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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1)
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University of California San Francisco
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United States
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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
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