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
Burbank, Allison J; Shah, Shaili N; Montgomery, Maureen et al. (2016) Clinically focused exome sequencing identifies an homozygous mutation that confers DOCK8 deficiency. Pediatr Allergy Immunol 27:96-8
Cowan, Morton J (2016) The Primary Immune Deficiency Treatment Consortium: how can it improve definitive therapy for PID? Expert Rev Clin Immunol 12:1007-9
Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D et al. (2016) Primary Immune Deficiency Treatment Consortium (PIDTC) update. J Allergy Clin Immunol 138:375-85
Chan, Alice Y; Punwani, Divya; Kadlecek, Theresa A et al. (2016) A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J Exp Med 213:155-65
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Jackson, Shaun W; Scharping, Nicole E; Jacobs, Holly M et al. (2016) Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation. J Immunol 197:4529-4534
Punwani, Divya; Kawahara, Misako; Yu, Jason et al. (2016) Lentivirus Mediated Correction of Artemis-deficient Severe Combined Immunodeficiency. Hum Gene Ther :
Punwani, Divya; Zhang, Yong; Yu, Jason et al. (2016) Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B. N Engl J Med 375:2165-2176
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Chinen, Javier; Notarangelo, Luigi D; Shearer, William T (2016) Advances in clinical immunology in 2015. J Allergy Clin Immunol 138:1531-1540

Showing the most recent 10 out of 64 publications