Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.

Published

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

  • 18952502

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