A breeding colony of dogs has been established in which XSCID exists. This is a unique naturally occurring animal model with clinical, immunologic and pathologic findings similar to ADA+XSCID in man which is thought to be the most common form of human SCID in the United STates. The canine disease is characterized by normal levels of adenosine deaminase; failure to thrive; chronic infections; normal numbers of circulating B lymphocytes; and an absence of a blastogenic response to T cell mitogens. Since the immunologic abnormalities and pathogenesis of human XSCID remain unknown, the overall objectives of the proposal are to use this unique model to define the immunologic abnormalities in XSCID and to initiate studies to determine the basic underlying immunologic defect(s) in XSCID.
The specific aims of this proposal are: 1. To define the immune competence of XSCID patients and to distinguish the immunologic abnormalities due to XSCID alone and those resulting form secondary infections present at the time of clinical presentation by comparing the immune competence of conventionality-reared and gnotobiotic XSCID dogs. 2. To determine the basic immunologic defect(s) in XSCID. 3. To evaluate the role of the thymic microenvironment and/or thymocyte- thymic stromal interaction in the etiology of XSCID. These proposed studies offer, for the first time, the opportunity to document the immunologic abnormalities and possibly determine the basic underlying immunologic defect(s) in a large, well-defined population of XSCID patients. The advantages of studying XSCID in this canine model compared to human patients with XSCID are: (1) This is a rare disease in man and few patients are available to study. Those patients who are available for study are difficult to characterize as truly XSCID; (2) Many of the proposed studies can no longer be performed in human patients since the method of treatment id a bone marrow transplant which negates temporal study of the patient's T cells; (3) The unique opportunity to study the natural history and pathogenesis of XSCID in a well-defined population of gnotobiotic SCID dogs in a great compressed period of time; (4) Biopsy and/or necropsy tissue can be collected in order to evaluate the immunoregulation in treated and untreated XSCID patients; (5) The validity of carrier detection assays can be tested by test breedings; (6) Test breedings can be performed to test genetic hypotheses developed from future linkage studies; (7) Studies can be designed to evaluate novel approaches to immunotherapy for treating XSCID or gene therapy to correct the basic underlying genetic defect in a manner not appropriate in human patients.
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