The research proposed in this project is designed to investigate the mechanisms of allogeneic stem cell development into mature and functioning T and B cells in humans with severe combined immunodeficiency (SCID). SCID infants who have become chimeric after receiving T cell-depleted allogeneic bone marrow stem cells without pretransplant cytoreduction or post-transplant GVHD prophylaxis provide a rare opportunity to study the mechanism of development of phenotypically normal T (and, in some cases, B and NK) cells from normal stem cells in an iatrogenically unaltered microenvironment.
The First Aim i s to study the mechanism of T cell development in human SCID infants given haploidentical T cell-depleted parental marrow stem cells and the characteristics of those T cells. Three hypotheses will be tested: a) that the maturation of normal stem cells to phenotypically and functionally normal T cells may not always occur in the SCID infant's thymus, b) that the T cells in some infants may derive from transplacentally acquired maternal T cells that persist and become expanded after stem cell transplantation, and c) that the T cells that develop extra-thymically or by expansion of transplacentally-transferred maternal T cells will have a restricted TCR Vbeta repertoire.
The Second Aim i s to study the mechanism of apparent tolerance to host antigens of T cells that develop from donor stem cells in human SCID chimeras. Two hypotheses will be tested: a) that donor T cells are 'tolerant' to host tissue antigens due to immune deviation resulting from a T cell cytokine imbalance and b) that such tolerant T cells can become cytotoxic T cells in the presence of an appropriate cytokine.
The Third Aim i s to determine whether the B cells that are present in human SCID infants function poorly following stem cell transplantation because of intrinsic abnormalities in the B cells or as a result of defective collaboration with the tolerant haploidentical genetically-donor T cells that develop.
The Fourth Aim i s to determine whether the B cell functional deficiency in SCID recipients of T cell-depleted bone marrow stem cells derives from restricted utilization of immunoglobulin (Ig) genes. Two hypotheses will be tested initially a) that Ig gene utilization differs among the different molecular forms of SCID and b) that the extent of Ig gene utilization also changes with time post-transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047605-02
Application #
6171220
Study Section
Special Emphasis Panel (ZAI1-SCO-I (01))
Program Officer
Ridge, John P
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$273,407
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
071723621
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
Sarzotti-Kelsoe, Marcella; Daniell, Xiaoju G; Whitesides, John F et al. (2011) The long and the short of telomeres in bone marrow recipient SCID patients. Immunol Res 49:44-8
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

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