Transgenic Animal Models Of Human Immune Defects

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Abstract

We seek to understand the role of enzyme systems in host immune defense, specifically the NADPH oxidase. We study the NADPH oxidase in the generation and control of inflammation, its role in protection from infection, and its role in how cells signal to each other. These are important issues to understand in order to better appreciate how to manipulate the immune system pharmacologically, immunologically, and genetically. We actively pursue a mixed approach to these issues by studying patients, animals, and laboratory specimens. We follow a large number of patients with NADPH oxidase deficiency, chronic granulomatous disease (CGD), and we have been involved in characterizing the infections and complications that they develop. We have also used a mouse created in my laboratory that is deficient in the NADPH oxidase and therefore closely mimics human CGD. Numerous studies in these mice have shown a critical role for this enzyme system in not only protection from infection but also in the magnitude and character of the inflammatory response. This mixed approach to understanding the NADPH oxidase in CGD has been very informative about the role of the innate immune system in both early and late aspects of the inflammatory response. We are also pursuing the genetic and cellular basis of another complex host defense defect, hyper-IgE and recurrent infection syndrome (Job's syndrome or HIE), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino- pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities. The gene(s) involved in Job's must be critically important to innate immunity, the early and late host immune responses, skeletal growth and development, and tooth deciduation. We have developed a comprehensive patient evaluation system and are now in the process of examining the data from over 90 candidate families. In the course of these studies we have identified novel phenocopies of Job's syndrome that are transmitted in a recessive pattern. The search for the genes responsible for these syndromes continues and will eventually lead to pathways that we can disrupt in mice to perform functional studies.