title: The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice. Differential impact on pulmonary and immunologic abnormalities.
abstract: Adenosine deaminase (ADA) deficiency results in a combined immunodeficiency brought about by the immunotoxic properties of elevated ADA substrates. Additional non-lymphoid abnormalities are associated with ADA deficiency, however, little is known about how these relate to the metabolic consequences of ADA deficiency. ADA-deficient mice develop a combined immunodeficiency as well as severe pulmonary insufficiency. ADA enzyme therapy was used to examine the relative impact of ADA substrate elevations on these phenotypes. A "low-dose" enzyme therapy protocol prevented the pulmonary phenotype seen in ADA-deficient mice, but did little to improve their immune status. This treatment protocol reduced metabolic disturbances in the circulation and lung, but not in the thymus and spleen. A "high-dose" enzyme therapy protocol resulted in decreased metabolic disturbances in the thymus and spleen and was associated with improvement in immune status. These findings suggest that the pulmonary and immune phenotypes are separable and are related to the severity of metabolic disturbances in these tissues. This model will be useful in examining the efficacy of ADA enzyme therapy and studying the mechanisms underlying the immunodeficiency and pulmonary phenotypes associated with ADA deficiency.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston Medical School, Houston, Texas 77030, USA. Michael.R.Blackburn@uth.tmc.edu
authors.forename: M R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: M
authors.initials: M
authors.lastname: Aldrich
authors.forename: J B
authors.initials: JB
authors.lastname: Volmer
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.forename: S
authors.initials: S
authors.lastname: Kelly
authors.forename: M S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: S K
authors.initials: SK
authors.lastname: Datta
authors.forename: R E
authors.initials: RE
authors.lastname: Kellems
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency* / Q000378:metabolism / Q000627:therapeutic use*; D043383:Adenosylhomocysteinase; D000818:Animals; D003838:Deoxyadenine Nucleotides / Q000032:analysis; D003839:Deoxyadenosines / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D006651:Histocytochemistry; D006867:Hydrolases / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000503:physiopathology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000276:immunology; D008231:Lymphopenia / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012435:S-Adenosylhomocysteine / Q000032:analysis; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy*; D013154:Spleen / Q000276:immunology* / Q000503:physiopathology; D013950:Thymus Gland / Q000276:immunology* / Q000503:physiopathology
chemical_list: D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase; C051409:pegademase bovine; D000241:Adenosine; C026600:2'-deoxyadenosine triphosphate