipocytes and higher systemic BAFF/ APRIL levels correlate with a greater BMI decline in post- bariatric surgery. Their collective findings for the very first time, uncover a novel pathway of immune-mediated regulation of AT/adipocyte lipid handling and may represent novel targets for the treatment of weight gain / obesity.

This year the Alenghat lab published a study in Cell Host & Microbe (Commensal segmented filamentous bacteria-derived retinoic acid primes host defense to intestinal infection.) revealing commensal bacteria can generate retinoic acid from vitamin A in the diet. This diet-microbiome interaction played an important role in priming the intestine to defend against infection. Interestingly, this occurred separately from the retinoic acid produced by mammalian cells and represented the first description that resident bacteria can be a direct source of retinoic acid that physiologically regulates the host. This discovery suggests that targeted microbiome-based treatment strategies may reduce infections by helping commensal bacteria maintain proper levels of retinoic acid. In addition to the Alenghat lab, collaborators on this study include Rebekah Karns, Joseph Qualls, and David Haslam, MD.

The Herro lab, led by Rana Herro, PhD, made significant progress in understanding mechanisms controlling severe asthma. Mucus secretion is an important feature of asthma that highly correlates with morbidity. Current therapies, including administration of mucolytics and anti-inflammatory drugs, show limited effectiveness and durability, underscoring the need for novel effective and longer-lasting therapeutic approaches. The Herro lab developed an organoid technology to screen for novel anti-fibrosis therapies. It published a paper in Frontiers in Immunology (Targeting TL1A/DR3 Signaling Offers a Therapeutic Advantage to Neutralizing IL13/IL4Rα in Muco-Secretory Fibrotic Disorders) implicating the tumor necrosis factor superfamily member TL1A in controlling mucus secretion and fibrosis associated with asthma. Herro’s discovery implicates TL1A as a promising therapeutic target in reversing mucus production, airway inflammation and fibrosis, cardinal features of severe asthma in humans.

Research in the Herr lab recently identified a novel mechanism that regulates type 1 diabetes in a pre-clinical animal model. Type 1 diabetes is a devastating disease often occurring in children, where their immune system attacks and destroys insulin-producing cells in the pancreas. While insulin therapy allows patients to manage the disease, it is costly and requires lifelong management. Thus, additional work is needed to find new therapeutic strategies to stave off the autoimmune attack and rescue insulin-producing cells in the pancreas. As part of a long-standing collaboration with William Ridgway, MD, at the University of California-Davis, the Herr lab recently published a paper in the journal Diabetes (Endosomal Sequestration of TLR4 Antibody Induces Myeloid-Derived Suppressor Cells and Reverses Acute Type 1 Diabetes). Their study focused on understanding the mechanism by which an antibody called UT18 is able to reverse acute type 1 diabetes in a NOD mouse model. They showed that this agonistic antibody stimulated the TLR4/MD2 complex, inducing its internalization and sequesters TLR4/MD2 inside the endosome, substantially reducing MyD88-dependent signaling and prolonged suppression of inflammation. Treatment of NOD mice with UT18 increased CD11b+ myeloid derived suppressor cells (MDSCs) in the spleen and islets of NOD mice; these CD11b+Gr1+ cells sorted from UT18-treated mice suppressed T cell proliferation and ameliorated progression of acute T1D. Overall, their data suggested that by sequestering TLR4/MD2 in the endosome, UT18 induces a prolonged, decreased inflammatory response that functions as a ‘second signal’ for activation of MDSCs.

Translational Breakthroughs

Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome that develops in children with genetic defects of immune regulation. Research in the Jordan lab led by Michael B. Jordan, MD, recently published in Blood (An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis), showed HLH is increasingly seen in patients with cancer. In cancer patients, HLH associates with very poor survival, and there is little understanding of how it develops. The Jordan lab studied a large international series of patients with cancer that was either complicated or not complicated by HLH and found that specific inflammatory markers were a better way to define the syndrome in this context and were better predictors of poor outcomes. This work will change how physicians and scientists think about this fatal syndrome and will change clinical practice. Though specific immune cells are harnessed to fight cancer, this work points to how the immune response may sometimes be harmful for patients with cancer.

In addition, early diagnosis of HLH is often critical for optimal ability to treat this devastating disease. Notably, HLH is often difficult to distinguish from other severe illnesses in children. The Jordan lab publication in Blood Advances (IFN-γ signature in the plasma proteome distinguishes pediatric hemophagocytic lymphohistiocytosis from sepsis and SIRS), in collaboration with colleagues at Texas Children’s Hospital, found children with HLH may be readily distinguished from other sick children with bacterial sepsis using a panel of cytokine markers. This finding has implications for understanding the nature of immune activation in these patients and for developing new diagnostic tests to rapidly identify children who may need very different forms of treatment.

Collaborative COVID-19 Science

During the COVID-19 pandemic, the Hildeman, Jordan, and Herr labs, collaborated with the Molkentin, Spearman, and Ware labs as part of a Cincinnati Children's COVID-19 serology group. Early in the pandemic, before the availability of commercial antibody tests, we developed a COVID-19-specific antibody test. We made enough SARS-COV2 protein for three million antibody tests and made the protein available to multiple investigators at Cincinnati Children's. In partnership with the Hoxworth Blood Center, we investigated the rates of SARS-COV2 infection in random blood donors in the greater Cincinnati regional area, from August –December 2020, just before the national vaccination program. Published in PLoS One (Seroprevalence of SARS-CoV-2 infection in Cincinnati Ohio USA from August to December 2020), ~10,000 serum samples were tested and found that the regional rates of COVID-19 infection hovered around 9% from August-October and then increased to 12% in December, paralleling the regional and national spread of infection. We also found local areas with higher infection levels, which informed local vaccine efforts at the beginning of the national vaccination campaign.

Faculty Awards

Congrats to Theresa Alenghat, VMD, PhD, who received the Young Investigator Award from the Society for Mucosal Immunology.

Congrats to David Hildeman, PhD, who received the Cincinnati Children's Senior Faculty Education Achievement Award.

Congrats to Rana Herro, PhD, for being nominated for a trailblazer award for innovative research in pulmonary fibrosis.