title: The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders.
abstract: In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.
authors.affiliation: Willink Biochemical genetics unit, Manchester center for genomic medicine, St Mary's Hospital, Central Manchester Foundation Trust, Manchester, M13 9WL, UK. alexander.broomfield@cmft.nhs.uk.
authors.forename: A
authors.initials: A
authors.lastname: Broomfield
authors.affiliation: Willink Biochemical genetics unit, Manchester center for genomic medicine, St Mary's Hospital, Central Manchester Foundation Trust, Manchester, M13 9WL, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Department of Immunology, Royal Manchester children's Hospital, Central Manchester Foundation Trust, Manchester, M13 9WL, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Hughes
authors.affiliation: Stem Cell & Neurotherapies Laboratory, Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: B W
authors.initials: BW
authors.lastname: Bigger
mesh_terms: D000917:Antibody Formation; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D057487:Enzyme Therapy; D004798:Enzymes / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000502:physiology*; D016464:Lysosomal Storage Diseases / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000276:immunology / Q000627:therapeutic use
chemical_list: D004798:Enzymes; D000520:alpha-Glucosidases