Food, drug, insect sting allergy, and anaphylaxis
Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice

https://doi.org/10.1016/j.jaci.2013.06.008Get rights and content

Background

Studies with c-kit mutant mast cell (MC)–deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA). However, interpretation of data obtained by using such approaches is complicated because c-kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs.

Objective

We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response.

Methods

Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later.

Results

Peanut-challenged, MC-deficient KitW-sh/W-sh mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin–mediated selective depletion of MCs or basophils in Mcpt5-Cre;iDTR and Mcpt8DTR mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non–c-kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1fl/fl mice had reduced but still significant responses to peanut.

Conclusion

Inducible and selective ablation of MCs or basophils in non–c-kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in KitW-sh/W-sh mice might influence the responses of these mice in this PIA model.

Section snippets

Mice

C57BL/6J mice and iDTR mice (C57BL/6-Gt[ROSA]26Sortm1(HBEGF)Awai/J) were purchased from Jackson Laboratories (Bar Harbor, Me). C57BL/6-KitW-sh/W-sh mice were originally provided by Peter Besmer (Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY); we then backcrossed these mice to C57BL/6J mice for more than 11 generations.29 Mcpt8DTR mice,39 Mcpt5-Cre mice,31, 34 and Cpa3-Cre;Mcl-1fl/fl mice (and the corresponding control Cpa3-Cre;Mcl-1+/+ mice)33 on the C57BL/6

PIA in c-kit mutant MC-deficient mice

We first assessed the response of c-kit mutant MC-deficient C57BL/6J-KitW-sh/W-sh (KitW-sh/W-sh) mice in this PIA model. Peanut-sensitized WT and KitW-sh/W-sh mice exhibited similar levels of peanut-specific IgE and IgG1 antibodies in the serum (see Fig E1 in this article's Online Repository at www.jacionline.org). KitW-sh/W-sh mice had reduced (although still significant) hypothermia compared with WT mice during the first hour after peanut challenge, and none of the mice died (3/18 WT mice

Discussion

Several studies using c-kit mutant KitW/W-v and KitW-sh/W-sh MC-deficient mice have suggested that MCs can significantly contribute to PIA.21, 22, 40 In this report we confirmed these findings by showing that KitW-sh/W-sh mice had reduced immediate hypothermia in this PIA model. However, we found that KitW-sh/W-sh mice also exhibited a previously unreported late decrease in body temperature that occurred between 3 and 6 hours after peanut challenge and after the hypothermia induced acutely by

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    L.L.R. is the recipient of fellowships from the French “Fondation pour la Recherche Médicale FRM” and the Stanford Pediatric Research Fund of the Lucile Packard Foundation for Children’s Health and the Stanford CTSA (National Institutes of Health grant UL1 RR025744). T.M. is supported by a fellowship from the Belgium American Educational Foundation and a Marie Curie International outgoing Fellowship for Career Development: 299954. K.H. acknowledges support from the German Research Council (DFG; CRC/SFB832, project A14). S.J.G. acknowledges support from National Institutes of Health grants AI023990, CA072074, and AI070813.

    Disclosure of potential conflict of interest: L. L. Reber, T. Marichal, K. Mukai, M. Tsai, and S. J. Galli have been supported by grants from the National Institutes of Health (AI070813, AI023990, and AI072074). The rest of the authors declare that they have no relevant conflicts of interest.

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