title: T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase.
abstract: Adenosine deaminase (ADA) deficiency causes severe combined immune deficiency (SCID) by interfering with the metabolism of deoxyadenosine, which is toxic to T lymphocytes at all stages of differentiation. Enzyme replacement with polyethylene glycol-modified ADA (PEG-ADA) has been previously shown to correct deoxyadenosine metabolism and improve mitogen-induced T lymphocyte proliferation. We studied the biochemical and immunologic effects of PEG-ADA in two infants with ADA-deficient SCID. While in a catabolic state, higher doses of PEG-ADA than previously described were required to normalize deoxyadenosine metabolism. After biochemical improvement, the patients recovered immune function in a pattern similar to that observed in normal thymic ontogeny and in patients with immunological reconstitution after bone marrow transplantation. Immune reconstitution was marked by the sequential appearance in the peripheral blood of phenotypic T lymphocytes corresponding to successive stages of thymic differentiation. Functional reconstitution was marked by the successive appearance of mitogen responses dependent on exogenous in vitro IL-2, mitogen responses not requiring exogenous IL-2, antigen-specific responses dependent on exogenous IL-2, and finally, antigen-specific responses not requiring exogenous IL-2. Natural killer function was tested in one patient and normalized with PEG-ADA therapy. Optimal PEG-ADA therapy appears to normalize thymic differentiation in ADA-deficient SCID, resulting in normal antigen-specific immune function.
authors.affiliation: Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital, Los Angeles, CA 90027.
authors.forename: K
authors.initials: K
authors.lastname: Weinberg
authors.forename: M S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: J
authors.initials: J
authors.lastname: Bastian
authors.forename: D
authors.initials: D
authors.lastname: Kohn
authors.forename: L
authors.initials: L
authors.lastname: Sender
authors.forename: R
authors.initials: R
authors.lastname: Parkman
authors.forename: C
authors.initials: C
authors.lastname: Lenarsky
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000627:therapeutic use*; D015703:Antigens, CD / Q000097:blood; D003241:Consanguinity; D003602:Cytotoxicity, Immunologic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008213:Lymphocyte Activation; D008875:Middle Aged; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000243:Adenosine Deaminase; C051409:pegademase bovine