title: Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients.
abstract: Impairment of purine metabolism due to adenosine deaminase (ADA) deficiency is associated with a severe combined immunodeficiency (SCID). Polyethylene glycol-modified ADA (PEG-ADA) has provided noncurative, life-saving treatment for these patients, but full immune recovery is not achieved with this therapy. Since ADA-SCID is perhaps the most difficult form of SCID to handle clinically, understanding the benefits and limitations of PEG-ADA therapy may be relevant for treatment selection. To this purpose, we analyzed the rate of thymic output, T and B cell repertoires, number of T cell divisions, IFN-gamma and IL-4 production, and the extent of cell death in five ADA-SCID patients following a prolonged period of treatment with PEG-ADA. We found that thymic output was low in these patients. However, their T cell repertoire was heterogeneous, and their T lymphocytes produced cytokines upon activation and responded to mitogen stimulation, although with different kinetics. Furthermore, a high number of peripheral T lymphocytes were committed to apoptosis. Anomalies were also observed in the B cell compartment, with oligoclonal expansions of B cell clonotypes in two patients. Our data indicate that decreased thymic function, B cell oligoclonality, and increased spontaneous apoptosis may be the mechanisms by which the immunodeficiency of ADA-SCID patients persists in spite of treatment with PEG-ADA.
authors.affiliation: Department of Laboratory Diagnostics, Terzo Servizio Analisi, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Malacarne
authors.forename: Tiziana
authors.initials: T
authors.lastname: Benicchi
authors.forename: Lucia Dora
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Luigi
authors.initials: L
authors.lastname: Mori
authors.forename: Silvia
authors.initials: S
authors.lastname: Parolini
authors.forename: Luigi
authors.initials: L
authors.lastname: Caimi
authors.forename: Michael
authors.initials: M
authors.lastname: Hershfield
authors.forename: Luigi Daniele
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
mesh_terms: D000243:Adenosine Deaminase / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016130:Immunophenotyping; D008231:Lymphopenia / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000473:pathology*
chemical_list: D007143:Immunoglobulin Heavy Chains; D000243:Adenosine Deaminase; C051409:pegademase bovine