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(1) Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Infection.[TOP]

Pubmed ID :30881923
Publication Date : //
Every year, up to 90,000 new cases of Visceral Leishmaniasis and 30,000 resultant deaths are estimated to occur worldwide. Such numbers give relevance to the continuous study of this complex form of the disease: a zoonosis and an anthroponosis; two known etiological agents ( and , respectively); with an estimated average ratio of 1 symptomatic per 10 asymptomatic individuals; and sometimes associated with atypical clinical presentations. This complexity, which results from a long co-evolutionary process involving vector-host, host-pathogen, and pathogen-vector interactions, is still not completely understood. The determinants of visceralization are not fully defined and the dichotomy resistance vs. susceptibility remains unsolved, translating into obstacles that delay the progress of global disease control. Inbred mouse models, with different susceptibility patterns to infection, have been very useful in exploring this dichotomy. BALB/c and C57BL/6 mice were described as susceptible strains to visceral infection, while SV/129 was considered resistant. Here, we used these three mouse models, but in the context of infection, the other species that cause visceral disease in humans, and dynamically compared their local and systemic infection-induced immune responses in order to establish a parallel and to ultimately better understand susceptibility vs. resistance in visceral leishmaniasis. Overall, our results suggest that C57BL/6 mice develop an intermediate "infection-phenotype" in comparison to BALB/c and SV/129 mouse strains, considering both the splenic parasite burden and the determined target organs weights. However, the immune mechanisms associated with the control of infection seem to be different in each mouse strain. We observed that both BALB/c and SV/129, but not C57BL/6 mice, show an infection-induced increase of splenic T follicular helper cells. On the other hand, differences detected in terms of CD21 expression by B cells early after infection, together with the quantified anti- specific antibodies, suggest that SV/129 are faster than BALB/c and C57BL/6 mice in the assembly of an efficient B-cell response. Additionally, we observed an infection-induced increase in polyfunctional CD4+ T cells in the resistant SV/129 model, opposing an infection-induced increase in CD4+IL-10+ cells in susceptible BALB/c mice. Our data aligns with the observations reported for infection and suggest that not only a single mechanism, but an interaction of several could be necessary for the control of this parasitic disease.

Authors : Pérez-Cabezas Begoña, Cecílio Pedro, Gaspar Tiago Bordeira, Gärtner Fátima, Vasconcellos Rita, Cordeiro-da-Silva Anabela,

(2) Mechanisms of Naturally Acquired Immunity to .[TOP]

Pubmed ID :30881363
Publication Date : //
In this review we give an update on the mechanisms of naturally acquired immunity against , one of the major human bacterial pathogens that is a common cause of pneumonia, septicaemia, and meningitis. A clear understanding of the natural mechanisms of immunity to is necessary to help define why the very young and elderly are at high risk of disease, and for devising new prevention strategies. Recent data has shown that nasopharynx colonization by induces antibody responses to protein and capsular antigens in both mice and humans, and also induces Th17 CD4+ cellular immune responses in mice and increases pre-existing responses in humans. These responses are protective, demonstrating that colonization is an immunizing event. We discuss the data from animal models and humans on the relative importance of naturally acquired antibody and Th17 cells on immunity to at three different anatomical sites of infection, the nasopharynx (the site of natural asymptomatic carriage), the lung (site of pneumonia), and the blood (site of sepsis). Mouse data suggest that CD4+ Th17 cells prevent both primary and secondary nasopharyngeal carriage with no role for antibody induced by previous colonization. In contrast, antibody is necessary for prevention of sepsis but CD4+ cellular responses are not. Protection against pneumonia requires a combination of both antibody and Th17 cells, in both cases targeting protein rather than capsular antigen. Proof of which immune component prevents human infection is less easily available, but two recent papers demonstrate that human IgG targeting protein antigens is highly protective against septicaemia. The role of CD4+ responses to prior nasopharyngeal colonization for protective immunity in humans is unclear. The evidence that there is significant naturally-acquired immunity to independent of anti-capsular polysaccharide has clinical implications for the detection of subjects at risk of infections, and the data showing the importance of protein antigens as targets for antibody and Th17 mediated immunity should aid the development of new vaccine strategies.

Authors : Ramos-Sevillano Elisa, Ercoli Giuseppe, Brown Jeremy S,

(3) Infection Decreases Smad7 Expression in Intestinal CD4 T Cells, Which Allows TGF-β to Induce IL-10-Producing Regulatory T Cells That Block Colitis.[TOP]

Pubmed ID :30850474
Publication Date : //
Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease. Induction of regulatory T cells (Tregs) may be an important part of this protective process. infection also promotes the production of the regulatory cytokines TGF-β and IL-10 in the gut. In the intestines, TGF-β helps induce regulatory T cells. This study used Foxp3/IL-10 double reporter mice to investigate the effect of TGF-β on the differentiation of colon and mesenteric lymph node-derived murine Foxp3 IL-10 CD4 T cells into their regulatory phenotypes. Foxp3 IL-10 CD4 T cells from -infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-β and anti-CD3/CD28 mAb differentiated into Foxp3 and/or IL-10 T cells. The IL-10-producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-β signaling. In contrast to gut T cells from uninfected mice, Foxp3 IL10 CD4 T cells from -infected mice displayed reduced Smad7 expression and responded to TGF-β with Smad2/3 phosphorylation. The TGF-β-induced Tregs that express IL-10 blocked colitis when transferred into the Rag/CD25 CD4 T cell transfer model of inflammatory bowel disease. TGF-β had a greatly diminished capacity to induce Tregs in -infected transgenic mice with constitutively high T cell-specific Smad7 expression. Thus, infection with causes down-modulation in Smad7 expression in intestinal CD4 T cells, which allows the TGF-β produced in response to the infection to induce the Tregs that prevent colitis.

Authors : Hang Long, Kumar Sangeeta, Blum Arthur M, Urban Joseph F, Fantini Massimo C, Weinstock Joel V,

(4) A humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells.[TOP]

Pubmed ID :30842333
Publication Date : //
Combination anti-retroviral drug therapy (ART) potently suppresses HIV-1 replication but does not result in virus eradication or a cure. A major contributing factor is the long-term persistence of a reservoir of latently infected cells. To study this reservoir, we established a humanized mouse model of HIV-1 infection and ART suppression based on an oral ART regimen. Similar to humans, HIV-1 levels in the blood of ART-treated animals were frequently suppressed below the limits of detection. However, the limited timeframe of the mouse model and the small volume of available samples makes it a challenging model with which to achieve full viral suppression and to investigate the latent reservoir. We therefore used an latency reactivation assay that allows a semi-quantitative measure of the latent reservoir that establishes in individual animals, regardless of whether they are treated with ART. Using this assay, we found that latently-infected human CD4 T cells can be readily detected in mouse lymphoid tissues, and that latent HIV-1 was enriched in populations expressing markers of T cell exhaustion, PD-1 and TIGIT. Additionally, we were able to use the latency reactivation assay to demonstrate that HIV-specific TALENs can reduce the fraction of reactivatable virus in the latently-infected cell population that establishes , supporting the use of targeted nuclease-based approaches for an HIV-1 cure. HIV-1 can establish latent infections that are not cleared by current antiretroviral drugs or the body's immune responses, and therefore represent a major barrier to curing HIV-infected individuals. However, the lack of expression of viral antigens on latently infected cells makes them difficult to identify or study. Here, we describe a humanized mouse model that can be used to detect latent but reactivatable HIV-1 in both untreated mice and those on ART, and therefore provides a simple system with which to study the latent HIV-1 reservoir and the impact of interventions aimed at reducing it.

Authors : Llewellyn George N, Seclèn Eduardo, Wietgrefe Stephen, Liu Siyu, Chateau Morgan, Pei Hua, Perkey Katherine, Marsden Matthew D, Hinkley Sarah J, Paschon David E, Holmes Michael C, Zack Jerome A, Louie Stan G, Haase Ashley T, Cannon Paula M,

(5) α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas.[TOP]

Pubmed ID :30832732
Publication Date : //
Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFβ signaling.

Authors : Dodagatta-Marri E, Meyer D S, Reeves M Q, Paniagua R, To M D, Binnewies M, Broz M L, Mori H, Wu D, Adoumie M, Del Rosario R, Li O, Buchmann T, Liang B, Malato J, Arce Vargus F, Sheppard D, Hann B C, Mirza A, Quezada S A, Rosenblum M D, Krummel M F, Balmain A, Akhurst R J,

(6) Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice.[TOP]

Pubmed ID :30829743
Publication Date : //
The combined combination antiretroviral therapy (cART) and anti-α4β7 RM-Act-1 antibody therapy allows macaques to durably control simian immunodeficiency virus (SIV) rebound after withdrawal of the interventions. Here, we aimed to investigate whether vedolizumab (VDZ), a clinical-grade humanized anti-α4β7 antibody, would have similar effects in controlling live HIV-1 infection in humanized mice.

Authors : Ling Lijun, Wu Tongjin, To Kelvin Kai Wang, Cheung Ka-Wai, Lui Kathy Oi Lan, Niu Mengyue, Lam Ka Shing, Wang Chi Chi, Li Jiatao, Wang Hui, Yuen Kwok-Yung, Chen Zhiwei,

(7) PRMT5 Associates With the FOXP3 Homomer and When Disabled Enhances Targeted p185 Tumor Immunotherapy.[TOP]

Pubmed ID :30800128
Publication Date : //
Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.

Authors : Nagai Yasuhiro, Ji Mei Q, Zhu Fuxiang, Xiao Yan, Tanaka Yukinori, Kambayashi Taku, Fujimoto Shigeyoshi, Goldberg Michael M, Zhang Hongtao, Li Bin, Ohtani Takuya, Greene Mark I,

(8) Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice.[TOP]

Pubmed ID :30790585
Publication Date : //
Autism is a neurodevelopmental disease which is characterized by its core behavioral symptoms such as impairment in social interaction and stereotyped repetitive behavior. Th17 immune responses and oxidative stress are reported to be elevated in both human autistic subjects and BTBR T + Itpr3tf/J (BTBR) mice. On the other hand, activation of nuclear factor erythroid 2 related factor (Nrf2), a master transcription factor is essential for the management of anti-inflammatory and antioxidant genes. Sulforaphane activates Nrf2 and thus is considered a potential approach to treat several neurological disorders including autism. In the current work, we used sulforaphane in asocial BTBR mice and its social counterpart C57/BL6 (C57) mice to assess its therapeutic potential and molecular mechanisms (Th17 immune responses, and oxidant-antioxidant balance) through which it acts. Our results demonstrate that BTBR treated with sulforaphane had reduced self-grooming/marble burying behavior, and increased social interaction in three chambered sociability test as compared to untreated BTBR mice. Further, sulforaphane-treated BTBR mice had reduced Th17 immune responses (STAT3, RORC, IL-17 A and IL-23R expression in CD4 + T cells), oxidative stress parameters in neutrophils/cerebellum (NFkB, iNOS, and lipid peroxides). Furthermore, sulforaphane-treated BTBR and C57 mice had upregulated enzymatic antioxidant defenses in neutrophils/cerebellum (SOD, GPx and GR expression and activity). We reason that activation of Nrf2 by sulforaphane corrected Th17 immune dysfunction and oxidant-antioxidant imbalance in periphery and brain in BTBR mice. These mechanisms lead to improvement in autism-like symptoms in BTBR mice.

Authors : Nadeem Ahmed, Ahmad Sheikh F, Al-Harbi Naif O, Attia Sabry M, Bakheet Saleh A, Ibrahim Khalid E, Alqahtani Faleh, Alqinyah Mohammed,

(9) Tailoring the immune response to wheat gliadin by enzymatic transamidation.[TOP]

Pubmed ID :30784897
Publication Date : //
Enzymatic transamidation of wheat gliadin by microbial transglutaminase inhibits IFN-γ secretion by intestinal T cell lines from celiac disease (CD) patients. Here, we analysed its effects on intestinal biopsies from CD patients and studied the underlying mechanisms in HLA-DQ8 transgenic (tg) mice, a model of T-cell mediated gluten sensitivity. In vitro challenge with a soluble form of transamidated gliadin (spf) upregulated IL-10 transcript levels in human biopsy samples. Furthermore, the ratio of IL-10/IFN-γ transcripts was significantly increased following treatment with spf. In DQ8 tg mice, recall responses in vitro in the presence of dendritic cells pulsed with transamidated gliadin showed that gliadin-specific CD4 T cells did not produce IFN-γ at any tested dose. On the contrary, spf-specific CD4 T cells still secreted IFN-γ, but they also produced significant levels of IL-10 with both native and transamidated gliadin. Interestingly, this anti-inflammatory activity was restricted to a specific reverse-phase high-pressure liquid chromatography (RP-HPLC) fraction encompassing α-gliadins. These findings suggested an ability of transamidated gliadin to revert, as well as to prevent, the inflammatory phenotype triggered by native gliadin. This property was intrinsically associated with specific components of the α-gliadin fraction.

Authors : Luongo Diomira, Bonavita Roberta, Rossi Stefano, Rotondi Aufiero Vera, Feliciello Nicoletta Rosaria, Maurano Francesco, Iaquinto Gaetano, Mazzarella Giuseppe, Rossi Mauro,

(10) Tetrandrine inhibits differentiation of proinflammatory subsets of T helper cells but spares de novo differentiation of iTreg cells.[TOP]

Pubmed ID :30769211
Publication Date : //
Tetrandrine (TET) is an anti-inflammatory compound isolated from Chinese herb Stephania tetrandra S. Moore. It was reported recently that the differentiation of Th17 cells was inhibited, while the generation of induced Treg cells (iTregs) was promoted, by TET treatment. We therefore carefully examined the effect of TET on the differentiation of four major subsets of T helper cells. The results showed that in vitro treatment with TET potently inhibited the differentiation of Th1, Th2 and Th17 cells. Administration of LPS resulted in a mixed Th1, Th2 and Th17 responses in normal mice, and such effect of LPS was inhibited by in vivo TET treatment as well. In contrast, TET did not promote or inhibit the in vitro generation of iTregs from naïve CD4CD25Foxp3/gfp T cells. Furthermore, spontaneous and rapamycin-induced conversion of naïve CD4CD25Foxp3/gfp T cells into Foxp3-expressing iTregs in congenic mice was not affected by TET treatment. Thus, TET had the capacity to inhibit the differentiation of proinflammatory Th1, Th2 and Th17 cells, while sparing the generation of Tregs. As a Treg-friendly and broad spectrum anti-inflammatory agent, the molecular mechanism and the therapeutic potential of TET in various human inflammatory diseases should be further studied.

Authors : Zou Huimin, He Tianzhen, Chen Xin,