Antibody response against Betaferon® in immune tolerant mice: involvement of marginal zone B-cells and CD4+ T-cells and apparent lack of immunological memory.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Netherlands NLM ID: 8102137 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2592 (Electronic) Linking ISSN: 02719142 NLM ISO Abbreviation: J Clin Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Springer
      Original Publication: New York : Plenum, c1981-
    • Subject Terms:
      B-Lymphocyte Subsets/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; Immune Tolerance/*drug effects ; Immunoglobulin G/*biosynthesis ; Immunologic Memory/*drug effects ; Interferon-beta/*antagonists & inhibitors ; Interferon-beta/*immunology ; Lymphoid Tissue/*immunology; Animals ; B-Lymphocyte Subsets/classification ; B-Lymphocyte Subsets/drug effects ; CD4-Positive T-Lymphocytes/drug effects ; Female ; Interferon beta-1b ; Interferon-beta/administration & dosage ; Lymphocyte Cooperation/drug effects ; Lymphocyte Cooperation/immunology ; Lymphocyte Depletion ; Lymphoid Tissue/cytology ; Lymphoid Tissue/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Animal ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/antagonists & inhibitors ; Recombinant Proteins/immunology
    • Abstract:
      Purpose: 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.
      Conclusion: 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).
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    • Accession Number:
      0 (Immunoglobulin G)
      0 (Recombinant Proteins)
      145155-23-3 (Interferon beta-1b)
      77238-31-4 (Interferon-beta)
    • Publication Date:
      Date Created: 20120905 Date Completed: 20130423 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      10.1007/s10875-012-9783-z
    • Accession Number:
      22945588