Defining the Basis of the T-cell Immunodeficiency of Schimke Immuno-osseous Dysplasia and Identifying Potential Therapies

David B. Lewis, M.D.

Stanford University School of Medicine

Funded in December, 2004: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Understanding T Cell Immunodeficiency

Collaborating Baylor and Stanford researchers will determine how a particular gene mutation causes a disease characterized by a deficiency of immune T cells. This will enable them to identify specific therapeutic targets for improving T cell function in this disease. Their findings may lead to a better understanding of T cell biology in immune system functioning, and of the consequences of its dysfunction.

Schimke immuno-osseous dysplasia (SIOD) is an inherited immune T cell deficiency disease in which patients have abnormal bone growth resulting in short stature and renal failure. This disease frequently leads to death in childhood or adolescence. The researchers recently identified mutations in both copies of a gene (named SMARCAL1) which produces one of several proteins known to regulate the functions of many cells by modifying their DNA. The investigators hypothesize that this protein modifies immune T cell DNA and thereby regulates the production, replication, and maintenance of T cells. This results in fewer and weaker T cells that are unable to mount an effective response to infections.

The collaborators, studying patients and mouse models of the disease, will examine immunological, genetic, and biochemical factors of SIOD and integrate this information using bioinformatics. This research is anticipated to clarify the function of the mutated gene and the protein it produces, which could lead to identifying targets for therapeutic interventions.

Significance: Clarifying the genetic mutation and the abnormal protein produced by the mutated gene could provide fundamental understanding of immune T cell deficiency in this and other immunodeficiency diseases, and lead to development of new treatment methods.

ABSTRACT

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Defining the Basis of the T-cell Immunodeficiency of Schimke Immuno-osseous Dysplasia and Identifying Potential Therapies

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive multisystem disorder that characteristically includes prenatal or neonatal growth retardation from spondyloepiphyseal dysplasia and the development of T-cell deficiency and renal failure in early childhood. Patients have decreased helper (CD4) and cytotoxic (CD8) peripheral T-cells, reduced delayed-type hypersensitivity skin test reactions to antigens, and impaired DNA synthesis in response to activation of T-cells by mitogenic lectins. However, the response of patient T-cells to more physiological activation via the T-cell receptor (TCR)/CD3 complex and CD28 is poorly understood. SIOD is usually fatal within the first two decades of life; one third of the patients die from opportunistic infections such as disseminated herpesviral infections and Pneumocystis pneumonia, which are indicative of a serious T-cell immunodeficiency. Mutations in SMARCAL1 cause SIOD. SMARCAL1 encodes an unstudied protein homologous to the SNF2 family of chromatin remodeling proteins. Remodeling of chromatin structure regulates developmental and tissue-specific gene expression as well as DNA recombination, methylation, repair, and replication. Therefore, we hypothesize that clarifying the function of SMARCAL1 in T-cells will provide insight into the biology of T-cell development and peripheral function and its regulation by a putative SNF chromatin-remodeling protein.

To define this new area of T-cell biology and identify potential therapies for the T-cell deficiency of SIOD patients, we propose to 1) characterize the T-cell deficit in human patients, 2) develop a mouse knockout of SMARCAL1 by homologous recombination and analyze these mice to further elucidate the T-cell disorder associated with SIOD and test potential therapies, and 3) delineate the regulatory network within which SMARCAL1 functions by suppression of the T-cell proliferative defect through screening of potential therapeutic cytokines and by characterizing the differential gene expression in response to mitogens using gene expression microarray analysis.

INVESTIGATOR BIOGRAPHIES

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David B. Lewis, M.D.

Dr. David Lewis is an Associate Professor of Pediatrics at Stanford University School of Medicine and Director of the Jeffrey Modell Center for Primary Immunodeficiency at Stanford. He received his medical degree at the University of California at San Francisco, and pursued pediatric residency training at the institution and the University of Washington, Seattle, WA. He completed a fellowship in Pediatric Infectious Diseases at the University of Washington, where he remained as a faculty member until 1997, when he joined the Stanford University faculty. Dr. Lewis has a long-standing interest in developmental and genetic limitations in T-cell immunity, including in humans. He is particularly interested in limitations in immunity mediated by CD4 T cells and how this compromises host defenses against intracellular pathogens. As part of his activities with the Modell Center, Dr. Lewis spends about 25% of his time seeing patients with primary immunodeficiencies. Dr. Cornelius Boerkoel is an Assistant Professor of Human Genetics at Baylor College of Medicine. He received his medical degree and Ph. D. from Case Western University, Cleveland, OH. Following completion of a pediatric residency at the University of Washington, Seattle, WA, he completed a fellowship in Clinical Genetics at The Hospital for Sick Children and the University of Toronto, Toronto, Canada. He then completed postdocatoral research training at Baylor College of Medicine and remained as faculty in the Department of Molecular and Human Genetics. Dr. Boerkoel has a longstanding interest in inherited human diseases, and as part of his activities, Dr. Boerkoel spends approximately 25% of his time seeing patients with inherited disorders. He began his studies of Schimke immuno-osseous dysplasia (SIOD) in 1997. SIOD is characterized by skeletal dysplasia, progressive renal failure, and T-cell immunodeficiency. Additional but more variable disease features include arteriosclerosis, hypothyroidism, and tooth and pigmentary abnormalities. SIOD is usually fatal within the first two decades of life because of renal failure, infection, bone marrow failure, or cerebral ischemia. Dr. Boerkoel's challenge is to explain how mutations of SMARCAL1 cause this severe pleiotropic disease, identify potential therapies to treat or ameliorate the disease, and derive insights into general principles of developmental biology and pathophysiology. To accomplish this, he and his co-workers are using a combination of patient studies, Drosophila and murine genetics, and cell culture systems.