The research will investigate longitudinally the development and persistence of T, B, and NK cell function in infants and children with human severe combined immunodeficiency (SCID) who are or who become HLA-identical or haploidentical stem cell chimeras. The unique study population will consist of 101 surviving SCIDs who have been given bone marrow stem cells without pre-transplant chemotherapy or post-transplant GVHD prophylaxis.
The first aim i s to examine longitudinally the phenotypes, functions and genetic origins of T cells in the 101 surviving SCID recipients of HLA-identical (n= l5) or haploidentical (n=86) T cell-depleted parental marrow stem cells post-transplantation. Three hypotheses will be tested: a) that the decline in T cell function with time is associated with phenotypic changes in the genetically-donor T cells suggestive of regulatory T cell dominance, b) that the latter cells will dampen the responsiveness of CD4+CD25- T cells, c) that the degree of HLA matching between the donor and recipient initially will be predictive of whether this pattern is seen, and d) that these T cells arise as a mechanism of maintaining tolerance of the haploidentical donor-derived T cells to the patients' non-shared HLA antigens.
The second aim i s to examine the role of donor-versus-recipient natural killer (NK) cell alloreactivity in determining marrow allograft acceptance and whether GVHD occurs. Two hypotheses will be tested initially: a) that the presence of HLA Class I mismatches between the donor and recipient in the direction of GVHD correlates with good graft acceptance, and b) that the presence of HLA Class I mismatches between the donor and recipient in the direction of GVHD correlates with the development of no or low grade GVHD.
The third aim i s to assess the role of abnormal dendritic cell function in the development and persistence of NK cells post-transplantation in X-linked and Jak3-deficient SCIDs. The hypothesis to be tested is that NK cell numbers and function will decline with time after stem cell transplantation in these two types of SCIDs due to abnormalIL-15-dependent dendritic cell (DC) functions.
The fourth aim i s to continue to investigate the molecular bases of the 18% of SCIDs for whom the cause remains unknown. The hypotheses to be tested are 1) that the lymphocyte phenotype will facilitate the search for known or unknown genes that cause SCID and 2) that the molecular form of SCID will influence the development and persistence of immunity post-transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042951-10
Application #
7379946
Study Section
Immunobiology Study Section (IMB)
Program Officer
Wedgwood, Josiah F
Project Start
1998-12-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
10
Fiscal Year
2008
Total Cost
$322,302
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
McWilliams, Laurie M; Dell Railey, Mary; Buckley, Rebecca H (2015) Positive Family History, Infection, Low Absolute Lymphocyte Count (ALC), and Absent Thymic Shadow: Diagnostic Clues for All Molecular Forms of Severe Combined Immunodeficiency (SCID). J Allergy Clin Immunol Pract 3:585-91
Teigland, C L; Parrott, R E; Buckley, R H (2013) Long-term outcome of non-ablative booster BMT in patients with SCID. Bone Marrow Transplant 48:1050-5
Buckley, Rebecca H; Win, Chan M; Moser, Barry K et al. (2013) Post-transplantation B cell function in different molecular types of SCID. J Clin Immunol 33:96-110
Roberts, Joseph L; Buckley, Rebecca H; Luo, Biao et al. (2012) CD45-deficient severe combined immunodeficiency caused by uniparental disomy. Proc Natl Acad Sci U S A 109:10456-61
Buckley, Rebecca H (2012) The long quest for neonatal screening for severe combined immunodeficiency. J Allergy Clin Immunol 129:597-604; quiz 605-6
Buckley, Rebecca H (2011) Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res 49:25-43
Chinen, Javier; Buckley, Rebecca H (2010) Transplantation immunology: solid organ and bone marrow. J Allergy Clin Immunol 125:S324-35
Buckley, Rebecca H (2010) B-cell function in severe combined immunodeficiency after stem cell or gene therapy: a review. J Allergy Clin Immunol 125:790-7
Railey, Mary Dell; Lokhnygina, Yuliya; Buckley, Rebecca H (2009) Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis. J Pediatr 155:834-840.e1
Sarzotti-Kelsoe, Marcella; Win, Chan M; Parrott, Roberta E et al. (2009) Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras. Blood 114:1445-53

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