Rheumatology

Basic Research

The Division of Pediatric Rheumatology at 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 rheumatoid arthritis (JRA) and other rheumatic conditions.

Basic research includes a National Institutes of Health-funded laboratory led by Division Chief Raphael Hirsch, MD, that focuses on the delivery of gene therapy directly to diseased joints, identifying the genetic characteristics of JRA using DNA “chips,” constructing fusion proteins capable of preventing arthritis that will allow scientists to better quantify and interpret genetic profiles of the disease. Other programs include the work of Abbe Vallejo, PhD, whose laboratory is investigating the immunobiology of inflammatory syndromes and aging.

Gene Transfer

New biologic drugs, such as etanercept, have dramatically eased the symptoms of arthritis in children and adults. These therapies are currently delivered systemically through injection. The laboratory of Dr. Hirsch is investigating ways these biologic drugs can be delivered locally to minimize the risk of toxicity associated with systemic delivery.

The goal is to achieve steady-state levels of short-lived biologic agents in the diseased joints of patients using recombinant adeno-associated virus (rAAV) vectors, which have been shown to be capable of delivering genes to tissue in vivo. Research focuses on using rAAV to deliver a therapeutic biologic agent directly to the synovium, where synovial cells would incorporate it into their genetic machinery and produce the protein locally.

Genetic Characteristics of JRA

Using DNA micro arrays, or “DNA chips,” Dr. Hirsch’s laboratory is examining the gene profiles of both mice with induced arthritis and JRA patients to identify the genetic characteristics of the disease. Of particular importance is learning which genes are being over-expressed and which are being under-expressed at a specific point in time, in a particular patient. Dr. Hirsch and Margalit Rosenkranz, MD, are also studying proteomic profiles of patients with pediatric rheumatic diseases in order to improve diagnosis and develop prognostic indicators, as well as to discover novel disease mediators. The investigation includes identifying gene expression profiles that differentiate chronic disease in three JRA subtypes, pauciarticular, polyarticular and systemic onset.

Gene expression and proteomic profiles are expected to help identify new targets for therapy and might someday enable physicians to more accurately diagnose JRA, predict outcomes and determine which therapies individual patients are most likely to respond to. Gene expression analysis has already led to the discovery of several genes that appear to be involved in the destruction of the joint. These studies are expected to result in a comprehensive database to be used as a road map for developing and testing novel hypotheses and investigating specific pathways and genes in the development of JRA.

Fusion Proteins

Dr. Hirsch’s laboratory is investigating whether a specific fusion protein can be constructed that would protect children from arthritis, similar to the way children are vaccinated against a virus. Research focuses on a specific cell type, T-lymphocyte, that appears to play an important role in autoimmune processes. Investigators are looking at whether fusion proteins can be constructed to generate a new molecule capable of delivering an inhibitory signal to the T-lymphocytes that cause an autoreactive response to Type-2 collagen, the collagen in the joint.

The study provides an opportunity to test the concept that disease can be prevented by preventing the T-cell autoimmune response to collagen. The fusion protein constructed in the laboratory has been successful in protecting mice from arthritis by blocking the T-cells that induce the disease.

Inflammatory Syndromes and Aging

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. 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.

His laboratory is investigating various aspects pertaining to T-cell replicative senescence, the immunobiology of aging, the biology of autoimmune/inflammatory syndromes including paraneoplastic autoimmune disorders 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.

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