Microbiota control immune regulation in humanized mice

Gülden, Elke; Vudattu, Nalini; Deng, Songyan; Preston-Hurlburt, Paula; Mamula, Mark J.; Reed, James Christopher; Mohandas, Sindhu; Herold, Betsy C.; Torres, Richard; Vieira, Sílvio M.; Lim, Bentley; Herazo-Maya, José D.; Kriegel, Martin; Goodman, Andrew L.; Cotsapas, Chris; Herold, Kevan C.

doi:10.1172/jci.insight.91709

Cited by 26 publications

(16 citation statements)

References 48 publications

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“…Nevertheless, ABX treatment had little effect on the apoptosis of tumor cells induced by diosgenin, and the group treated with ABX alone showed a weak CD4 + /CD8 + T-cell infiltration. It has been reported that the ABX-treated mice had relatively higher frequency of effector T cells in gut wall or spleen and higher circulating level of IFN-γ along with lower IL-10 level to increase the susceptibility to inflammation 38 , 39 . Thus, it is better to apply germ-free mice to confirm the role of intestinal microbiota in the antitumor effect of diosgenin in further studies.…”

Section: Discussionmentioning

confidence: 99%

Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota

et al. 2018

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Diosgenin, a natural steroidal saponin, can exert antitumor effect by regulating immune function and improving intestinal microbiota. The response to anti-PD-1 immunotherapy is associated with intestinal microbiota and effector T cells in tumor microenvironment. We hypothesize that the modulation of diosgenin on intestinal microbiota can facilitate antitumor immunity and the therapeutic efficacy of PD-1 antibody. In melanoma-bearing C57BL/6 mice, we observed that the anti-melanoma effect of diosgenin relied more on antitumor immunity than direct tumor inhibition activity evidenced by obvious CD4+/CD8+ T-cell infiltration and IFN-γ expression in tumor tissues, and it could improve the compositions of intestinal microbiota. Antibiotics impaired the therapeutic efficacy and immunity responses of diosgenin through disturbing intestinal microbiota, indicating the importance of intestinal microbiota in diosgenin’s in vivo antitumor activity. More importantly, the combined administration of PD-1 antibody with diosgenin aggravated the tumor necrosis and apoptosis by eliciting augmented T-cell responses. Taken together, diosgenin can be used as a microecological regulator to induce antitumor immunity and improve the efficacy of immune checkpoint antibody, making it more suitable for the treatment of malignant tumors.

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Section: Discussionmentioning

confidence: 99%

Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota

et al. 2018

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“…HIS mice present a significant advantage over humans for the study of the microbiota as their microbiome can be easily tracked and manipulated throughout the animal's life. Protocols have been recently developed to generate HIS mice engrafted with human microbiota [340], and few preliminary studies have been conducted in conventional HIS mouse models [341]. As we approach the role of the microbiota in regulating human health, the development of innovative HIS mouse models able to mount superior adaptive responses and co-engrafted with human microbiota would open notable opportunities to investigate LAV-induced immunity in a more relevant physiological context and to better understand microbiota-mediated regulation of immune priming (Figure 3).…”

Section: His Mice and Lav: Limitations And Future Opportunitiesmentioning

confidence: 99%

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

O'Connell

Douam

2020

Vaccines

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Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor.

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“…Switch between preventive and pathological roles could be due to microbiota metabolites presented by CD11b+CD11c+dendritic cells (DCs), sensor of the intestinal environment. 49 The next question is how this "leaky gut" affect the onset of T1D. It is proposed that the increased gut permeability might allow more exogenous antigen into the mucosal immune system, which further leads to increased production of cytokine that may attack and damage pancreatic beta cells.…”

Section: Gut Microbiota Affects Intestinal Integrity Of the Hostmentioning

confidence: 99%

Untitled

2018

GHOA

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the damage of autoantibody against β islet cells. Because of the painful suffering of the patients and the heavy social burdens, T1D has attracted increasing research interests. Several observations made in both rodent models and human patients shed lights on the association between T1D and gut microbiota, yet the underlying mechanism of how microorganisms in the gastrointestinal tract contribute to T1D remain elusive. In the present review we have mainly reviewed recent hypothesis including: (1) interference of gut microbiota with host metabolism and creation of an inflammatory milieu; (2) influence of specific strains or metabolic by-products on the differentiation of host T cell; and (3) moderation of host gut integrity by certain microbial metabolite. We believe that these knowledge are crucial for the early detection and proper intervention of T1D.

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Microbiota control immune regulation in humanized mice

Cited by 26 publications

References 48 publications

Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota

Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

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