Research Advances

Faculty in the division use cutting-edge research tools at the cellular, molecular, and genetic levels to further understand mechanisms underlying immune-mediated diseases. With this knowledge, we strive to identify novel mechanistic insights for translational exploitation, devising new preventive and therapeutic strategies for diseases affecting children.

Type I diabetes (T1D) is the most common autoimmune disease in children and young adults. Unfortunately, there is no durable cure for T1D; for the last 90-odd years the sole therapy for T1D remains daily and costly insulin replacement. Autoreactive T cells that destroy insulin-producing beta cells in the pancreas is the cause of T1D. In a collaborative research effort with the Jordan lab, the Katz lab exploited the oncologic pharmacopeia to target key cell cycle regulators along with p53 to kill these rogue T cells in the nonobese diabetic mouse model. This approach, which they termed p53 potentiation and checkpoint abrogation (PPCA) therapy, led to the prolongation of the remission period and the restoration of euglycemia in these mice, as well as restoring the balance of T cell regulatory cell control of the autoimmunity at the site of inflammation, the islets of Langerhans. This study is critical in that it used spontaneous diabetic NOD mice and was able to induce T1D reversal. The study, published last year in Diabetes, also received a highlight by the editors in the "In this issue" section of the online editions of the journal.

Understanding myelodysplastic-syndrome (MDS) pathobiology is critical to derive and evaluate new therapeutic interventions. Transforming growth factor-beta (TGFβ) signaling is abnormally active in early-stage MDS patient hematopoietic stem and progenitors (HSCP), and the level of TGFβ-signal-induced transcriptional changes may have prognostic value. However, the mechanism of TGFβ signaling resulting in ineffective hematopoiesis in MDS is not known. The Grimes lab delineated the selective pressure of TGF on HSC during early MDS. Specifically, inflammatory signals induce miR-21 expression which targets the Ski corepressor; an antagonist of TGFβ signaling. People with MDS and mice that lack Ski display abnormal regulation of RNA splicing, leading to hematopoietic stem cell dysfunction. Thus, inflammation-miR-21-Ski-splicing circuit is one factor in MDS that interferes with the TGFβ negative feedback loop to generate a chronic TGFβ signal and select mutant MDS clones. Muench published this work and featured this finding on the journal cover.

During the past year, the Pasare Lab made two major discoveries related to the role of IL-1R signaling in CD4 T cell biology. It is well known that specific innate cytokines are necessary for priming and differentiation of naïve CD4 T cells into various effector lineages. However, a long standing assumption is that once differentiated, effector and memory cells no longer need innate cues for their function. Work in the lab focused on understanding if innate cytokines regulate memory T cell functions. This led to the discovery that all the three major effector T cell lineages depend on IL-1R signaling to perform effector functions. More specifically, IL-1beta acts as a licensing signal to permit effector cytokine production by pre-committed Th1, Th2 and Th17 lineages. The lab discovered that the T cell effector cytokines have AU rich elements in their 3” UTR and IL-1R signaling stabilizes these cytokine transcripts to enable productive and rapid effector functions (Nature Communications, 2018). The lab further discovered that interaction of effector or memory CD4 T cells with antigen presenting myeloid cells leads to production of bioactive IL-1beta that is completely independent of pattern recognition receptor activation. Given that IL-1beta plays a major role in inducing T cell mediated auto-immune diseases, these findings have major implications in discovering new pathways for therapeutic intervention. The lab also uncovered a new role for TLR signaling adapter BCAP in IL-1R signaling in CD4 T cells. More specifically the lab found that BCAP plays a critical role in inducing pathogenic Th17 cell differentiation by linking IL-1R to PI3K-mTOR activation. Absence of BCAP, however, did not alter development of naturally arising Th17 lineages that participate in gut barrier function. Mice lacking BCAP in T cells show reduced susceptibility to experimental autoimmune encephalomyelitis suggesting that this molecule could potentially treat multiple sclerosis and other diseases caused by pathogenic Th17 cells without affecting the protective function of naturally arising Th17 cells (Journal of Experimental Medicine, 2018).

Faculty Development, Promotion and Recruitment

The division recruited Tamara Tilburgs, PhD, as an assistant professor with the Center for Inflammation and Tolerance. Dr. Tilburgs received her undergraduate degree from Hogeschool van Utrecht and her MS degree from the Free University Amsterdam in the Netherlands. She went on to Leiden University to pursue her PhD studying the phenotype and function of decidual T cells in human pregnancy. She then went to Harvard University to study NK cells and their interaction with HLA molecules in the context of pregnancy in the lab of Dr. Jack Strominger. Tamara made the observation that HLA-C expression on extravillal trophoblasts (EVT) is crucial to establish maternal-fetal immune tolerance. Strikingly, she also showed that HLA-C is the main HLA molecule that can provide immunity when EVT are infected. The central theme of her work is to investigate how maternal immune cells at the maternal-fetal interface establish tolerance to fetal antigens while at the same time maintaining immunity to viral and bacterial infections. Understanding the immune interactions at the maternal/fetal interface will enable her to gain insights and develop potential therapies in pregnancy complications including preterm birth, preeclampsia and congenital disease due in utero transmission of pathogens.

Senad Divanovic, PhD, received a promotion to Associate Professor.

Translational Breakthroughs

The Jordan lab finished a clinical trial for a novel treatment of hemophagocytic lymphohistiocytosis (HLH). Several years ago, in a mouse model, they discovered that IFN-γ was a critical driver of the disease. The lab led a multi-center clinical trial of emapalamab, a humanized anti-IFN-γ antibody for the treatment of HLH. Based on their work, emapalamab received FDA approval for the treatment of HLH.

In April, Andrew Herr, PhD, participated in the Nasdaq Closing Bell ceremony for Hoth Therapeutics, Inc., which went public in February of this year. Hoth is a biopharmaceutical company targeting atopic dermatitis and other dermatological and chronic wound disorders, and they licensed the BioLexa antimicrobial platform developed in the Herr lab. Clinical trials with BioLexa in atopic dermatitis will take place starting in early 2020. Dr. Herr serves on the Scientific Advisory Board of Hoth Therapeutics and was the lead inventor on several patents related to the BioLexa technology.