Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.
Journal Article (Journal Article)
We report detailed genetic and immunologic studies in a patient diagnosed with adenosine deaminase (ADA) deficiency and combined immune deficiency at age 5 years. At the time of diagnosis, although all other lymphocyte subsets were depleted, circulating CD8(+) T cells with a terminally differentiated phenotype were abundant and expressed normal ADA activity due to a reversion mutation in a CD8(+) T cell or precursor. Over the first 9 months of replacement therapy with PEG-ADA, the patient steadily accumulated mature naïve CD4(+) and CD8(+) T cells, as well as CD4(+)/FOXP3(+) regulatory T cells, consistent with restoration of a functional cellular immune system. While CD19(+) naïve B cells also accumulated in response to PEG-ADA therapy, a high proportion of these B cells exhibited an immature surface marker phenotype even after 9 months, and immunization with neoantigen bacteriophage varphiX174 demonstrated a markedly subnormal humoral immune response. Our observations in this single patient have important implications for gene therapy of human ADA deficiency, as they indicate that ADA expression within even a large circulating lymphocyte population may not be sufficient to support adequate immune reconstitution. They also suggest that an immature surface marker phenotype of the peripheral B cell compartment may be a useful surrogate marker for incomplete humoral immune reconstitution during enzyme replacement, and possibly other forms of hematopoietic cell therapies.
Full Text
Duke Authors
Cited Authors
- Liu, P; Santisteban, I; Burroughs, LM; Ochs, HD; Torgerson, TR; Hershfield, MS; Rawlings, DJ; Scharenberg, AM
Published Date
- February 2009
Published In
Volume / Issue
- 130 / 2
Start / End Page
- 162 - 174
PubMed ID
- 18952502
Pubmed Central ID
- PMC2727638
Electronic International Standard Serial Number (EISSN)
- 1521-7035
Digital Object Identifier (DOI)
- 10.1016/j.clim.2008.08.026
Language
- eng
Conference Location
- United States