The intent of the proposed research is to follow prospectively all available SCID infants born in the United States and Canada to evaluate systematically for the first time factors influencing the outcomes of the multiple forms of hematopoietic cell therapy (HCT) for SCID currently being employed. This study will use state of the art methods to define the molecular genotypes and characterize serially multiple key parameters of immunological reconstitution.
Aim 1) To determine the effects patient-related factors have on survival, time course of immune reconstitution and clinical outcome of HCT for SCID, including age at transplantation, presence of viral infections, lymphocyte phenotype, molecular genotype and the presence of transplacentally transferred maternal lymphocytes.
Aim 2) To determine the effects adequacy of HLA matching of donor and recipient have on survival, the time course of immune reconstitution and clinical outcome of HCT for SCID. For the majority of patients who must receive HLA-mismatched transplants, source of donor cells (haploidentical mother vs. father, HLA-matched unrelated adult or cord blood), methods of T cell depletion or CD34 cell selection, and cell numbers given (both CD34+ stem cells and CD3+ T cells) will be comparatively examined, with particular focus on the occurrence, severity and duration of GVHD and ultimate multilineage engraftment.
Aim 3) To determine the effects the use (or not) and type of pre-transplant conditioning have on survival and on the immunologic and clinical outcomes of HCT. This project will help accomplish the proposal's overall objective of improving definitive therapy for SCID by comparing relatively short term outcomes of the different treatments currently being employed for HCT in SCID in a temporally homogeneous cohort of patients under defined patient and donor circumstances. It will define early biomarkers that predict survival, the earliest immune reconstitution or lack of it, and the risk for chronic GVHD and/or autoimmune disease. It can be anticipated that the results of this prospective study will help design clinical trials aiming at defining strategies to optimize survival, long-term immune reconstitution and to reduce complications after HCT for SCID.

Public Health Relevance

Primary immune deficiencies (PIDs) are rare, life-threatening inherited defects in the immune system. This prospective study of children with severe combined immunodeficiency (SCID) will help accomplish the Primary Immune Deficiency Treatment Consortium (PIDTC)'s overall objective of identifying pre-HCT and early post HCT biologic factors that best predict successful engraftment, immune reconstitution, and outcome with minimal toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI082973-05
Application #
8522130
Study Section
Special Emphasis Panel (ZRG1-HOP-Y)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$75,050
Indirect Cost
$11,696
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Heimall, Jennifer; Logan, Brent R; Cowan, Morton J et al. (2017) Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood 130:2718-2727
Heimall, Jennifer; Puck, Jennifer; Buckley, Rebecca et al. (2017) Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium Biol Blood Marrow Transplant 23:379-387
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Hoenig, Manfred; Lagresle-Peyrou, Chantal; Pannicke, Ulrich et al. (2017) Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome. Blood 129:2928-2938
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