Unifying roles for regulatory T cells and inflammation in cancer

Erdman, Susan E.; Rao, Varada P.; Olipitz, Werner; Taylor, Christie L.; Jackson, Erin A.; Levkovich, Tatiana; Lee, Chung-Wei; Horwitz, Bruce H.; Fox, James G.; Ge, Zhongming; Poutahidis, Theofilos

doi:10.1002/ijc.24923

Cited by 87 publications

(155 citation statements)

References 71 publications

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“…An additional benefit is that sterile extracts of microbes have fewer health risks for immune-compromised patients, lowering risk of microbial overgrowth in patients who may otherwise suffer inappropriate immune responses. Some earlier work has suggested that killed bacteria or their extracts have healthful antiinflammatory properties, in particular during inflammatory bowel conditions [82][83][84][85][86]. Precise characterization of the dog bacterial extract and potential in human subjects remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Dog Bacteria Up-Regulate Oxytocin and Lower Risk of Obesity

Varian¹,

Levkovich²,

Poutahidis³

et al. 2017

J Prob Health

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AnimalsC57BL/6 wild type (wt), oxytocin-wt (oxt-wt) and oxytocin- AbstractCohabitation with pet dogs imparts diverse health benefits to humans including a slim physique. It is known that neuropeptide hormone oxytocin fundamental in human-canine social bonds regulates appetite and body weight. It was recently shown in mice that consuming Lactobacillus reuteri ATCC 6475 from human breast milk lowers body weight and up-regulates oxytocin levels in blood. Here we test the hypothesis that bacteria from dog saliva may similarly modulate recipient host body weight. We find that a Lactobacillus spp isolate from dog saliva led to lower body weight when fed to C57BL/6 wild type mice. Mice consuming the canineborne L. reuteri also had elevated oxytocin levels in blood plasma, and exhibited body weight in an oxytocin-dependent manner. Interestingly, killed (lysed) canine bacteria were sufficient to achieve the physiological effects. Taken together, these studies provide evidence that dog bacteria modulate oxytocin levels and body weight in recipient mice, and thus may help reduce risk of obesity in individuals cohabitating with pet dogs. knockout (oxt-ko) B6; 129S-Oxttm1Wsy/J mice (purchased initially from Jackson labs; Bar Harbor, ME) were used in three separate experiments (Figure 1). Mice were housed and handled in Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facilities using techniques and diets including Lactobacillus reuteri as specifically approved by Massachusetts Institute of Technology's (MIT) Committee on Animal Care (CAC). Mice were housed under standard 12:12 light cycle conditions with lights on at 7 AM. Mice were fed a standard control chow Purina RMH3000. Beneficial Dog Bacteria Up-Regulate Oxytocin and Lower Risk of ObesityMice were bred in-house to achieve experimental groups. Each experiment included 5-15 animals per group with one or two replications (total N=10-30 mice examined per group) unless otherwise specified. For the initial studies, C57BL/6 wt mice received Lactobacillus reuteri 2546 isolated from dog saliva. To test putative roles for microbeinduced oxytocin in obesity, oxt-ko mice and their oxt-wt littermates entered experiments at eight weeks of age. At the conclusion of the study mice were euthanized with CO 2 overdose, and were examined as described below. Eight pet dogs served as saliva microbe donors as approved by the MIT-CAC. Saliva was collected from these dogs in the morning before feeding using sterile swabs [Puritan Sterile Polyester Tipped applicators Guilford, Me Ref: 25-806 1PD] in 1.5 ml centrifuge tubes (Safeseal Microcentrifuge Tubes, Sorenson Bioscience Inc. Salt Lace City, UT Cat# 16070). Bacteria were purified from dog saliva as described in detail below. PCR of dog saliva for all Lactobacillus speciesSaliva was collected from eight pet dogs and prepared using High Pure PCR Template kit (Roche Diagnostics) was used without changes to the manufacturer's directions to isolate DNA from the canine saliva. DNA was measured using Nan...

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Section: Discussionmentioning

confidence: 99%

Beneficial Dog Bacteria Up-Regulate Oxytocin and Lower Risk of Obesity

Varian¹,

Levkovich²,

Poutahidis³

et al. 2017

J Prob Health

Self Cite

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“…Although Tregs may reduce the risk of inflammation-associated cancer by downregulating inflammation, it is believed that, in cancer, they mainly function by suppressing the antitumor immune response. However, under poorly regulated pro-inflammatory conditions, Tregs fail to inhibit, and may stimulate, a proinflammatory T helper 17 (Th17) response, driving the pro-carcinogenic process (5).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, IL-23, a heterodimer produced by dendritic cells (DC) comprising the unique p19 subunit plus the p40 subunit in common with IL-12, also contributes to differentiation and maintenance of Th17 cells (8). Moreover, recent data indicate late-stage plasticity of a subpopulation of Tregs, which can be selectively induced to adopt a Th17 phenotype, suggesting that Tregs may do more to modulate cancer than simply block constructive anticancer responses (5).…”

Section: Introductionmentioning

confidence: 99%

Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome

Vizio

Novarino

Giacobino

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. CD4+ CD25 + FoxP3 + regulatory T cells (Tregs) are understood to maintain peripheral tolerance to self-antigens and inhibit antitumor immune responses. However, compelling evidence suggests that, Tregs provide no anti-inflammatory protection in the tumor microenvironment, but rather contribute to a T helper 17 (Th17)-driven pro-carcinogenic process. Using three-color flow cytometry, we evaluated the percentage of circulating CD4 + CD25 + FoxP3 + Tregs in the peripheral blood of pancreatic carcinoma patients prior to and after chemotherapy [gemcitabine (GEM) alone, or GEM+oxaliplatin (GEMOX) or bevacizumab+capecitabine+ radiotherapy (BEV+CAPE+RT)]. Correlations were sought between Treg counts and plasma levels of cytokines relevant to controlling the Treg/Th17 balance, i.e., interleukin (IL)-23, IL-17A, IL-6 and transforming growth factor β 1 (TGF-β1), as measured by ELISA and the clinical features of pancreatic cancer. Treg, IL-6 and TGF-β1 levels were higher in locally advanced and metastatic pancreatic carcinoma patients compared to controls. No parameter was correlated with disease stage except IL-6. IL-17A and TGF-β1 were significantly associated with increased risk of poor prognosis. IL-17A was positively correlated with IL-23. Treg and IL-6 levels decreased following GEM monochemotherapy, IL-17A levels decreased after GEMOX, and IL-6 levels were reduced subsequent to BEV+CAPE+RT treatment. IL-23, IL-17A and TGF-β1 levels were significantly lower in patients responding to chemotherapy (partial remission/stable disease) than in nonresponders to chemotherapy (progressive disease). These results suggest an impact of the Treg/Th17-balance in pancreatic carcinoma, highlighting the significance of TGF-β1 and IL-17A as potential prognostic and predictive indicators. Immunological changes induced by mono and/or combined chemotherapy indicate specific windows of opportunity for introducing integrative interventions on a new target in pancreatic cancer, i.e. IL-17A, possibly improving survival in this highly lethal disease.

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“…In a series of studies in mice we have shown that some GI tract bacteria induce regulatory T-cells (Treg) of increased anti-inflammatory potency, which in turn counteract epithelial tumors throughout the body, instead of promoting them through anti-tumor immunity downregulation (6,(8)(9)(10)(11). Importantly, the bacteria-primed Treg activate clinically silent local GI tract and systematic immunity networks, which confer decreased risk of epithelial carcinogenesis (10,11).…”

Section: Introductionmentioning

confidence: 99%