Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII

Rathod, Sanjay; Ramsey, Manda; Relling, Mary V.; Finkelman, Fred D.; Fernandez, Christian A.

doi:10.3324/haematol.2018.199448

Cited by 24 publications

(37 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previously, we demonstrated that ASNase-specific recognition and hypersensitivity in mice are Fc-gRIIIdependent, suggesting that soluble anti-ASNase antibodies are required for both to occur (19). In agreement with our previous findings, we found that the binding of ASNase to leukocytes, including B cells and basophils, is significantly decreased after removing soluble antibodies (Supplemental Fig.…”

Section: Asnase Ics Are Detected After Asnase Hypersensitivity In Micesupporting

confidence: 92%

“…Pooled eluate samples were lyophilized overnight and reconstituted with 100 ml of sterile water. Murine anti-ASNase IgG concentrations were determined using a Bovine Serum Albumin Kit (Thermo Fisher Scientific), and confirmation of anti-ASNase IgG antibody activity was demonstrated by ELISA (18,19).…”

Section: Anti-asnase Igg Antibody Purification and Characterization Bmentioning

confidence: 99%

“…Blood from sensitized mice (i.e., 1 d before challenge) was incubated with EM-95 (Zelig Eshhar, Weizmann Institute, Rehovot, Israel), 2.4G2 (American Type Culture Collection; Rockville, MD, USA), both (1 mg/ml), or medium (as a negative control) for 1 h. Samples were stained with ASNase ICs, CD45, CD49b, and IgE for 30 min in the dark at 4°C, erythrocyte lysed, washed, and acquired by flow cytometry to determine ASNase IC binding on leukocytes (CD45) or basophils in the presence and absence of blocking antibodies. To determine the extent of ASNase IC binding that is independent of soluble anti-ASNase IgG antibody, samples were first washed and erythrocyte lysed to remove soluble antibodies before staining with fluorochrome-labeled ASNase, as previously described in Rathod et al (19).…”

Section: Effect Of Asnase Ics Binding To Immune Cells After Fc-gr Andmentioning

confidence: 99%

“…The cells were then lysed, washed, and acquired by flow cytometry. The percent change of CD200R1 and CD200R3 expression were calculated as previously described in Rathod et al (19).…”

Section: Murine Basophil Activationmentioning

confidence: 99%

“…Recent studies of murine ASNase hypersensitivity demonstrate that the classic and alternative pathways of anaphylaxis simultaneously contribute to hypersensitivity reactions (18,19). However, no study has reported detecting the presence of ASNase ICs after hypersensitivity reactions or investigating whether they can directly contribute to the severity and onset of ASNase hypersensitivity.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

Asparaginase (ASNase) is an important drug for the treatment of leukemias. However, hypersensitivity to ASNase can increase the risk of leukemia relapse. Two mechanisms of ASNase hypersensitivity have been identified in mice. The existence of a pathway involving anti‐ASNase IgG and Fc‐γ receptor III (FC‐γRIII) implies that IgG and ASNase immune complexes (ICs) could directly induce hypersensitivity. The aim of this study was to detect ASNase ICs in mice after hypersensitivity reactions and determine their role in hypersensitivity. Protein G beads were used to detect plasma ASNase ICs by flow cytometry. Anti‐ASNase IgG was purified from the plasma of sensitized mice, and ASNase ICs were prepared ex vivo at various ratios of ASNase to anti‐ASNase IgG. The levels of ASNase ICs detected after hypersensitivity reactions correlated with reaction severity (R2 = 0.796; P = 0.0005). ASNase ICs prepared ex vivo required high levels of anti‐ASNase IgG for formation, and binding to naive and sensitized immune cells depended on soluble anti‐ASNase IgG, antigen:antibody ratio, and FC‐γRIII. Similarly, basophil activation by ASNase ICs depended on the antigen:antibody ratio and FC‐γRIII. Consistent with the ex vivo results, naive mice receiving ASNase ICs developed hypersensitivity reactions. Our data demonstrate that ASNase ICs can directly contribute to the onset and severity of ASNase hypersensitivity.—Rathod, S., Ramsey, M., DiGiorgio, D., Berrios, R., Finkelman, F. D., Fernandez, C. A. Asparaginase immune complexes induce Fc‐γRIII‐dependent hypersensitivity in naive mice. FASEB J. 33, 10996–11005 (2019). http://www.fasebj.org

show abstract

Section: Asnase Ics Are Detected After Asnase Hypersensitivity In Micesupporting

confidence: 92%

Section: Anti-asnase Igg Antibody Purification and Characterization Bmentioning

confidence: 99%

Section: Effect Of Asnase Ics Binding To Immune Cells After Fc-gr Andmentioning

confidence: 99%

“…The cells were then lysed, washed, and acquired by flow cytometry. The percent change of CD200R1 and CD200R3 expression were calculated as previously described in Rathod et al (19).…”

Section: Murine Basophil Activationmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

Finch

Smith

Yang

et al. 2019

Pediatric Blood & Cancer

Self Cite

View full text Add to dashboard Cite

Background Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l‐asparaginase was front‐line therapy versus the pegylated formulation (PEG‐asparaginase) in Total XVI (TXVI). Procedure Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low‐risk (LR) or standard/high‐risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride‐PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. Results The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG‐asparaginase (4.5‐fold increase; P <1 × 10−15). SHR patients treated with PEG‐asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l‐asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride‐PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). Conclusion Triglycerides were affected more by PEG‐asparaginase than native l‐asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

show abstract

Immunogenicity and Immune-Related Adverse Drug Reactions

Mihalcik,

Bussiere,

Allamneni

et al. 2024

Reference Module in Biomedical Sciences

View full text Add to dashboard Cite

Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII

Cited by 24 publications

References 41 publications

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

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

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

Immunogenicity and Immune-Related Adverse Drug Reactions

Contact Info

Product

Resources

About