The Primary Immune Deficiency Treatment Consortium (PIDTC) was established in 2009 as a collaborafion among North American centers with expertise in treating infants and children with rare, but serious primary immunodeficiencies (PIDs). While life-saving therapies, including hematopoiefic cell transplantafion (HCT), have been used for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD), these condifions remain so rare that single centers are unable to perform clinical studies to define the best treatments. The PIDTC has developed protocols to study systematically the diagnosis, treatment and outcomes of patients with these conditions who are followed throughout North America. The goal ofthe PIDTC Pilot Project Program is to take maximum advantage of new clinical research opportunities in rare primary immunodeficiencies (PIDs) to further promote the goals and objecfives ofthe PIDTC. Specifically, projects are preferenfially selected thatwill (a) establish new biomarkers predictive of PID outcomes;(b) generate feasibility data for future PIDTC aims arid protocols, including clinical trials;(c) address questions that are important to our patients, pafient advocacy groups (PAGs) and stakeholders;and (d) encourage early faculty to apply their talents in the fields of PID immunology and therapeufics, including opfimizafion of hematopoietic cell transplantafion (HCT) and other therapies. During its first 4 years, PIDTC Pilot Projects addressed newborn screening and B cell reconstitufion after transplantafion for SCID, and a current project explores why immunity in some post-HCT pafients wanes after initial success. Dr. David Rawlings is the PI ofthe proposed pilot project, """"""""Analysis of B cell tolerance in Wiskott-Aldrich svndrome followincf stem cell transplant"""""""". A significant proportion (up to 20%) of pafients with WAS develop severe, humoral autoimmunity following HCT and this complicafion correlates with mixed donor chimerism including lower levels of donor myeloid cells. A mechanisfic explanafion behind these observations, however, has been lacking.
The Specific Aims of this study are to: a) Determine whether post-HCT autoimmunity correlates with skewed B vs. T cell donor chimerism;b) Determine whether post-HCT autoimmunity correlates with serum BAFF or APRIL levels;and, c) Determine whether post-HCT autoimmunity is preceded by evidence for B cell activation, serum autoanfibodies, and/or an altered B and T cell repertoire. This pilot study will begin to analyze key biomarkers the may predict autoimmunity in WAS pafients post-HCT and will confinue in years 8-10.

Public Health Relevance

The PIDTC Pilot Project Program research projects are a key strategic aspect ofthe PIDTC, enriching the established aims of our protocols and revealing important areas ripe to be addressed in future aims and spin-off protocols. The proposed project on autoimmunity in patients with WAS will focus on critical biomarkers that predict outcome in this rare primary immunodeficiency and could positively impact other disorders with autoimmune manifestafions.

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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