We propose to create an Autoimmunity Center of Excellence that will incorporate the efforts of clinicians, human immunologists (both basic and translational), physician-scientists with clinical expertise and research experience in autoimmunity, bioinformaticians, and geriomics/systems biologists. Together, the assembled group has an extensive background in clinical trials and a proven track record for merging basic and clinical science. This team is committed to bringing innovative treatments from the laboratory bench to their patients'bedside. Within this collaborative setting, a systems biology approach is proposed to focus on both pediatric and adult autoimmune diseases. The goals of the Center are: 1) To assess the efficacy of novel targeted therapies, 2) To develop simple and robust biomarkers using state-of-the-art genomic approaches, 3) To understand the role of recently identified T cell subsets in disease pathogenesis, and 4) To assess antigen-specific responses in pediatric and adult autoimmune diseases. These projects will provide a better understanding of the pathogenesis of specific autoimmune diseases and allow us to develop a strategy to assess disease activity based on novel transcriptional markers as well as to identify autoantigen-specific immune responses. The Center will deliver: 1) Innovative clinical trials targeting specific cytokines in psoriasis &dermatomyositis. 2) Development of biomarkers for dermatomyositis, psoriasis, lupus and multiple sclerosis. 3) Identification of novel therapeutic targets in dermatomyositis. 4) Development of assays to test autoantigen-specific immune responses. 5) Development of a unique microarray database of human autoimmune diseases. CLINICAL COMPONENT (Cush, J) CLINICAL COMPONENT DESCRIPTION (provided by applicant): Baylor Institute for Immunology Research aims to bring together a distinguished team of clinical investigators to conduct cutting-edge clinical trials on specific autoimmune diseases. This unique group of investigators and clinicians has appointments at Baylor University Medical Center, UT Southwestern Medical Center, Texas Scottish Rite Hospital in Dallas and Northwestern University. These talented individuals have been enlisted from diverse programs with subspecialties in dermatology, rheumatology, neurology, pediatrics, and human immunology. They provide a set of inimitable resources for clinical trials and have a proven track record for merging basic and clinical science. Indeed, this team is committed to bringing innovative treatments from the laboratory bench to their patients'bedside. With such outstanding collaborative players, a systems biology approach is proposed here which investigates both pediatric and adult autoimmune disease. To this end, two Phase II randomized, double-blind, placebo-phase controlled clinical trials are proposed. The first trial investigates whether blocking IL-1 with Anakinra will result in objective disease improvement for patients with Juvenile Dermatomysitis. The trial design will demonstrate: 1) if the time to improvement for patients receiving Anakinra early in the study will be earlier than those who receive later treatment;and 2) if the proportion of patients improved at week 8 of the blinded phase will be significantly greater in the early treatment group. Mechanistic studies will utilize gene expression profiling assays to find a novel diagnostic test for JDM as well as disease activity measures and biomarkers to follow and predict patients'response to therapy. The second clinical project proposes to use a-IL-17 in patients with plaque psoriasis as well as psoriatic arthritis. Specifically, this study will assess the safety and efficacy of a-IL-17 in these patients and determine both the time to achieve endpoints of a PASI 75 or ACR20 and sustainability of such responses at 24 weeks. Associated studies will establish blood transcriptional markers to predict clinical responses in patients treated with a-IL-17, determine if transcriptional scores can be used to assess disease activity, and analyze the effect(s) of IL-17 blockade on B and T cell subsets. A dynamic team of clinical investigators assembled at BUR to conduct state-of-the-art clinical trials on autoimmune disease would be of great value and accelerate the process of bringing research from the laboratory bench to the bedside. This team proposes two important trials that will assess a-IL-1 treatment in Juvenile Dermatomyositis and IL-17 blockade in psoriatic diseases.
The Center will utilize the strong interactions in place at Baylor between clinicians and research scientists. It offers all necessary infrastructure to collect clinical samples and develop state-of-the-art technological and analytical tools that will benefit each of the projects. There is a significant institutional commitment to advance autoimmune research and bring relief to patients with these diseases.
|Caielli, Simone; Veiga, Diogo Troggian; Balasubramanian, Preetha et al. (2018) A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat Med :|
|Horiuchi, Shu; Ueno, Hideki (2018) Potential Pathways Associated With Exaggerated T Follicular Helper Response in Human Autoimmune Diseases. Front Immunol 9:1630|
|Gu, Jinghua; Wang, Xuan; Chan, Jinyan et al. (2017) Phantom: investigating heterogeneous gene sets in time-course data. Bioinformatics 33:2957-2959|
|Cepika, Alma-Martina; Banchereau, Romain; Segura, Elodie et al. (2017) A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med 214:3449-3466|
|Banchereau, Romain; Cepika, Alma-Martina; Banchereau, Jacques et al. (2017) Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics. Annu Rev Immunol 35:337-370|
|Ueno, Hideki (2016) T follicular helper cells in human autoimmunity. Curr Opin Immunol 43:24-31|
|Banchereau, Romain; Hong, Seunghee; Cantarel, Brandi et al. (2016) Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell 165:551-65|
|Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-1095|
|Blanco, Patrick; Ueno, Hideki; Schmitt, Nathalie (2016) T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. Eur J Immunol 46:281-90|
|Caielli, Simone; Athale, Shruti; Domic, Bojana et al. (2016) Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 213:697-713|
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