Physical Characterization and Innate Immunogenicity of Aggregated Intravenous Immunoglobulin (IGIV) in an In Vitro...

Area of Science:

• Immunology
• Biochemistry
• Materials Science

Background:

• Intravenous immunoglobulin (IGIV) is a critical therapeutic agent.
• Stress conditions can induce aggregation of IGIV, potentially impacting its safety and efficacy.
• Understanding the innate immune response to IGIV aggregates is crucial for patient safety.

Purpose of the Study:

• To investigate the in vitro innate immune response to stress-induced IGIV aggregates.
• To correlate aggregate physical properties with the innate immune response.
• To evaluate a human monocyte cell line as a model for assessing IGIV aggregate immunogenicity.

Main Methods:

• IGIV aggregates were prepared using various accelerated stress methods.
• Aggregate characteristics (size, count, structure) were analyzed.
• Immune cell activation was assessed by measuring inflammatory cytokine release from peripheral blood mononuclear cells (PBMC), primary monocytes, and THP-1 cells.

Main Results:

• Mechanical stress-induced IGIV aggregates elicited higher cytokine release from PBMC and primary monocytes compared to other stress methods.
• The THP-1 cell line demonstrated similar trends to primary monocytes.
• The response was dose-dependent, enhanced by complement opsonization, and partially inhibited by blocking Toll-like Receptors (TLR2/4) and Fc gamma receptors (FcγRs).

Conclusions:

• Stress-induced IGIV aggregates stimulate a dose-dependent cytokine response in human monocytes and THP-1 cells.
• Toll-like receptors (TLRs), Fc gamma receptors (FcγRs), and complement opsonization partially mediate this response.
• The THP-1 cell line serves as a viable model for screening the innate immunogenicity of IgG aggregates, highlighting the role of aggregate structure.