title: Antibody response against Betaferon® in immune tolerant mice: involvement of marginal zone B-cells and CD4+ T-cells and apparent lack of immunological memory.
abstract: OBJECTIVE
  The immunological processes underlying immunogenicity of recombinant human therapeutics are poorly understood. Using an immune tolerant mouse model we previously demonstrated that aggregates are a major trigger of the antidrug antibody (ADA) response against recombinant human interferon beta (rhIFNβ) products including Betaferon®, and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNβ. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon®. This hypothesis was tested.
  
  
  METHODS
  Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNβ (Betaferon®) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon® could act as Tind antigen by inactivation of marginal zone (MZ) B-cells during treatment. MZ B-cells are major effector cells involved in a Tind immune response. In a following experiment we depleted the mice from CD4+ T-cells to test their involvement in the ADA response against Betaferon®.
  
  
  RESULTS
  Inactivation of MZ B-cells at the start of Betaferon® treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon® treatment abolished the ADA response in almost all mice.
  
  
  CONCLUSIONS
  The immune response against rhIFNβ in immune tolerant mice is neither a T-cell independent nor a classical T-cell dependent immune response. Further studies are needed to confirm absence of immunological memory (cells).
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, the Netherlands.
authors.forename: Melody
authors.initials: M
authors.lastname: Sauerborn
authors.forename: Miranda M C
authors.initials: MM
authors.lastname: van Beers
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Kijanka
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Huub
authors.initials: H
authors.lastname: Schellekens
authors.forename: Vera
authors.initials: V
authors.lastname: Brinks
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000145:classification / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007156:Immunologic Memory / Q000187:drug effects*; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008211:Lymphocyte Cooperation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta