PMID- 32931581
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20220531
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 4
IP  - 18
DP  - 2020 Sep 22
TI  - Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice.
PG  - 4406-4416
LID - 10.1182/bloodadvances.2020002478 [doi]
AB  - 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-beta1 levels, and lower IL-4/IL-13 levels relative to WT mice. Basophils 
      and peritoneal mast cells from ASNase-immunized, but not naive, NFATC2-deficient 
      mice had lower FcepsilonRI expression and decreased IgE-mediated mast cell activation 
      than WT mice. Furthermore, ASNase-immunized, but not naive, 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.
CI  - (c) 2020 by The American Society of Hematology.
FAU - Rathod, Sanjay
AU  - Rathod S
AD  - Center for Pharmacogenetics and.
AD  - Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA.
FAU - Ramsey, Manda
AU  - Ramsey M
AD  - Center for Pharmacogenetics and.
AD  - Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA.
FAU - Finkelman, Fred D
AU  - Finkelman FD
AD  - Division of Immunology, Allergy and Rheumatology, Department of Internal 
      Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; and.
AD  - Division of Immunobiology, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH.
FAU - Fernandez, Christian A
AU  - Fernandez CA
AD  - Center for Pharmacogenetics and.
AD  - Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA.
LA  - eng
GR  - R01 CA216815/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Antibodies)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Nfatc2 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - EC 3.5.1.1 (Asparaginase)
SB  - IM
MH  - Animals
MH  - Antibodies/therapeutic use
MH  - *Antineoplastic Agents/therapeutic use
MH  - Asparaginase/therapeutic use
MH  - Mice
MH  - NFATC Transcription Factors
MH  - *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics
MH  - Transcription Factors
PMC - PMC7509855
COIS- Conflict-of-interest disclosure: The authors declare no competing financial 
      interests.
EDAT- 2020/09/16 06:00
MHDA- 2021/05/15 06:00
PMCR- 2020/09/15
CRDT- 2020/09/15 17:14
PHST- 2020/05/28 00:00 [received]
PHST- 2020/08/12 00:00 [accepted]
PHST- 2020/09/15 17:14 [entrez]
PHST- 2020/09/16 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2020/09/15 00:00 [pmc-release]
AID - S2473-9529(20)31522-6 [pii]
AID - 2020/ADV2020002478 [pii]
AID - 10.1182/bloodadvances.2020002478 [doi]
PST - ppublish
SO  - Blood Adv. 2020 Sep 22;4(18):4406-4416. doi: 10.1182/bloodadvances.2020002478.