Section 0 feasibility shorter lifespan but that circulating T cells are maintained by homeostatic proliferation.
Aim 3) To investigate something missing in the microenvironment in that does not permit survival of NK cells and 2) that, instead, of these cells. We will also examine for clonality or the lack of it. The hypothesis to be tested is that there is other unique surface markers characteristic of this type of cell, and to characterize the phenotype and function by the development of normally functioning whether the decline in natural killer (NK) cell function in X-SCID and Jak3-deficient SCID is compensated for returning or new chimeras who are available during the two years of support, with the intent to show permit application for further support. NKT cells develop as a compensatory mechanism that protects SCIDs with those two molecular types from of the proposed methods UN, to NKT address cells. The approach would be to analyze these NKT cells for the hypotheses and to generate sufficient data many to the development of elevated percentages of double negative and y6 T cells in these SCID chimeras post- of some molecular types of SCID is less able to produce T cells in normal number and that the T cells have a To approach this question, we plan to measure telomere length in the T cells of the various molecular types of transplants, 3) reducing the incidence of autoimmunity, and 4) contributing to their overall successful immune transplantation may be beneficial to these chimeras by 1) increasing their resistance to infection, 2) whether the decline in other unique surface markers characteristic of this type of cell, something severe viral investigate the possible roles of elevated percentages of double negative and y8 T cells in the longterm SCID and to examine for abnormal apoptosis and homeostatic proliferation. The hypothesis is that the thymus cell numbers and function and lower thymic output post-transplantation than SCIDs of other molecular types. SCID. SCIDs with adenosine deaminase deficiency and VDJ recombination defects have lower than normal T reconstitution.
Aim 2) To examine why the immune reconstitution differs in the various molecular forms of maintaining tolerance of the genetically donor T cells to host alloantigens in the setting of half-matched marrow cytometry, cellular cytokine staining and assays of I cell and T cell function. The hypothesis to be tested is that immune reconstitution of these SCID chimeras. We will characterize the phenotypes and functions of DN and y6 T cells after allogeneic stem cell therapy in SCID using monoclonal antibodies and multi-color flow cells cells. develop We but that circulating will as also examine for r.+ mechanism clonality or the are maintained NKT cells. by severe viral infections. Because this is a longitudinal study, the three aims will be pursued in as many feasibility of the proposed methods to address the hypotheses and to generate sufficient data to returning or new chimeras who are available during the two years of support, with the intent to show permit application for further support. 'NO To approach this question, we plan to measure telomere length in the T cells of the various molecular types of by the development of normally functioning of these of some molecular types of SCIO is less able to shorter lifespan NKT SCID and to examine for abnormal apoptosis and homeostatic proliferation. The hypothesis is that the thymus missing infections. in the cell function produce T cells in in X-SCID and SCIDs of other molecular types. function E'' transplants, transplantation the maintaining tolerance of the genetically donor T cells to host alloantigens in the setting of half-matched marrow reconstitution. SCID. cell cytometry, cellular cytokine staining and assays of T cell and T cell function. The hypothesis to be tested is that development numbers SCIDs with adenosine deaminase deficiency and VDJ 3) and Aim reducing the incidence of autoimmunity, may of elevated function 2) be To beneficial examine and percentages lower thymic why to these the of double output post-transplantation than immune chimeras negative reconstitution and by 4) contributing to their overall recombination defects have lower than normal T 1) and increasing differs yB T cells in their the in these various resistance SCID molecular successful immune to chimeras infection, longterm forms infants 1) To post- fl. flow and 2) of graft-versus-host disease (GVHD) prophylaxis. immune reconstitution (16 HLA-identical, investigate identical in patients with severe combined immunodeficiency (SCID) given transplants of rigorously T cell-depleted HLA- The overall goal of the proposed research is to further elucidate mechanisms of allogeneic stem cell education T cells f'3 or haploidentical after allogeneic 145 haploidentical) over the past 26.4 years, with an related stem bone marrow percentages The PI cells without pre-transplant has administered the of double negative latter therapy to chemotherapy or 161 post-transplant such TIL-he overall goal of the proposed research is to further elucidate mechanisms of allogeneic stem c ell education in patients with severe combined immunodeficiency (SCID) given transplants of rigorously T cell-depleted HLA- identical or haploidentical related bone marrow cells without pre-transplant chemotherapy or post-transplant infants 1) To possible roles of (Op graft-versus-host disease (GVHD) prophylaxis. The P1 has administered the latter therapy to 161 such (16 HLA-identical, 145 haploidentical) over the past 26.4 years, with an overall survival rate of 77%.
Aim yB the of these elevated f'0 .O-., 0_q Coo 3o?n?1 nip SCID chimeras. We will characterize the phenotypes and functions of ON cell therapy in SCIO using monoclonal overall survival rate of 77%.
Aim antibodies and yB T cells and -0O in multi-color the 0)-N 0-0 -Ow --? E-QCD -M, Sam :3NE-0ccc unit CDz .."""""""" C>, natural killer (NK) T cells coo ... __j a compensatory Because this is a longitudinal study, the three aims will be microenvironment in 00) 0-2 that does not permit survival that The approach would be to analyze these NKT cells for lack of it. protects homeostatic proliferation. and to characterize the phenotype and SCIDs The normal number and that the T cells have a Jak3-deficient SCIO hypothesis to with of NK cells those two be tested Aim pursued in as molecular types from and is 3) compensated for 2) is To investigate that, that there is instead, rt. (?A O?< -550 0.- ?'c :.. (Op Ow. 'C7 .-"""""""" r-. w'- .-. .n_. -.z w01 (Da ?-v, E fl, .-, tin tin Q,0
Because we have not used pre-transplant chemotherapy or GVHD prophylaxis for successful immune reconstitution by transplanted matched or half-matched related donor bone marrow stem cells, human SCID chimeras are a unique resource for studying the mechanisms of allogeneic stem cell education. Our studies to date demonstrate that the vestigial thymus of SCID infants can produce enough T cells of donor genotype to confer T cell function by 3-6 months after transplantation and that this thymic output continues into the second and early third decades post-transplantation. In addition, we have demonstrated that these T cells have a diverse TCR repertoire. We have also discovered that SCID recipients of allogeneic related hematopoietic stem cells in the first 3.5 months of life had higher and earlier levels of T cell reconstitution and thymic output and a higher survival rate (96%) than those transplanted after that age (71%). Bone marrow transplantation is likely to remain the primary treatment for SCID until gene therapy can be perfected for all genetic types. The proposed research will elucidate 1) whether elevated levels of certain types of T cells (double negative and gamma delta T cells) help maintain tolerance of the engrafted donor T cells to the SCID recipients and also assist them in resisting infection, 2) why certain molecular types of SCID do not experience the same degree of immune reconstitution as most of the others, and 3) whether or not the development of NKT cells is potentially protective for the types of SCID who do not have NK cells.
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