Antibody Response Against Betaferon(R) in Immune Tolerant Mice: Involvement of Marginal Zone B-cells and CD4+ T-cells and Apparent Lack of Immunological Memory

Publication Type:

Journal Article


J Clin Imm, Volume 33, Number 1, pp. 255-63 (2013)


1573-2592 (Electronic)02

DOI Name (links to online publication)



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 (rhIFNbeta) products including Betaferon(R), and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNbeta. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon(R). This hypothesis was tested. METHODS: Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNbeta (Betaferon(R)) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon(R) 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(R). RESULTS: Inactivation of MZ B-cells at the start of Betaferon(R) treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon(R) treatment abolished the ADA response in almost all mice. CONCLUSION: The immune response against rhIFNbeta 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).