Human severe combined immunodeficiency, or SCID, is a rare and fatal syndrome characterized by profound deficiencies of T and B cell function. Some cases have been shown to be caused by mutation in the genes encoding adenosine deaminase (ADA) or the gamma chain of the lL-2 receptor (lL- 2Rgamma). However, for a significant proportion of human SCID's, the primary biologic errors remain unknown.
The Specific Aims are: 1) to conduct analyses of phenotypes, functions and genetic origins of blood lymphocytes from infants with the various forms of human SCID before and serially after they have received T cell-depleted marrow stem cells without pre-transplant conditioning to a) identify unique phenotypic and functional characteristics of SCID lymphocytes associated with specific molecular derangements, b) gain a greater understanding of the influence the SCID microenvironment has on stem cell maturation, c) obtain information about T, B, and NK cell ontogeny not available in any other human experimental system; 2) to expand preliminary findings which strongly support the hypothesis that, among SCID infants, impaired natural killer (NK) cell production and function is a feature unique to the x- linked form by conducting NK phenotypic and functional studies on lymphocytes from patients with all forms of SCID; 3) to investigate the basis for abnormal NK function by attempting to correct it in vitro with non-specific cell activators and by the addition of cytokines whose receptors do or do not contain IL2Rgamma; 4) to study the phenotypes and capacity of B cells from the different genetic types of SCID to isotype- switch and synthesize and secrete immunoglobulin in an effort to gain insight into why B cell unction develops in some after successful marrow stem cell transplantation but not in others; 5) to correlate the data from studies in the first four Aims with those from molecular analyses (for example, responses of x-linked SCID B cells and NK cells to different cytokines would be expected to differ, depending on whether specific mutations in the lL-2Rgamma gene -- identified by collaborator Dr. Jennifer Puck -- result in expression of an abnormal protein that affects or does not affect binding to another receptor protein; another example would be correlation of phenotypic and functional studies of SCID lymphocytes with the results of the molecular analyses to be conducted by Dr. Harville and 6) to correlate the phenotypic and functional studies of SCID lymphocytes before and after stem cell transplantation with the thymic microenvironmental findings by Dr. Haynes.
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