Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

Area of Science:

• Immunology
• Pharmacogenetics
• Molecular Biology

Background:

• Nuclear factor of activated T cells (NFAT) transcription factors are crucial for immune responses.
• NFATC2 is linked to hypersensitivity reactions to L-asparaginase (ASNase), impacting pediatric acute lymphoblastic leukemia treatment.
• Previous studies suggest a pharmacogenetic association between NFATC2 and ASNase hypersensitivity risk.

Purpose of the Study:

• To investigate the hypothesis that genetic inhibition of NFATC2 protects against anti-ASNase antibodies and hypersensitivity.
• To elucidate the immunological mechanisms underlying NFATC2's role in ASNase hypersensitivity.

Main Methods:

• Utilized NFATC2-deficient mice and wild-type (WT) controls.
• Administered L-asparaginase (ASNase) to induce immunization and hypersensitivity.
• Assessed antibody levels (IgE), T cell populations (CD4+ regulatory T cells, IL-4+ cells), cytokine levels (IL-10, TGF-β1, IL-4, IL-13), FcεRI expression on basophils and mast cells, and anaphylactic shock severity.

Main Results:

• NFATC2-deficient mice showed protection against ASNase hypersensitivity with lower IgE levels compared to WT mice.
• NFATC2 deficiency led to increased regulatory T cells, decreased IL-4+ cells, altered cytokine profiles (higher IL-10/TGF-β1, lower IL-4/IL-13), and reduced FcεRI expression on immune cells.
• NFATC2-deficient mice exhibited less severe anaphylaxis and shock following ASNase immunization.

Conclusions:

• Genetic inhibition of NFATC2 effectively protects against L-asparaginase (ASNase) hypersensitivity.
• This protection is mediated by the impairment of T helper 2 responses and reduced immune cell activation.
• Targeting NFATC2 presents a potential novel therapeutic strategy for mitigating hypersensitivity and anti-drug antibody development, particularly for ASNase treatment.