Description of work
Laboratory and clinical studies are directed toward understanding the production, fate and functions of neutrophils, the white blood cells which protect the body from bacterial and fungal infections. Neutrophils are formed from hematopoietic stem cells in the bone marrow through an elaborate and highly regulated process. Neutrophil formation and deployment are regulated through myeloid growth factors, and the laboratory has conducted many pioneering studies on the physiological effects and clinical applications of these growth factors, particularly the growth factor called "granulocyte colony-stimulating factor" or "G-CSF.”
Neutropenia, a reduced number of neutrophils in the blood, occurs for many reasons. Our laboratory studies have focused on understanding the physiological, molecular and genetic mechanisms for the disease in causing severe chronic neutropenia. These diseases include cyclic neutropenia, congenital neutropenia (various types of congenital neutropenia) and a number of specific syndromes. We are currently studying neutropenia in cyclic and congenital neutropenia, Barth syndrome and WHIM syndrome and collaborating with numerous investigators in studies on other causes of neutropenia. We also investigate the consequences and treatment of chronic neutropenia through collaborative investigations.
The laboratory investigates new drugs and therapies for neutropenia and inflammatory and autoimmune diseases. Ongoing studies involve agents to promote neutrophil survival and enhance or suppress the trafficking of neutrophils from the bone marrow through the blood to tissue sites of inflammation.
The Severe Chronic Neutropenia International Registry
The Severe Chronic Neutropenia International Registry (SCNIR) is an international disease registry of patients with severe neutropenia lasting for months, years or a lifetime. The Registry has offices in Seattle and in Hannover, Germany and includes patients from more than 40 countries but predominantly from North America and Europe. The goal of the Registry is to follow patients on a long-term basis in a cooperative relationship with their physicians and learn about the natural history and responses to various treatments. The Registry began when we learned that most patients with severe chronic neutropenia can be successfully treated on a long-term basis with the myeloid growth factor called "granulocyte colony-stimulating factor” or “G-CSF.” Through the activities of the Registry and cooperating researchers and a parallel Tissue Repository, much has been learned about the genetic and molecular causes for neutropenia, as well as the risk of these patients evolving to develop acute leukemia. The Registry is overseen by an international advisory board that works together throughout the year and meets on an annual basis. The Registry and Tissue Repository were originally supported by Amgen, a biopharmaceutical company, and are now supported by a grant from the National Institutes of Health, National Institute of Allergy and Infectious Diseases.
Molecular, Genetic and Therapeutic Studies on Neutropenia
Cyclic neutropenia and severe congenital neutropenia are caused by mutations in the gene for neutrophil elastase, in most cases. Through the Registry and Repository we have collected tissue samples from many patients with these diseases and are studying the relationship of the specific mutations to the clinical course, response to treatment, and risk of leukemia. We are also investigating new therapies for these conditions.
Chronic idiopathic neutropenia is a relatively common acquired condition predominantly affecting women. It is presumed to be caused by immune or autoimmune disruption of neutrophil formation. Chronic idiopathic neutropenia responds to treatment with G-CSF and does not evolve to leukemia. We are beginning studies of a new oral agent for treating this disease.
Barth syndrome is a sex linked recessive disease, primarily affecting young boys and causing severe congestive heart failure and infections due to chronic neutropenia. We are investigating the mechanism of neutropenia and potential approaches to therapy for this severe condition.
WHIM syndrome is usually an autosomal dominant disorder causing severe neutropenia and lymphocytopenia as well as severe wart infections. We are investigating the molecular mechanisms for this disease and a potential new targeted therapy.