Massive immune response against IVIg interferes with response against other antigens in mice: A new mode of action?

PLoS One. 2017 Oct 12;12(10):e0186046. doi: 10.1371/journal.pone.0186046. eCollection 2017.

Abstract

Administration of high dose intravenous immunoglobulin (IVIg) is widely used in the clinic to treat autoimmune and severe inflammatory diseases. However, its mechanisms of action remain poorly understood. We assessed the impact of IVIg on immune cell populations using an in vivo ovalbumin (Ova)-immunization mouse model. High dose IVIg significantly reduced the Ova-specific antibody response. Intriguingly, the results obtained indicate an immediate and massive immune reaction against IVIg, as shown by the activation and expansion of B cells and CD4+ T cells in the spleen and draining lymph nodes and the production of IVIg-specific antibodies. We propose that IVIg competes at the T-cell level with the response against Ova to explain the immunomodulatory properties of IVIg. Two monoclonal antibodies did not succeeded in reproducing the effects of IVIg. This suggests that in addition to the mouse response against human constant domains, the enormous sequence diversity of IVIg may significantly contribute to this massive immune response against IVIg. While correlation of these findings to IVIg-treated patients remains to be explored, our data demonstrate for the first time that IVIg re-directs the immune response towards IVIg and away from a specific antigen response.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibody Formation / drug effects
  • Antibody Formation / immunology*
  • Antigens / immunology
  • B-Lymphocytes / immunology
  • Bevacizumab / immunology
  • Bevacizumab / pharmacology
  • CD4-Positive T-Lymphocytes / immunology
  • Dose-Response Relationship, Immunologic
  • Epitopes / immunology
  • Female
  • Humans
  • Immunoglobulins, Intravenous / administration & dosage
  • Immunoglobulins, Intravenous / immunology*
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Mice, Inbred C57BL
  • Ovalbumin / immunology*
  • Spleen / drug effects
  • Spleen / immunology
  • Thymus Gland / drug effects
  • Thymus Gland / immunology

Substances

  • Adjuvants, Immunologic
  • Antibodies, Monoclonal
  • Antigens
  • Epitopes
  • Immunoglobulins, Intravenous
  • Bevacizumab
  • Ovalbumin

Grant support

This work was funded by Novartis Pharma AG. Laetitia Sordé, Sebastian Spindeldreher and Anette C. Karle are current or former full-time employees at Novartis Pharma AG. The funder provided support in the form of salaries for authors [L.S., S.S. and A.K.], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.