2023
Development Grant
Pilot Grants
Jason Crawford, PhD, Associate Professor of Chemistry and Associate Professor of Microbial Pathogenesis
Anna Eisenstein, Assistant Professor of Dermatology
Richard Flavell, PhD, FRS, Sterling Professor of Immunobiology; Investigator, Howard Hughes Medical Institute
Nikhil Joshi, PhD, Associate Professor of Immunobiology
Jordan Pober, MD, PhD, Bayer Professor of Translational Medicine and Professor of Immunobiology
Marie Robert, MD Professor of Pathology and of Medicine (Digestive Diseases)
Matthew Vesely, MD, PhD
2022
Development Grants
David A. Hafler, MD, FANA
Unbiased characterization of the antigenic targets driving autoimmunity
Project description: We will sequence the T cell receptors (TCR) from T cells migrating in the central nervous system of patients with multiple sclerosis. We will conduct a high-throughput personalized screen of self-antigens to deorphan TCRs from MS patients to identified antigens for immunotherapy.
Pilot Grants
Alicia Little, MD, PhD
Targeting HIF1 to Treat Discoid Lupus Erythematosus
Project description: Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with limited and often ineffective treatments. DLE pathogenesis is poorly understood, but aberrant T-cells are implicated. I propose to define the pathogenic role of hypoxia inducible factor, a novel therapeutic target, in driving autoreactive T cells in DLE.
Carrie L. Lucas, PhD
Defining roles of a targetable kinase in autoantibody production
Project description: This proposal builds from our prior discovery of a monogenic kinase defect underlying human immunodeficiency to elucidate translationally relevant new biology of the antibody response. We further seek to test the efficacy of kinase inhibition in blunting autoantibody production using preclinical lupus models and patient cells.
Christopher Pittenger, MD, PhD
Pathogenic antibodies in rapid-onset neuroinflammatory pediatric obsessive-compulsive disorder (OCD): Towards clarification of nosology and development of novel diagnostic tests
Project description: Pediatric obsessive-compulsive disorder (OCD) sometimes has a rapid onset that has been attributed to post-infectious autoimmunity. Pathogenic antibodies have proven elusive, which impedes diagnosis. We are identifying candidate pathogenic antibodies, enabling novel precision diagnostics.
Mehran M. Sadeghi, MD
Molecular Imaging in Autoimmunity
Project description: There is currently no non-invasive tool for in vivo detection of biological processes that are involved in tissue damage in autoimmunity. To address this gap, we propose to develop a novel molecular imaging approach and test it in a novel murine model. Ultimately, this should lead to new tools to manage autoimmune disorders.
Stephanie Thorn, MSc, PhD
Novel SPECT/CT Imaging to Evaluate a PPARγ agonist for Reversal of Pulmonary Hypertension in a Systemic Sclerosis Murine Model
Project description: Systemic sclerosis (SSc) is a chronic autoimmune disease wherein an estimated 8-15% of SSc patients will develop pulmonary hypertension (PH), which is one of the major causes of mortality in SSc, with a 55% one-year survival. We propose to evaluate novel SPECT non-invasive imaging techniques to monitor progression of fibrosis (99mTc-RP805) and angiogenesis (99mTc-NC100692) in relation to perfusion and function in a mouse model of SSc induced PH (SIRT3-/-). Additionally, we will evaluate the efficacy of the PPAR-γ agonist pioglitazone to inhibit the induction of tissue fibrosis and prevention of SSc induced PH.
2021
Development Grant
Anna Marie Pyle, PhD
Development of MDA5 and LGP2 Modulators as Therapeutics for Autoimmunity and Dysregulated Inflammatory Response
Project Description: Although the innate immune receptor MDA5 plays a key role in RNA sensing and antiviral response, numerous human interferonopathies result from inappropriate upregulation of MDA5 signaling and interferon induction. We have developed sensitive, biochemical, structural and cell-based assays for monitoring MDA5 function, two of which have been adapted for high-throughput screening of small molecules that downregulate MDA5 signaling. Using these approaches, we are developing target-specific drugs for the treatment of MDA5-associated interferonopathy and autoimmunity.
Pilot Grants
David N. Assis, MD
A Personalized Medicine Co-Culture System using Bile-Derived Organoids to study Epithelial/Immune cell interactions in Primary Sclerosing Cholangitis
Project Description: This project will investigate serum biomarkers in patients with active autoimmune hepatitis that are not seen in remission, including gene expression, proteoforms, and immunophenotyping. The goal is to improve our ability to predict relapses before clinical presentation, and thereby better tailor immunosuppression, in autoimmune hepatitis and related autoimmune diseases.
William Damsky, MD, PhD
Cytokine RNA in situ hybridization to guide targeted treatment selection in dermatology
Project Description: Cytokine-targeted monoclonal antibody drugs are commonly used to treat inflammatory disorders in dermatology and are generally selected empirically (trial-and-error approach) without incorporating immunologic data. We propose to evaluate the role for RNA in situ hybridization, a highly specific approach which can be performed in diagnostic skin biopsies, in characterization of cytokine production patterns as they relate to both diagnosis and treatment selection in two common dermatologic disorders treated with these drugs, psoriasis and atopic dermatitis. We plan to characterize the heterogeneity in expression of cytokines targeted by current and emerging therapies in skin biopsies from patients with these disorders using this approach and correlate patterns of cytokine expression with response to monoclonal antibody drugs in a prospective clinical setting.
Stephanie Eisenbarth, MD, PhD
Identifying a biomarker for response to peanut oral immunotherapy
Project Description: Our goal is to identify how the gut immune system prevents life-threatening allergic reactions to food in order to develop new diagnostic or therapeutic interventions for those with food allergy. One mechanism of protection that has been proposed, but remains unproven, is production of IgA antibodies in the gut to food allergens. We have collated the relevant patient cohorts and developed new mouse models to determine how food-specific IgA is induced and under what circumstances it can protect from allergy.
Jeff Gehlhausen, MD, PhD & Akiko Iwasaki, Ph.D.
Validation of the CXCR3 Signaling Pathway as a Therapeutic Target in Chronic Interferon-driven Disease
Project Description: Chronically elevated interferon signaling is suspected as a key mediator of human lupus disease and is a molecular hallmark of the disease, though how exactly interferons orchestrate tissue pathology remains incompletely understood. CXCR3 and its chemokine ligands are highly induced by interferons and are important molecules for homing of effector cells to target areas of inflammation. The proposed studies genetically and pharmacologically validate the CXCR3 signaling axis as a therapeutic target in a lupus-like disease murine model.
Kevan Herold, MD
Effects of EBV on immune responses following anti-CD3 mAb
Project Description: EBV has been associated with several autoimmune diseases but the ways in which it may modulate autoimmunity are poorly understood. We have found that the response to anti-CD3 mAb are modified depending on EBV serostatus at the time that patients are treated with the mAb. We plan to identify the ways in which EBV modifies immune responses in this setting of immune modulation to understand the immune regulatory effects of the virus.
Mary Tomayko, MD, PhD
Predicting risk for autoimmunity triggered by PD-1/PD-L1 inhibitor blockade
Project Description: Immune checkpoint inhibitor therapy can induce tissue-specific autoimmune disease. Using bullous pemphigoid as a model disease, this study will determine if checkpoint inhibition unmasks or newly induces autoimmunity. The goal is to identify risk biomarkers and novel therapeutic targets.
Matthew Vesely, MD, PhD
Deciphering immune regulatory pathways in lichen planus
Project Description: Lichen planus (LP) is a chronic mucocutaneous inflammatory disease with limited and often ineffective treatments. The immunopathogenesis of LP remains unknown. Using single-cell spatial proteomic and transcriptomic technologies, I will identify immune inhibitory receptors within LP that may be targeted for therapy.
2020
Development Grants
Richard Flavell, PhD, FRS
Ian Odell, MD, PhD, FAAD
Development of a Human Epiregulin Therapeutic Antibody for Treatment of Fibrotic Disease
Project Description: We previously identified an epidermal growth factor receptor (EGFR) ligand that drives fibrosis in patients with scleroderma and chronic graft-vs-host disease. We propose to develop a therapeutic human antibody against this ligand for pre-clinical development and use in patients.
Andrew Wang, MD/PhD, AB
Death Sensors for Targeting Cell the Treatment of Lupus Nephritis
Project Description: Systemic Lupus Erythematosus (SLE) nephritis remains an intractable disease that leads to dialysis and death. We developed a novel class of biologics targeting cell death that was potently efficacious in reversing nephritis and death in pre-clinical SLE models that we aim to further understand and develop for clinical translation.
Pilot Grants
Stephanie Eisenbarth, MD, PhD
Identifying a biomarker for risk of peanut anaphylaxis
Project Description: IgA is the dominant antibody in the gut and has been shown to regulate the composition and balance of gut commensal microbiota. Whether IgA regulates the gut immune response to food antigens is not clear in part because experimental systems to study the isolated role of food-specific IgA do not exist. These studies will test whether peanut-specific gut IgA is a biomarker of clinical tolerance in children with food allergy and define the fundamental immunologic rules that govern the production of food-reactive IgA in mice.
Eric Meffre, PhD
CXCL10 interferes with TLR9 function and central B cell tolerance in SLE
Project Description: We aim at testing whether IFN-inducible chemokine CXCL10 (IP-10) elevated in the serum of patients with systemic lupus erythematosus (SLE) inhibits TLR9 responses in human B cells and abrogates central B cell tolerance. Hence, inhibiting CXCL10 in SLE may prevent production and activation of autoreactive B cells.
Anna M. Pyle, Ph.D.
Molecular mechanism and therapeutic strategies for MDA-5 associated autoimmunity
Project Description: MDA5 plays an essential role in innate immunity, but hyperactive mutant variants are common in the human population and associated with autoimmune diseases. We aim to elucidate the molecular mechanism by which disease-associated MDA5 mutants dysregulate innate immunity and to identify small molecule antagonists of these mutants. This research will lead to valuable new tools for studying MDA5 and the development of potential drugs for autoimmune diseases.
Aaron Ring, M.D., Ph.D.
Discovery of Endogenous Therapeutic Antibodies in Autoimmune Disease Patients
Project Description: While autoreactive antibodies are central to the etiology of numerous autoimmune diseases, some autoantibody responses have paradoxically been found to have protective, disease-mitigating effects. These responses represent attractive therapeutic targets, since they are fully-human antibodies that have demonstrated efficacy in a "clinical trial of nature." Here, we propose to apply a novel autoantibody discovery platform to identify disease-mitigating responses that are naturally present within patients with less severe autoimmune disease, to isolate the specific antibody sequences underlying these responses, and to advance these antibodies as novel therapeutic agents.
David Spiegel, M.D., Ph.D., A.B.
Selective Degradation of Antibodies Implicated in Autoimmune Diseases
Project Description: We have designed bifunctional molecules that selectively deplete antibodies from circulation based on their epitope specificity while leaving the rest of the immunoglobulin repertoire intact. Having demonstrated the depletion of a model antibody in vivo, we plan to apply this approach to the degradation of clinically relevant human autoantibodies. Specifically, we will target anti-β1-AR antibodies in cardiomyopathy and anti-citrullinated protein antibodies in rheumatoid arthritis.