Our laboratory has identified and characterized an X-linked severe combined immunodeficiency (XSCID) in dogs that is due to mutations in the common gamma (gamma c) subunit of the interleukin-2 (IL2), IL4, IL7, IL9, and IL15 receptors. Canine XSCID, unlike genetically engineered gamma c-deficient mice, has a clinical and immunologic phenotype virtually identical to human XSCID. It appears that species-specific differences exist in the role of the gamma c and its associated cytokines in mice compared to their role in humans and dogs, suggesting gamma c-deficient dogs may be a more relevant model for studying the role of the gamma c in humans. We are utilizing this model for a variety of studies to address: 1. Fundamental questions concerning the role of the gamma c in cytokine regulation and lymphocyte development. 2. The pathogenesis of XSCID. 3. Strategies for improving bone marrow transplantation outcome. 4. Development and evaluation of strategies for gene therapy. 5. Human hematopoietic stem cell development.