The specific aim of Phase I research is to define the Class II major histocompatibility complex (MHC) restriction of antigen recognition by genetically donor T cells of patients with severe combined immunodeficiency disease engrafted with parental haploidentical bone marrow stem cells. Lymphocyte responses will be quantified by 3H thymidine incorporation studies of tetanus toxoid-specific T cell lines derived from the recipients and donors when presented antigen by various EBV-transformed B cell lines. The latter will be derived from the recipient, donor, non-donor parent, and unrelated normal control donors bearing Class II MHC antigens unique for each parental haplotype. Phase I will also consist of course work in the Departments of Microbiology/Immunology, Genetics, and Cell and Molecular Biology.
The specific aim of Phase II is to determine whether the MHC restriction pattern found in Phase I is associated with an altered T cell receptor (Ti) gene rearrangement pattern by genetically donor T cells that have matured in the recipient by Southern blot analysis. The ontogeny of T cell maturation in recipients will also be examined by serial determinations of Ti alpha and beta mRNA expression and DNA rearrangement patterns utilizing mRNA dot blot and Southern blot techniques. The proposed studies are highly relevant to the potential future usefulness of haploidentical (half-matched) bone marrow transplants in correcting a variety of disorders including malignancy, bone marrow aplasia, as well as immunodeficiency and other heritable diseases. If genetically donor T cells are truly modified by the host microenvironment to function as though they are recipient in T, B and macrophage interactions, the use of post-thymic T cell depleted haploidentical marrow may have wide clinical application.
| Roberts, J L; Volkman, D J; Buckley, R H (1989) Modified MHC restriction of donor-origin T cells in humans with severe combined immunodeficiency transplanted with haploidentical bone marrow stem cells. J Immunol 143:1575-9 |
