Research Advances
Faculty in the division are continuing to make a wide-ranging set of fundamental and translational advances. These are providing new insights into the functioning of the immune system in health and disease.
Early life environmental exposures, including those that occur in the prenatal period, influence the development of allergic asthma. However, whether maternal exposure to aeroallergens can influence the development of asthma in offspring is unknown. House dust mite (HDM) is a ubiquitous aeroallergen, and there are reports of HDM-derived allergens in amniotic fluid. Using a mouse model of HDM-induced allergic asthma, work from the Lewkowich lab demonstrated that HDM exposure during pregnancy markedly exacerbates HDM-induced airway hyperresponsiveness and eosinophilia in offspring. Importantly, maternal HDM exposure does not increase asthma-like symptoms following challenge of offspring with other aeroallergens, demonstrating a level of antigen specificity. These observations suggest that maternal HDM exposures may have under-appreciated influences on the overall prevalence of allergic asthma.
T helper 2 (TH2) cells mediate immunity against extracellular parasites but also promote allergic inflammation. Noting the implication of cytokine TSLP in the pathogenesis of TH2 cell–associated allergic disorders, the Singh laboratory investigated its role in TH2 cell differentiation. They found that TH2 cells that differentiated in the presence of TSLP and IL-4 produced increased amounts of cytokines and were more pathogenic compared to TH2 cells differentiated in the presence of IL-4 alone. Mice receiving CD4+ T cells deficient in the TSLP receptor saw a reduction in allergic responses compared to those that received wild-type cells. Given that pediatric asthma patients have increased frequency of TSLP responsive CD4+ T cells with enhanced TH2 cytokine production compared to that of healthy controls, these data suggest that TSLP is likely to be an effective therapeutic target in allergic diseases.
The Herr lab elucidated how a bacterial surface protein uses zinc and copper ions to form adhesive ‘ropes’ between staphylococcal cells in a biofilm. Biofilms are surface-adherent bacterial colonies that are resistant to antibiotics and can cause recurrent infections. The lab found that both several related metal ions can interact with the biofilm adhesion protein, but that only zinc and copper ions can induce assembly of the protein into molecular ropes. The lab had previously shown that chelating zinc to make it unavailable for the staphylococcal bacteria effectively inhibits biofilms from growing. An antimicrobial platform based on their research is being developed for clinical use by Hoth Therapeutics, Inc.
The Hildeman lab uncovered an intriguing role for a suppressive population of T cells, so-called regulatory T cells (Tregs) in controlling persistent cytomegalovirus (CMV) infection. CMV is a significant problem in immunosuppressed patients, including those undergoing organ transplantation. In collaboration with Dr. Rhonda Cardin, PhD, (formerly in the Division of Infectious Diseases) using a mouse model of CMV, they found that Tregs play a tissue specific role in controlling latent MCMV infection. Notably, when researchers depleted Tregs from mice after the establishment of viral latency, the viral load was significantly reduced in the spleen. Strikingly, in the salivary gland following Treg depletion, the virus emerged from latency and began replicating. Blockade of IL-10 prevented the CMV emergence from latency. Thus, these data show that, depending upon the tissue, Treg can promote or limit latent CMV infection. The results have important implications for Treg manipulation during organ transplantation.
Faculty Development, Promotion and Recruitment
The division, along with the Division of Biomedical Informatics, recruited Dr. Krishna Roskin, PhD, jointly as an assistant professor. He is a key addition to the Cincinnati Children's Hospital Medical Center initiative in systems immunology. Dr. Roskin attended the University of California Santa Cruz (UCSC) for undergraduate, and then graduate, studies under Dr. David Haussler. At UCSC, Krishna made early contributions to the UCSC genome browser and comparative genomic analysis of the mouse and rat genomes, focusing on using the murine genome to uncover regions of the human genome conserved due to evolutionary constraints. This led to major results on the share of the human genome under purifying selection and variation in evolutionary rates across the genome.
After studying whole genomes, Dr. Roskin became interested in the immunoglobulin and T cell receptor loci and pursued post-doctoral work in the laboratory of Dr. Scott Boyd at Stanford University. There he applied his multi-genomic analysis skills to the complexity of the B and T cell receptor repertoire, with the aim of better understanding the human immune system and the mechanisms of immune-mediated diseases. His work shows that common variable immuno-deficiency (CVID), long thought to be a deficiency of affinity maturation, has aberrations earlier in B cell development and increased our understanding of how and when the human immune system mounts stereotypical antibody responses in a variety of settings including in identical twins and in response to dengue and pandemic H1N1 influenza virus infection.
The division recruited Dr. Chandrashekhar (Shekhar) Pasare, DVM, PhD, as a tenured professor. Dr. Pasare obtained his PhD at National Institute of Immunology in New Delhi, India. His mentor was Dr. Satyajit Rath (1994-2000). Subsequently, he was a Howard Hughes Medical Institute postdoctoral fellow at Yale University School of Medicine in New Haven, CT mentored first by the late Charles A Janeway Jr. and then by Dr. Ruslan Medzhitov (2000-2006). He joined Genentech in 2006 as a scientist to head a discovery lab. He engaged in finding novel targets for treating inflammatory bowel disease and rheumatoid arthritis. In 2007, UT Southwestern Medical Center in Dallas recruited him as an endowed scholar in biomedical research where he joined the faculty of the Department of Immunology as an assistant professor. At UT Southwestern, Dr. Pasare engaged in research to understand the molecular pathways of regulation of inflammation in macrophages and the fundamental mechanism by which the innate immune system regulates adaptive immunity. In 2014, Dr. Pasare received tenure and promoted to associate professor. In 2015 he received the J. Wayne Streilein, MD Professorship in Immunology award and became chair of the Immunology Graduate Program. In the last 10 years, Dr. Pasare served on the membership committee of the American Association of Immunologists, as an ad hoc member of the Innate Immunity and Inflammation study section at National Institute of Health as well as a referee for major peer reviewed publications. Research in his lab led to discovery of two novel regulators of inflammatory responses in macrophages and identification of a key role for IL-1R signaling pathway in CD4 T cell effector function. His continuing interests include regulation of inflammation in cells and tissues and the cross-talk between the innate and the adaptive immune systems.
Systems Immunology Workshop
Drs. Andy Herr, PhD; Emily Miraldi, PhD; and Harinder Singh, PhD, co-organized the second biennial workshop. Its various sessions focused on the following themes: inference and validation of immune signaling and gene regulatory networks, computational modeling of immune processes, immuno-protein and cellular engineering along with applications and advances in human immunology. The intention of the meeting was to stimulate new research initiatives, and where possible, experimental and conceptual consolidation. The biennial forum serves to advance programmatic initiatives in systems immunology.
Both speakers and attendees provided excellent feedback. Given the success, there was discussion of holding the meeting annually at various host institutions, including the NIH (Gregoire Altan-Bonnet, NCI; Ron Germain and John Tsang, NIAID) and Yale (Kathryn Miller-Jensen).
