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The Division of Pediatric Rheumatology at UPMC Children’s Hospital of Pittsburgh has an active basic research program that explores fundamental issues of rheumatic disease critically important to the development of safer and more effective therapies for children with juvenile idiopathic arthritis (JIA) and other rheumatic conditions.
Basic research includes National Institutes of Health-funded laboratories of Abbe de Vallejo, PhD and Kathryn Torok, MD. Dr. de Vallejo‘s research program is in the area of Immunobiology of inflammatory syndromes and aging. Dr. Torok’s research is on the biology of pediatric scleroderma.
Because of the rapid degeneration of the thymus after birth, there is an age-dependent lack of replenishment of new naïve T-cells. Due to antigenic challenge throughout life, the T-cell pool is therefore susceptible to aging, which can contribute to higher risk of infections, malignancies, and autoimmunity as people grow older. In view of shared immunological phenotypes between the elderly and patients with inflammatory syndromes, Dr. de Vallejo is a proponent of the hypothesis that immune exhaustion and replicative senescence in the immune system underlies immune abnormalities related to age and disease. Inflammatory diseases currently being studied are JIA, juvenile dermatomyositis, and adult rheumatoid arthritis. Biology of aging studies currently being pursued is the immunology of successful aging, and an animal model of longevity.
His laboratory is investigating various aspects pertaining to immune cell replicative senescence, the immunobiology and health outcomes of aging, the biology of rheumatic diseases and T-cell homeostasis. With the implication of multigene families, such as the MHC, KIR, and NKG in the development of various inflammatory diseases and in the ontogeny of senescent lymphocytes, other projects are also designed to examine the differential regulation and molecular phylogeny of multigene families.
Localized scleroderma (LS), also known as ‘morphea’, is a potentially disfiguring autoimmune disease of the skin and underlying tissue affecting both children and adults, with the highest impact in childhood-onset disease. Disease activity leads to fibrosis and atrophy, causing potential physical and psychological disability that continues throughout childhood into adulthood. A type of immune cell, T-helper (Th) cells, and their associated cytokines (inflammatory proteins) have been found to contribute significantly to the disease process in systemic sclerosis (SSc), the other form of scleroderma. Their effect is supported by the presence of cytokines from these lineages in the sera (blood), peripheral blood cells (immune cells), and tissue (skin and other organs) in scleroderma patients. A better understanding of the inflammatory proteins involved in localized scleroderma, especially during the active inflammatory phase, would lead toward more directed and efficacious therapies. This concept is currently being investigated at the University of Pittsburgh with Dr. Kathryn Torok, MD as the Principal Investigator.
Dr. Torok directs the University of Pittsburgh Childhood Scleroderma Clinic, which is held 4 times a month. On average, 25 pediatric patients with localized scleroderma are seen in clinic each month (including 2 new patients). Patients seen at the Childhood Scleroderma Clinic can also participate in a research registry and ‘serumbank’, which includes the collection of the following biological specimens: serum, plasma, peripheral blood mononuclear cells (PBMC), RNA, DNA and skin biopsy specimens. Clinic visits include sufficient time for detailed examination and standardized data collection of outcome measures. At present there are 370 patients enrolled in the registry; 160 with complete clinical data and stored serum, and 70 patients with 3 or more serum samples from different time points. Repeat blood collection allows for the analysis of the change of the cytokine profile as the disease transitions from active to inactive disease with systemic immune-modulatory therapy (prednisone, methotrexate, mycophenolate mofetil, etc.).
Dr. Torok also collaborates with other institutions internationally by serving as a core member of the pediatric localized scleroderma group within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Localized Scleroderma Clinical and Ultrasound Study group (LOCUS). These multicenter studies further evaluate clinical, thermal, and ultrasound measures regarding disease activity and damage parameters, collect biological specimens, and evaluate treatment regimens in pediatric localized scleroderma. Two of these large studies have a specific longitudinal focus on biologic specimens, in which the University of Pittsburgh serves as the repository for biologic specimen processing and storage center. These projects also collect the same clinical outcome measures of activity and damage in LS as those collected at the University of Pittsburgh, therefore allowing a direct comparison of biological specimens and associated clinical status between centers.
Dr. Torok’s long-term goal is to utilize the above resources to ultimately improve the quality of life in patients with localized scleroderma (LS) by minimizing the burden of disease damage. Understanding which key inflammatory mediators are present during the active phase of disease may foster the development of more effective therapies in LS.
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