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Department of Medicine

Department of Medicine

  Division of Rheumatology and Clinical Immunology

RESEARCH

Basic Research

   

Mandy McGeachy, PhD

Research interests

The McGeachy lab studies mechanisms of activation and regulation of Th17 cells in autoimmune inflammation.  In the past decade, Th17 cells have moved to the forefront as drivers of autoimmune inflammation, and therapies to target Th17-associated pathways are making remarkable progress in clinic. Since these cells were only defined as a distinct subset a decade ago, there is still much to know about their functional regulation. Using models of multiple sclerosis (EAE), we have identified novel integrins that are expressed by Th17 cells and important for their inflammatory function. Ongoing NIH-funded mechanistic studies are investigating the mechanisms through which integrins regulate Th17 inflammation in different tissues. We are also studying inflammatory T cells in humans with rheumatoid arthritis and thyroiditis-associated eye disease (TED), analyzing peripheral blood and more recently RA joint synovial tissue. Biologic therapy in patients offers the opportunity to determine changes in T cells that are related to blockade of specific immune pathways, and we are collaborating with rheumatologists to conduct two controlled longitudinal clinical studies to track changes in T cell populations that correspond to therapy: i) blockade of TNF, CD28 or IL-6R in RA and ii) B cell depletion in TED. Pittsburgh is one of five sites chosen nationally for the NIH/industry-funded AMP consortium, which aims to dissect the immune networks that are active in different cellular populations isolated from joint tissues using state-of-the-art assays and bioinformatics. 

Immunology Profile

            

                   

   

Sarah Gaffen, PhD

Research Interests

The main focus of the Gaffen lab centers around the cytokine Interleukin-17. T cell derived cytokines are critical for mediating host defense against infectious disease, but they also mediate disease pathology in autoimmunity. A subset of CD4+ T cells, known as "Th17 cells" based on production of IL-17, plays a key role in driving autoimmunity. Conversely, IL-17 plays important roles in fungal immunity particularly in protection against opportunistic infections caused by the commensal yeast Candida albicans. The Gaffen lab studies mechanisms of signal transduction mediated by IL-17, as well as its role in mediating host defense against fungi.  IL-17 and its receptor are unique in structure and sequence from other known cytokines, and the Gaffen lab has been a leader in studying signaling pathways mediated by this this novel family of cytokines. In addition, antibodies against IL-17 and its receptor are in clinical trials to treat various autoimmune conditions. Studies in Dr. Gaffen's lab also focus on the consequences of anti-IL-17 therapy with respect to infection.

Immunology Profile

 

 

   

Partha Sarathi Biswas, BVSc, MVSc, PhD

Research Interests


My lab aims to understand the cellular and molecular mechanisms involved in the pathogenesis of rheumatoid disorders such as lupus and RA, with a particular focus on:

    1. Cytokine abnormalitites in Lupus and Rheumatoid Arthritis, with a particular focus on IL-17 and related cytokines
    2. Abnormal Th17 and Follicular helper T cells response in lupus and RA
    3. Role of transcription factor IRF4 in the pathogenesis of lupus and RA

Immunology Profile

 

   

Patrizia Fuschiotti, PhD

Research Interests

Dr. Fuschiotti's research interests focus on the cellular and molecular mechanisms of pathogenesis by T cell and T cell-derived cytokines in inflammatory conditions. Particular emphasis is given to the roles played by cytokine IL-13 and its receptors (IL-13Ra1 and IL-13Ra2) in fibrosis, autoimmunity, and cancer. The context of this work has been in human diseases primarily affecting the skin, namely scleroderma (SSc), an autoimmune connective tissue disease whose main clinical feature is fibrosis, and cutaneous T cell lymphoma (CTCL). Dr. Fuschiotti has shown that IL-13 and its molecular pathways are involved in both diseases, acting as a major pro-fibrotic factor in SSc and as an autocrine factor for CTCL. In addition to understanding the underlying mechanisms of pathogenesis, she has also been developing strategies aimed at targeting IL-13 and its molecular pathways for therapeutic relief.

Immunology Profile

 

   

Robert Lafyatis, MD

Research Interests

Our laboratory effort is focused on understanding scleroderma, also known as systemic sclerosis, and developing novel therapeutic approaches based on identifying biomarkers of the disease process and utilizing biomarkers in clinical trials. We have utilized a biomarker approach in a clinical trial of fresolimumab (anti-TGF-beta) to show a role for TGF-beta in skin fibrosis associated with systemic sclerosis. We are also applying our pharmacodynamic biomarker of skin disease to trials of tocilizumab (trial completed), and C-82 and rilonacept (ongoing). Our group has a particular interest in understanding the mechanisms stimulating the immune response in systemic sclerosis, focusing on innate immune responses leading to fibrosis and vascular injury. Our data show increased expression of interferon responsive genes in circulating monocytes of scleroderma patients, prompting current investigations into the stimulus for this pattern of gene expression and the effect of interferon on fibrosis and vascular injury. Most recently, we have been examining the transcriptome of single cells in the skin and lungs of patients with systemic sclerosis to better understand the changes in gene expression in different immune and connective tissue cell types that lead to disease.

To aid in developing new therapies for systemic sclerosis, we are studying the pathogenesis through existing murine models, particularly bleomycin-induced skin and lung fibrosis, testing novel therapeutics to clarify the relationship between innate immunity and fibrosis. Our goal is to gain insight from these models that will enable us to propose more informative early phase clinical trials, utilizing biomarkers to show target engagement and as a surrogate clinical response.