Project 2 (PIDTC Protocol 6902) consists of a retrospective and a cross-sectional study of patients who received an hematopoietic cell transplant (HCT), gene therapy or enzyme replacement therapy for Severe Combined Immune Deficiency (SCID) in North America, with the goal of identifying prognosfic factors, defining opfimal treatment approaches, and providing a comprehensive assessment ofthe long term outcomes, late effects, and quality of life (QoL). An analysis of 240 patients transplanted from 2000 through 2009, showed that age <3.5 months and infecfion at HCT were the most important prognosfic factors. In addition, we found that ~ 30% of survivors exhibit impaired T and/or B cell reconstitufion.
The Specific Aims are: 1) to analyze the impact of patient, donor, and HCT-related factors on long-term outcome. We will complete and expand the retrospective analysis ofthe enfire cohort of 732 pafients and examine the impact of SCID genotypes and various factors at HCT on long-term outcome;2) to complete the ongoing crosssectional analysis of long-term survivors to characterize current level of T, B and NK cell chimerism and function, and clinical status in terms of health, growth, development and QoL;these results will be correlated with findings accrued in Specific Aim 1, and analyzed to assess the relative impact of patient and transplant-dependent variables on the long-term clinical status ofthe pafients and the quality and durability ofthe immune reconstitufion inifially achieved. 3) is a new aim designed to identify and characterize the machanisms underlying continuing deficits of T and B cell immunity detected in a proportion of longterm survivors. By collecting samples at the cross-sectional visits, we will perform mechanisfic studies specifically developed to test four hypotheses: a) residual T cell deficits are associated with T cell exhaustion;b) in recipients of HLA-haplotype mismatched transplants, diversity of T cells is limited by an absence of positive selection in the thymus for donor T cells that bear receptors restricted by HLA alleles not shared by the recipient;c) B cell deficits reflect an insufficient engraftment of hematopoietic progenitor cells, and/or an intrinsic B cell deficit in certain SCID phenotypes, and/or ineffective interactions between HLAdisparate donor T cells and host B cells;and d) long-term T and B cell deficits are principally ascribable to impaired engraftment of donor hematopoiefic stem cells. These studies will produce valuable informafion on outcomes of HCT for SCID and guide future clinical trials.

Public Health Relevance

This renewal of Project 6902, that incorporates and builds upon a series of new discoveries made by the PIDTC in the course ofthe inifial grant period, is of immediate importance to the development of prospective clinical trials that will result in better therapeufic approaches standardizing and optimizing care for SCID patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54AI082973-06
Application #
8890280
Study Section
Special Emphasis Panel (ZTR1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
Chinen, Javier; Cowan, Morton J (2018) Advances and highlights in primary immunodeficiencies in 2017. J Allergy Clin Immunol 142:1041-1051
Miggelbrink, Alexandra M; Logan, Brent R; Buckley, Rebecca H et al. (2018) B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation. Blood 131:2967-2977
Slack, James; Albert, Michael H; Balashov, Dmitry et al. (2018) Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol 141:322-328.e10
Langelier, Charles; Zinter, Matt S; Kalantar, Katrina et al. (2018) Metagenomic Sequencing Detects Respiratory Pathogens in Hematopoietic Cellular Transplant Patients. Am J Respir Crit Care Med 197:524-528
Haddad, Elie; Logan, Brent R; Griffith, Linda M et al. (2018) SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood 132:1737-1749
Barzaghi, Federica; Amaya Hernandez, Laura Cristina; Neven, Benedicte et al. (2018) Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol 141:1036-1049.e5
Kuo, Caroline Y; Long, Joseph D; Campo-Fernandez, Beatriz et al. (2018) Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome. Cell Rep 23:2606-2616
Belderbos, Mirjam E; Gennery, Andrew R; Dvorak, Christopher C et al. (2018) Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. J Allergy Clin Immunol 142:1628-1631.e4
Buchbinder, David; Smith, Matthew J; Kawahara, Misako et al. (2018) Application of a radiosensitivity flow assay in a patient with DNA ligase 4 deficiency. Blood Adv 2:1828-1832
Kohn, Donald B; Hershfield, Michael S; Puck, Jennifer M et al. (2018) Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol :

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