B1 Cell IgE Impedes Mast Cell-Mediated Enhancement of Parasite Expulsion through B2 IgE Blockade

Martin, Rebecca; Damle, Sheela R.; Valentine, Yolander A.; Zellner, Matthew; James, Briana N.; Lownik, Joseph C.; Luker, Andrea; Davis, Elijah; DeMeules, Martha M.; Khandjian, Laura M.; Finkelman, Fred D.; Urban, Joseph F.; Conrad, Daniel H.

doi:10.1016/j.celrep.2018.01.048

Cited by 23 publications

(18 citation statements)

References 49 publications

(69 reference statements)

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“…To do this we utilized MDSCs isolated from ADAM10Tg mice. These MDSCs result from a defect in hematopoiesis, do not overexpress ADAM10, are suppress T cells, express MDSC markers, are heterogeneous, have been extensively characterized, and are not tumor derived [19][20][21][22]. ADAM10Tg mice do not have any mature B cells.…”

Section: Resultsmentioning

confidence: 99%

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

et al. 2020

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Background: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. Results: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. Conclusions: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

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Section: Resultsmentioning

confidence: 99%

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

et al. 2020

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“…During the course of allergic sensitization process not only specific but also total IgE levels rise significantly. But the impact of such IgE antibodies with undefined specificity on antigen-induced mast cell activation may be negative especially in the case when specific IgE production is low [32]. Indeed, systematic anaphylaxis intensity did not correlate with total IgE levels ( Fig.…”

Section: The Degree Of Mice Sensitization By Low Antigen Doses Is Assmentioning

confidence: 97%

Tertiary lymphoid structures related B-cell IgE isotype switching and secondary lymphoid organs linked IgE production in mouse allergy model

Chudakov

Ryasantsev

Tsaregorotseva³

et al. 2020

Preprint

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Background: Numerous data obtained by different research laboratories around the world indicate that specific IgE production is triggered independently of specific IgG or IgA production and so did not linked to fully matured germinal centers of secondary lymphoid organs. The aim of this study is to clarify whether specific IgE production is triggered by low antigen doses administrated in tertiary lymphoid structure enriched tissues.Methods: OVA in different doses (100 ng or 10 µg) was administrated three times a week for 4–5 weeks intraperitoneally and subcutaneously to female BALB/c mice in the withers region enriched in fat-associated lymphoid clusters and in foot pad region not containing them.Results: OVA-specific IgE was predominantly induced by low but not by high antigen doses and only after immunization in withers. IgE isotype switching was triggered exclusively in withers adipose tissue but not in regional lymph nodes though mature IgE expressing cells were observed both in tissue and lymph nodes. Anti-proliferative genotoxic stress inducing drugs shifted the balance from IgG1 towards IgE production.Conclusion. Tertiary lymphoid structures possess unique environment where B-cell antibody isotype switching to IgE predominantly occurs. These phenomena are explained by hampered proliferation of B-cells in these structures.

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“…IL-25, a cytokine present in the mucosa, is produced by stressed epithelial tuft cells 74 . IL-25 rapidly activates the production of IL-5 and IL-13, the latter of which plays an important role in intestinal nematode and trematode expulsion 75 – 80 .…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal administration of the anti-IL-23 antibody prevents the establishment of intestinal nematodes in mice

Samblas

Bernal

Bolado-Ortiz

et al. 2018

Sci Rep

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Previous studies have established that an increased Th-9 response creates a hostile environment for nematode parasites. Given that IL-23, a cytokine required for maintenance of the IL-17–secreting phenotype, has inhibitory effects on IL-9 production, we hypothesized that reducing circulating IL-23 by treatment with anti-IL-23 antibodies would reduce the establishment and development of parasitic intestinal nematodes. In this study, we show that animals treated with anti-IL-23 monoclonal antibodies showed a drastic reduction in the number of mouse pinworms (Aspiculuris tetraptera) recovered from the intestine (p < 0.001) at 23 days post-infection compared to the untreated animals. The cytokine levels in Peyer’s patches (PP) in treated and infected animals increase the expression of interleukins such as IL-25, IL-21, and IL-9, augmenting mucus production in the crypts, and boosting chemokines, such as OX40 and CCL20 in the mucosa. Our results suggest that the Th17/Th2 regulatory mechanism provoked by the administration of the anti-IL-23 antibody prevents the implantation of the intestinal nematode in mice. The diminished inflammatory IL-17 levels alter the Th9 environment perhaps as a consequence of IL-17 inhibiting IL-9 expression. These Th9 conditions may explain the successful treatment against Inflammatory Bowel Disease (IBD) both with antibodies against IL-23 or through parasitization with nematodes.

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B1 Cell IgE Impedes Mast Cell-Mediated Enhancement of Parasite Expulsion through B2 IgE Blockade

Cited by 23 publications

References 49 publications

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

Tertiary lymphoid structures related B-cell IgE isotype switching and secondary lymphoid organs linked IgE production in mouse allergy model

Intraperitoneal administration of the anti-IL-23 antibody prevents the establishment of intestinal nematodes in mice

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