Asparaginase immune complexes induce Fc‐γRIII–dependent hypersensitivity in naive mice

Rathod, Sanjay; Ramsey, Manda; DiGiorgio, Danielle; Berrios, Roberto; Finkelman, Fred D.; Fernandez, Christian A.

doi:10.1096/fj.201900857

Cited by 5 publications

(14 citation statements)

References 29 publications

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“…The decreased antibody levels and fewer ASNase ICs suggest that NFATC2 deficiency could protect against hypersensitivity reactions, at least partially, by downmodulating both the IgE/FceR1 and IgG/FcgRIII pathways of anaphylaxis. 22,23 Because NFATC2 regulates cytokine expression, and cytokines can influence antibody and mast cell responses and responses to mast cell-produced mediators, we next investigated the effect of NFATC2 deficiency on Th2 cells and cytokines.…”

Section: Nfatc2 Ko Mice Are Protected Against Asnase Hypersensitivitymentioning

confidence: 99%

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

et al. 2020

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The family of nuclear factor of activated T cells (NFAT) transcription factors plays a critical role in mediating immune responses. Our previous clinical pharmacogenetic studies suggested that NFATC2 is associated with the risk of hypersensitivity reactions to the chemotherapeutic agent L-asparaginase (ASNase) that worsen outcomes during the treatment of pediatric acute lymphoblastic leukemia. We therefore hypothesized that the genetic inhibition of NFATC2 would protect against the development of anti-ASNase antibodies and ASNase hypersensitivity. Our study demonstrates that ASNase-immunized NFATC2-deficient mice are protected against ASNase hypersensitivity and develop lower antigen-specific and total immunoglobulin E (IgE) levels compared with wild-type (WT) controls. Furthermore, ASNase-immunized NFATC2-deficient mice develop more CD4+ regulatory T cells, fewer CD4+ interleukin-4–positive (IL-4+) cells, higher IL-10/TGF-β1 levels, and lower IL-4/IL-13 levels relative to WT mice. Basophils and peritoneal mast cells from ASNase-immunized, but not naïve, NFATC2-deficient mice had lower FcεRI expression and decreased IgE-mediated mast cell activation than WT mice. Furthermore, ASNase-immunized, but not naïve, NFATC2-deficient mice developed less severe shock than WT mice after induction of passive anaphylaxis or direct histamine administration. Thus, inhibition of NFATC2 protects against ASNase hypersensitivity by impairing T helper 2 responses, which may provide a novel strategy for attenuating hypersensitivity and the development of antidrug antibodies, including to ASNase.

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Section: Nfatc2 Ko Mice Are Protected Against Asnase Hypersensitivitymentioning

confidence: 99%

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

et al. 2020

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“…More severe hypersensitivity reactions are indicated by a more significant change in core body temperature and lower AUC values. Throughout our analysis, mice were either sacrificed before or after the onset of hypersensitivity to assess differences in the severity of anaphylaxis as described previously ( 11 – 13 ).…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that IgE- and IgG-mediated pathways are involved in ASNase hypersensitivity, both of which are associated with the severity of anaphylaxis ( 11 , 12 ). Based on these results, we have developed tools that can discern between IgE- and IgG-mediated ASNase hypersensitivity ( 11 – 14 ). Others have explored IgE-mediated basophil activation and measurement of anti-ASNase antibody levels of various antibody isotypes ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Asparaginase-specific basophil recognition and activation predict Asparaginase hypersensitivity in mice

Rathod,

Hoshitsuki,

Zhu

et al. 2024

Front. Immunol.

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BackgroundAsparaginase (ASNase) is a crucial part of acute leukemia treatment, but immune responses to the agent can reduce its effectiveness and increase the risk of relapse. Currently, no reliable and validated biomarker predicts ASNase-induced hypersensitivity reactions during therapy. We aimed to identify predictive biomarkers and determine immune cells responsible for anaphylaxis using a murine model of ASNase hypersensitivity.MethodsOur preclinical study uses a murine model to investigate predictive biomarkers of ASNase anaphylaxis, including anti-ASNase antibody responses, immune complex (IC) levels, ASNase-specific binding to leukocytes or basophils, and basophil activation.ResultsOur results indicate that mice immunized to ASNase exhibited dynamic IgM, IgG, and IgE antibody responses. The severity of ASNase-induced anaphylaxis was found to be correlated with levels of IgG and IgE, but not IgM. Basophils from immunized mice were able to recognize and activate in response to ASNase ex vivo, and the extent of recognition and activation also correlated with the severity of anaphylaxis observed. Using a multivariable model that included all biomarkers significantly associated with anaphylaxis, independent predictors of ASNase-induced hypersensitivity reactions were found to be ASNase IC levels and ASNase-specific binding to leukocytes or basophils. Consistent with our multivariable analysis, we found that basophil depletion significantly protected mice from ASNase-induced hypersensitivity reactions, supporting that basophils are essential and can be used as a predictive marker of ASNase-induced anaphylaxis.ConclusionsOur study demonstrates the need for using tools that can detect both IC- and IgE-mediated hypersensitivity reactions to mitigate the risk of ASNase-induced hypersensitivity reactions during treatment.

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“…The basis of hypersensitivity is undoubtedly immune-mediated [ 4 , 11 , 13 , 14 ]. PEGylation diminishes the immunogenicity of L-asp, and the antibodies in children receiving PEGasp appear to be mostly directed towards PEG rather than towards asparaginase itself [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia

Lee

Lim

et al. 2023

Cancers

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Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL.

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Asparaginase immune complexes induce Fc‐γRIII–dependent hypersensitivity in naive mice

Cited by 5 publications

References 29 publications

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice

Asparaginase-specific basophil recognition and activation predict Asparaginase hypersensitivity in mice

Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia

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