The overall goal of this research is to define the cellular and, ultimately, the molecular bases for both currently recognized and yet to be defined primary immunodeficiency diseases, so as to provide the most rational and effective therapies for them. Correlative studies of lymphocyte phenotypes and function in patients with genetically-determined immunodeficiency will provide clues to as yet undiscovered molecular derangements and also permit the discovery of atypical phenotypes resulting from known mutations. Results: During the current reporting period, we performed 23 stem cell transplants in patients with primary immunodeficiency. The creation of human SCID haploidentical bone marrow stem cell chimeras has allowed us a unique opportunity to examine the cellular and molecular bases of human thymic education.we reviewed stem cell transplants done in the neonatal period. The success rate is 93% success rate for stem cell transplants done in the neonatal period. We conclude that in utero therapy (currently being proposed) is not likely to offer any advantage over this high success rate. We hypothesize that abnormalities in B and NK cell development post-transplantation are related to the underlying molecular defect leading to SCID, and the development of normal B and/or NK cell function is due to the presence of donor B and/or NK cells or to double parental T cell chimerism. We are finding that diminished numbers of CD4+ T cells and an increase in alpha/beta T cells several years after transplantation in some SCIDs are an indication of incomplete or inadequate T cell reconstitution and/or autoimmune reactions and may signal the need for a booster transplant. The studies proposed take advantage of a unique large population of patients with genetically-determined immunodeficiency diseases who are referred to the investigators at this GCRC. Future plans: Plans for this protocol are to continue to examine patients with primary immunodeficiency for their fundamental abnormalities so that gene therapy might be accomplished when the technology for this becomes perfected. We will continue to characterize all such patients at a cellular level so that consistent phenotypic and functional patterns can be used as an aid in predicting underlying molecular defects, as it did in the case of Jak3 deficiency. Our plans also include the continued study of T and B cell ontogeny, MHC restriction, and tolerance induction in the 75 surviving human SCID bone marrow stem cell chimeras that we have developed over the past 16.5 years. Significance: Bone marrow stem cell transplantation is currently the most successful therapy for all forms of human SCID (82% success rate at this Institution) and will continue to be so until gene therapy becomes perfected. This GCRC protocol has permitted us to become a world leader in this type of transplantation. However, since T cell- depleted haploidentical marrow transplantation was only developed 17 years ago, the long term extent of immune reconstitution is unknown and can only be known through continued and careful longitudinal immunologic studies in these rare and informative infants and children.
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