Regulatory CD4+Foxp3+ T Cells Control the Severity of Anaphylaxis

Kanjarawi, Reem; Dy, Michel; Bardel, Emilie; Sparwasser, Tim; Dubois, Bertrand; Mécheri, Salaheddine; Kaiserlian, Dominique

doi:10.1371/journal.pone.0069183

Cited by 26 publications

(26 citation statements)

References 35 publications

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“…The regulatory T‐cell related cytokine IL10 reduced the release of cytokines in rat peritoneal mast cells and mast cell degranulation in in vivo models . Recently, it has been shown that constitutive Foxp3+ regulatory T‐cells can control mast cell activation and IgE‐dependent anaphylaxis in mice . These findings support the finding that cross‐talk between mast cells and T‐cell subsets and thereby a change in cytokine profiles underlie the reduction in anaphylactic shock symptoms, acute skin response and mast cell degranulation.…”

Section: Discussionsupporting

confidence: 69%

Post‐sensitization administration of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V reduces allergic symptoms in mice

Esch

Abbring

Diks

et al. 2016

Immunity Inflam & Disease

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To support dietary management of severe cow's milk allergic infants, a synbiotic mixture of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V (B. breve) was designed from source materials that are completely cow's milk‐free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hen's egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non‐sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short‐chain‐ (scFOS) and long‐chain fructo‐oligosaccharides (lcFOS), B. breve or scFOSlcFOS + B. breve for 3 weeks starting after the last sensitization. Non‐sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP‐1 and galectin‐9 were measured upon OVA challenge. Activated Th2‐, Th1‐cells and regulatory T‐cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS + B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP‐1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS + B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen‐specific re‐stimulation of splenocytes showed a decrease in IL5 production. In summary; post‐sensitization administration of scFOSlcFOS + B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T‐cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS + B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies.

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Section: Discussionsupporting

confidence: 69%

Post‐sensitization administration of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V reduces allergic symptoms in mice

Esch

Abbring

Diks

et al. 2016

Immunity Inflam & Disease

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“…Similar effects of Tregs on mast cells have been shown in other experimental models of anaphylaxis 230,231 and contact hypersensitivity. 232…”

Section: Ntregs Attenuate Mast Cell-dependent Lung Allergic Responsessupporting

confidence: 79%

“…Degranulation of mast cells was decreased in cells co‐cultured with nTregs but not with naive CD4 + CD25 − T cells. Similar effects of Tregs on mast cells have been shown in other experimental models of anaphylaxis and contact hypersensitivity …”

Section: Cd4+ Tregs Modulate Lung Allergic Responsessupporting

confidence: 78%

Spectrum of T‐lymphocyte activities regulating allergic lung inflammation

Gelfand

Joetham

Wang

et al. 2017

Immunological Reviews

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Despite advances in the treatment of asthma, optimization of symptom control remains an unmet need in many patients. These patients, labeled severe asthma, are responsible for a substantial fraction of the disease burden. In these patients research is needed to define the cellular and molecular pathways contributing to disease which in large part are refractory to corticosteroid treatment. The causes of steroid-resistant asthma are multifactorial and result from complex interactions of genetics, environmental factors, and innate and adaptive immunity. Adaptive immunity, addressed here, integrates the activities of distinct T cell subsets and by definition is dynamic and responsive to an ever-changing environment and the influences of epigenetic modifications. These T-cell subsets exhibit different susceptibilities to the actions of corticosteroids and, in some, corticosteroids enhance their functional activation. Moreover, these subsets are not fixed in lineage differentiation but can undergo transcriptional reprogramming in a bidirectional manner between protective and pathogenic effector states. Together, these factors contribute to asthma heterogeneity between patients but also in the same patient at different stages of their disease. Only by carefully defining mechanistic pathways, delineating their sensitivity to corticosteroids, and determining the balance between regulatory and effector pathways, will precision medicine become a reality with selective and effective application of targeted therapies.

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“…Interestingly, Tregs express very high levels of GITR and OX40, but not 4-1BB; this expression pattern may explain the more potent antibody responses caused by agonizing GITR and OX40, especially in light of recent findings that Tregs are involved in control of the germinal center response and that depletion of Tregs can enhance anaphylaxis. [57][58][59][60][61][62][63] An important question is whether anaphylaxis caused by repetitive intraperitoneal dosing of DTA-1 and OX86 in mice is translatable to humans treated with humanized versions of these antibodies. Our preclinical observations will heighten awareness that anaphylaxis may be of particular concern when using antibodies targeting GITR and OX40.…”

Section: Discussionmentioning

confidence: 99%

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

Murphy

Burey

Beebe

et al. 2014

Blood

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• Repeated doses of agonist antibodies targeting the costimulatory receptors GITR and OX40 result in anaphylaxis in mice.• Anaphylaxis caused by the GITR agonist antibody DTA-1 is dependent on GITR, IL-4, basophils, and plateletactivating factor.Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4 1 T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies. (Blood. 2014;123(14):2172-2180) IntroductionImmune modulation using monoclonal antibodies has a significant impact on the overall survival of patients with cancer, based on the results of clinical trials using antibodies to block CTLA-4 and PD-1. [1][2][3][4][5][6] In an approach that differs from using antibodies to mitigate immune checkpoint, agonist monoclonal antibodies can be used to directly stimulate T-cell function. Antibodies that engage members of the tumor necrosis factor receptor (TNFR) superfamily have shown promising tumor protection in preclinical models. 3,[7][8][9][10][11][12][13] Glucocorticoid-induced TNFR-related (GITR) is a costimulatory receptor in the TNFR superfamily with high homology to the other TNFR superfamily members OX40, 4-1BB, and CD27.14 GITR and OX40 are expressed primarily on activated CD41 and CD8 1 effector T cells as well as on CD4 1 Foxp3 1 regulatory T cells (Tregs). 15,16Engagement of GITR and OX40 through agonist monoclonal antibodies results in increased T-cell activation, cytokine secretion, proliferation, and survival. [17][18][19][20][21][22][23] We and others have shown that the GITR agonist antibody DTA-1 and the OX40 agonist antibody OX86 are very effective antitumor therapies in murine tumor models by increasing antitumor CD4 1 and CD8 1 T-cell effector function as well as destabilizing and causing apoptosis of Tregs i...

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Regulatory CD4+Foxp3+ T Cells Control the Severity of Anaphylaxis

Cited by 26 publications

References 35 publications

Post‐sensitization administration of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V reduces allergic symptoms in mice

Post‐sensitization administration of non‐digestible oligosaccharides and Bifidobacterium breve M‐16V reduces allergic symptoms in mice

Spectrum of T‐lymphocyte activities regulating allergic lung inflammation

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

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