Ectoplacental Cone Induces Resistance to Apoptosis in High Doses of Interferon (IFN)-γ-Treated Decidual Cells

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

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Resistance of Natural Killer T Cell–Deficient Mice to Systemic Shwartzman Reaction

Journal of Experimental Medicine ◽

10.1084/jem.192.11.1645 ◽

2000 ◽

Vol 192 (11) ◽

pp. 1645-1652 ◽

Cited By ~ 46

Author(s):

Francesco Dieli ◽

Guido Sireci ◽

Domenica Russo ◽

Masaru Taniguchi ◽

Juraj Ivanyi ◽

...

Keyword(s):

Natural Killer ◽

Severe Combined Immunodeficiency ◽

Nkt Cells ◽

Nkt Cell ◽

Natural Killer T Cell ◽

Shwartzman Reaction ◽

Ifn Γ ◽

High Doses ◽

Deficient Mice ◽

Natural Killer T

The generalized Shwartzman reaction in mice which had been primed and challenged with lipopolysaccharide (LPS) depends on interleukin (IL)-12–induced interferon (IFN)-γ production at the priming stage. We examined the involvement in the priming mechanism of the unique population of Vα14 natural killer T (NKT) cells because they promptly produce IFN-γ after IL-12 stimulation. We report here that LPS- or IL-12–primed NKT cell genetically deficient mice were found to be resistant to LPS-elicited mortality. This outcome can be attributed to the reduction of IFN-γ production, because injection of recombinant mouse IFN-γ, but not injection of IL-12, effectively primed the NKT cell–deficient mice. However, priming with high doses of LPS caused mortality of severe combined immunodeficiency, NKT cell–deficient, and CD1-deficient mice, indicating a major contribution of NKT cells to the Shwartzman reaction elicited by low doses of LPS, whereas at higher doses of LPS NK cells play a prominent role. These results suggest that the numerically small NKT cell population of normal mice apparently plays a mandatory role in the priming stage of the generalized Shwartzman reaction.

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Prevention Of Murine FVIII-Specific Memory B Cells Due To FcγR2B (CD32) Blockade Is Associated With Distinctive Alterations In The FVIII-Specific Cytokine Profile

Blood ◽

10.1182/blood.v122.21.572.572 ◽

2013 ◽

Vol 122 (21) ◽

pp. 572-572

Author(s):

Nadine Vollack ◽

Arne Trummer ◽

Andreas Tiede ◽

Sonja Werwitzke

Keyword(s):

T Cell ◽

B Cells ◽

Cell Response ◽

Research Funding ◽

Hemophilia A ◽

T Cell Response ◽

Memory B Cells ◽

Ifn Γ ◽

High Doses ◽

Very High

Abstract Development of neutralizing antibodies against factor VIII (FVIII) is a severe complication of replacement therapy in hemophilia A. Long-term application of high doses of FVIII can induce tolerance in the context of immune tolerance therapy (ITT). Very high concentrations of FVIII have been shown to prevent the development of FVIII-specific antibody-secreting cells (ASCs) from memory B cells by inducing apoptosis. We have previously demonstrated that ASC differentiation from memory B cells is also abolished when CD32, an inhibitory Fc-gamma receptor expressed on B cells and dendritic cells, was genetically deleted or blocked by monoclonal antibodies (mAb). Here, we addressed the question how CD32 inhibition prevented ASC development by studying the FVIII-specific T cell response in the absence or presence of CD32 inhibition. Hemophilia A mice (B6;129S4-F8tmKaz/J) were immunized with recombinant human FVIII (rhFVIII) for 4 weeks, and spleen cells were re-stimulated with rhFVIII (0, 0.5, 1 or 10 IU/ml) ex vivo in the presence or absence of anti-CD16/CD32 antibody (2.4G2) to inhibit CD32. Formation of FVIII-specific ASCs was assessed on day 6 by ELISPOT. IFN-γ, IL-2, IL-4, IL-6, IL-10, and TNF-α were detected in culture supernatant using a cytometric bead-based multiplex assay on days 1 to 6. In line with previous findings, very high doses of rhFVIII (10 IU/ml) or blockade of CD32 with mAb 2.4G2 (at high or low doses of rhFVIII) inhibited the differentiation of FVIII-specific ASCs. We observed a FVIII-dose dependent increase in the secretion of IFN-γ, IL-2, IL-4, IL-6, and IL-10. Very high doses of rhFVIII (10 IU/ml) suppressed ACS formation, but not the formation of these cytokines indicating an intact FVIII-specific T cell response. Secretion of TNF-α appeared not to be FVIII-dose dependent and was also observed in the cultures without rhFVIII. Inhibition of CD32 with mAb 2.4G2 in the presence of ASC stimulating FVIII concentrations (e.g. 1 IU/ml) prevented the development of ASC, but also diminished the formation of IFN-γ (334.2 ± 58.0 pg/ml versus 14.9 ± 1.4 pg/ml) and significantly reduced IL-10 (297.7 ± 78.5 pg/ml versus 131.3 ± 26.8 pg/ml). IL-6 was only slightly reduced, whereas IL-4 remained unchanged. IL-2 was even increased at later time points during cell culture (day 4: 16.1 ± 3.4 pg/ml versus 24.0 ± 1.4 pg/ml, day 6: 3.1 ± 0.6 pg/ml versus 21.8 ± 3.6 pg/ml). These results indicate that very high doses of FVIII prevented ASC formation, but not FVIII-specific T cell stimulation. In contrast, inhibition of CD32 prevented ASC formation, but also changed the secretion of T cell dependent cytokines. The lack of IFN-γ and IL-10 production after re-stimulation with various doses of rhFVIII indicates a reduced stimulation of Th1 and Th2 helper cells. Similar effects have been described previously, when B7-1 co-stimulation of CD4+ T cells was prevented by anti-CD80 mAb. In conclusion, inhibition of FVIII-specific ASC formation by means of very high doses of FVIII or inhibition of CD32 appears to occur differently. High doses of FVIII induce apoptosis in FVIII-specific memory B cells, but do not prevent FVIII-specific T cell responses. In contrast, inhibition of the Fcγ receptor CD32 on B cells and dendritic cells interferes with the FVIII-specific T cell response indicating a defective antigen presentation. Both high dose FVIII treatment and CD32 blockade, alone or in combination, should be further investigated to specifically address the FVIII-specific immune response in hemophilia A, and to evaluate a potential improvement of ITT. Disclosures: Vollack: Biotest AG: Research Funding. Trummer:Biotest AG: Research Funding. Tiede:CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Werwitzke:Biotest AG: Honoraria, Research Funding.

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Role of Gamma Interferon in Cellular Immune Response against Murine Encephalitozoon cuniculiInfection

Infection and Immunity ◽

10.1128/iai.67.4.1887-1893.1999 ◽

1999 ◽

Vol 67 (4) ◽

pp. 1887-1893 ◽

Cited By ~ 50

Author(s):

Imtiaz A. Khan ◽

Magali Moretto

Keyword(s):

Interleukin 2 ◽

Transient State ◽

Gamma Interferon ◽

No Production ◽

Ifn Γ ◽

High Doses ◽

Cellular Immune ◽

Parasite Challenge

ABSTRACT Microsporidia are obligate intracellular protozoan parasites that cause a wide variety of opportunistic infection in patients with AIDS. Because it is able to grow in vitro, Encephalitozoon cuniculi is currently the best-studied microsporidian. T cells mediate protective immunity against this parasite. Splenocytes obtained from infected mice proliferate in vitro in response to irradiated parasites. A transient state of hyporesponsiveness to parasite antigen and mitogen was observed at day 17 postinfection. This downregulatory response could be partially reversed by addition of nitric oxide (NO) antagonist to the culture. Mice infected withE. cuniculi secrete significant levels of gamma interferon (IFN-γ). Treatment with antibody to IFN-γ or interleukin-2 (IL-12) was able to neutralize the resistance to the parasite. Mutant animals lacking the IFN-γ or IL-12 gene were highly susceptible to infection. However, mice unable to secrete NO withstood high doses of parasite challenge, similar to normal wild-type animals. These studies describe an IFN-γ-mediated protection against E. cuniculi infection that is independent of NO production.

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Oral administration of Lactobacillus plantarum attenuates inflammatory damage in mice challenged with two pathogens

European Journal of Inflammation ◽

10.1177/2058739219833542 ◽

2019 ◽

Vol 17 ◽

pp. 205873921983354

Author(s):

Dayong Ren ◽

Di Wang ◽

Fengjun Rong ◽

Hongyan Liu ◽

Minghao Shen ◽

...

Keyword(s):

Body Weight ◽

Lactobacillus Plantarum ◽

Immunoglobulin A ◽

The Body ◽

Weight Changes ◽

Th2 Response ◽

Aureus Infection ◽

Inflammatory Damage ◽

Ifn Γ ◽

High Doses

This study aimed to determine the immunomodulatory effect of Lactobacillus plantarum on Salmonella typhimurium and Staphylococcus aureus infection. A mouse inflammation model was established using S. aureus and S. typhimurium. The infected mice were treated with low, medium, and high doses (2 × 108, 4 × 108, and 8 × 108 colony forming units (CFU)/mL, respectively) of three antibacterial L. plantarum strains. The body weight changes, spleen and thymus indexes, cytokines (interleukin (IL)-4 and interferon (IFN)-γ), and secreted immunoglobulin A levels were measured. Compared with the model group, all the L. plantarum-treated groups show increased body weight, reduced spleen swelling, decreased IFN-γ content, significantly increased IL-4 content, and significantly decreased ratio of IFN-γ to IL-4. sIgA levels increased at the end of the experiment. The three L. plantarum strains can effectively attenuate the symptoms of S. typhimurium and S. aureus infection by regulating the Th1/Th2 response and enhancing sIgA secretion.

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A Burkholderia pseudomallei ΔpurM Mutant Is Avirulent in Immunocompetent and Immunodeficient Animals: Candidate Strain for Exclusion from Select-Agent Lists

Infection and Immunity ◽

10.1128/iai.01313-09 ◽

2010 ◽

Vol 78 (7) ◽

pp. 3136-3143 ◽

Cited By ~ 66

Author(s):

Katie L. Propst ◽

Takehiko Mima ◽

Kyoung-Hee Choi ◽

Steven W. Dow ◽

Herbert P. Schweizer

Keyword(s):

Burkholderia Pseudomallei ◽

The United States ◽

Culturable Bacteria ◽

Level 3 ◽

Ifn Γ ◽

High Doses ◽

Basic Studies ◽

Derivatives Of ◽

Thiamine Biosynthesis

ABSTRACT Burkholderia pseudomallei causes the disease melioidosis in humans and is classified as a category B select agent. Research utilizing this pathogen is highly regulated in the United States, and even basic studies must be conducted in biosafety level 3 (BSL-3) facilities. There is currently no attenuated B. pseudomallei strain available that is excluded from select-agent regulations and can be safely handled at BSL-2 facilities. To address this need, we created Bp82 and Bp190, which are ΔpurM derivatives of B. pseudomallei strains 1026b and K96243 that are deficient in adenine and thiamine biosynthesis but replication competent in vitro in rich medium. A series of animal challenge studies was conducted to ensure that these strains were fully attenuated. Whereas the parental strains 1026b and K96243 and the complemented mutants Bp410 and Bp454 were virulent in BALB/c mice following intranasal inoculation, the ΔpurM mutants Bp82 and Bp190 were avirulent even when they were administered at doses 4 logs higher than the doses used for the parental strains. Animals challenged with high doses of the ΔpurM mutants rapidly cleared the bacterium from tissues (lung, liver, and spleen) and remained free of culturable bacteria for the duration of the experiments (up to 60 days postinfection). Moreover, highly susceptible 129/SvEv mice and immune incompetent mice (IFN-γ−/−, SCID) were resistant to challenges with ΔpurM mutant Bp82. This strain was also avirulent in the Syrian hamster challenge model. We concluded that ΔpurM mutant Bp82 is fully attenuated and safe for use under BSL-2 laboratory conditions and thus is a candidate for exclusion from the select-agent list.

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153 Nanoscale, antigen-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.153 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A162-A163

Author(s):

Zhifen Yang ◽

Francesco Marincola

Keyword(s):

T Cells ◽

Tumor Growth ◽

Tumor Cells ◽

Car T Cells ◽

Car T ◽

Ifn Γ ◽

High Doses ◽

Fadu Cells

BackgroundInterleukin(IL)-12 activates T cells pivoting the switch that turns lingering inflammation into acute inflammation and cancer rejection. However, its clinical utilization is limited by severe systemic toxicity. IL-12 is a potent inducer of PD-1 expression in T cells. Here, we present a conditional, antigen-dependent, non-editing CRISPR-activation (CRISPRa) circuit (RB-312) that delivers nanoscale doses of IL-12 for autocrine activation of CAR-T cells. RB-312 was also tested in combination with PD-L1 blocking antibody (atezolizumab).MethodsRB-312 is a CAR T cell engineered to express the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. The circuit includes two lentiviral constructs with one encoding HER2-specific chimeric antigen receptor and two sgRNAs targeting IL-12A or IL-12B and the other encoding linker for activation of T cells, complexed to dead Cas9 (dCas9)-VP64-p65-Rta transcriptional activator (VPR) (LdCV). Activation of CAR allows the release of dCas9 for nuclear localization and hence conditionally and reversibly induces the secretion of IL-12 p70 heterodimer.ResultsRB-312 induced low concentrations of IL-12 upon exposure to HER2+ FaDu cancer cells engineered to overexpress PD-L1 and this resulted in significantly enhanced production of IFN-γ, cytotoxicity and CAR-T proliferation (figure 1A). These effects were comparable to co-culturing conventional HER2 CAR with FaDu cells modified to express high doses of IL-12 (figure 1B). In vivo administration of RB-312 significantly enhanced survival of mice carrying FaDu xenografts compared to mice treated with the respective conventional HER2 CAR or cRB-312 (control lacking the IL-12 sgRNAs, figure 2A). RB-312 induced a strong upregulation of PD-1 in CAR-T cells in vivo (figure 2B). The critical role of the PD-1/PD-L1 interaction was demonstrated in vitro by comparing RB-312 proliferation when exposed to FaDu overexpressing PD-L1 or PD-L1 knock out cells (figure 3A). Indeed, combined treatment of RB-312 and atezolizumab resulted in significant reduction in tumor growth (figure 3B and C) and significantly enhanced survival (figure 3D).Abstract 153 Figure 1Conditional autocrine release of nanoscale-dose p70/IL-12 by RB-312 resulting in enhanced IFN-γ production in vitro after three days of exposure to HER2+ FaDu cells (figure 1A), and the level of IFN-γ production was comparable to co-culturing conventional HER2-specific CAR-T cells with a modified FaDu cell line engineered to constitutively express high doses of IL-12 (FaDu/IL-12, figure 1B)Abstract 153 Figure 2Intra-tumoral administration of RB-312 extended survival in mice carrying FaDu xenografts compared to NT (non-transduced T cells), HER2 CAR (conventional HER2 CAR-T cells) and cRB-312 CAR-T cells missing the sgRNAs for the two IL-12 subunits (figure 2A). Analysis of necropsy material demonstrated that PD-1 expression was dramatically increased in RB-312 compared with the respective control cRB-312 (figure 2B)Abstract 153 Figure 3RB-312 cellular function in vivo. PD-L1 expression by FaDu cell lines is a critical mechanism of repression of RB-312 function. In vitro CAR-T proliferation of RB-312 upon stimulation with FaDu tumor cells (orange solid lines) or FaDu/PD-L1 knockout tumor cells (orange dashed lines) over 6-day time course (figure 3A). In vivo efficacy of intra-tumoral RB-312 against FaDu tumor cells with (orange solid lines) or without (orange dashed lines) addition of PD-L1 blocking antibody atezolizumab (administered intravenously at 5 mg/kg twice per week), as shown by tumor growth followed till day 29 and scatter plot at day 29 (figure 3B), tumor growth spider plots (figure 3C) and Kaplan-Meier survival curve (figure 3D)ConclusionsWe concluded that addition of a Th1 polarizing component such as IL-12 exponentially increases the efficacy of reprogrammed CAR-T cells by combining enhancement of effector functions to cellular fitness. The autocrine effects of nanoscale IL-12 production limit the risk of off-tumor leakage and systemic toxicity. Here, we tested the combination of PD-1/PD-L1 blockade with IL-12-induced CAR-T cell activation demonstrated dramatic synergistic effects. We are currently evaluating the intrinsic combination of IL-12 delivery and PD-L1 resistance for the next generation of RB-312 product eliminating the need for systemic checkpoint blockade.

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Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia

Reproductive Sciences ◽

10.1177/1933719118815592 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1256-1265 ◽

Cited By ~ 4

Author(s):

S. Joseph Huang ◽

Chie-Pein Chen ◽

Lynn Buchwalder ◽

Ya-Chun Yu ◽

Longzhu Piao ◽

...

Keyword(s):

Protein Kinase ◽

Nk Cells ◽

Nk Cell ◽

First Trimester ◽

Mitogen Activated Protein Kinase ◽

Decidual Cells ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

Protein Kinase Kinase

C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant numbers and/or activation of these decidual immune cells elicit preeclampsia development. Decidual macrophages and NK cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester decidual cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16− NK cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and decidual cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16− NK cell migration. In conclusion, the current study suggests that decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.

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Protection of Mice with a Divalent Tuberculosis DNA Vaccine Encoding Antigens Ag85B and MPT64

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/36.4.269 ◽

2004 ◽

Vol 36 (4) ◽

pp. 269-276 ◽

Cited By ~ 13

Author(s):

Xia Tian ◽

Hong Cai ◽

Yu-Xian Zhu

Keyword(s):

Dna Vaccine ◽

Protective Efficacy ◽

Vaccine Group ◽

Control Group ◽

Lung Weight ◽

Promising Tool ◽

Ifn Γ ◽

Immunodominant Antigens ◽

High Doses ◽

Tuberculosis Disease

Abstract DNA vaccine may be a promising tool for controlling tuberculosis development. However, vaccines encoding single antigens of mycobacterium did not produce protective effect as BCG did. In the present study, we evaluated the immunogenicity and protective efficacy of a divalent DNA vaccine encoding two immunodominant antigens Ag85B and MPT64 of Mycobacterium tuberculosis. We found that both humoral and Th1-type (high IFN-γ, low IL-4) cellular responses obtained from the divalent DNA vaccine group were significantly higher than that conferred by BCG. RT-PCR results showed that antigens were expressed differentially in various organs in divalent DNA vaccine group. The survival rate for mice treated with the divalent DNA vaccine after challenging with high doses of virulent M. tuberculosis H37Rv was significantly higher than that of the BCG group or any of the single DNA vaccine group. Significant differences were also found between the single and divalent DNA vaccinated mice in terms of body, spleen and lung weight. Bacterial loading decreased about 2000-fold in lungs and about 100-fold in spleens of divalent DNA vaccinated mice when compared with that of the control group. We conclude that our divalent DNA vaccine may be a better choice for controlling tuberculosis disease in animals.

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Ultrastructural Localization of Acetylcholinesterase in the Arcuate Nucleus and Median Eminence of the Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100079644 ◽

1977 ◽

Vol 35 ◽

pp. 440-441

Author(s):

K.A. Carson ◽

C.B. Nemeroff ◽

M.S. Rone ◽

J.S. Kizer ◽

J.S. Hanker

Keyword(s):

Choline Acetyltransferase ◽

Median Eminence ◽

Arcuate Nucleus ◽

Cholinergic Neurons ◽

Ultrastructural Localization ◽

Male Rats ◽

Neonatal Rats ◽

Good Marker ◽

Chemical Studies ◽

High Doses

Biochemical, physiological, pharmacological, and more recently enzyme histo- chemical data have indicated that cholinergic circuits exist in the hypothalamus. Ultrastructural correlates of these pathways such as acetylcholinesterase (AchE) positive neurons in the arcuate nucleus (ARC) and stained terminals in the median eminence (ME) have yet to be described. Initial studies in our laboratories utilizing chemical lesioning and microdissection techniques coupled with microchemical and light microscopic enzyme histo- chemical studies suggested the existence of cholinergic neurons in the ARC which project to the ME (1). Furthermore, in adult male rats with Halasz deafferentations (hypothalamic islands composed primarily of the isolated ARC and the ME) choline acetyltransferase (ChAc) activity, a good marker for cholinergic neurons, was not significantly reduced in the ME and was only somewhat reduced in the ARC (2). Treatment of neonatal rats with high doses of monosodium 1-glutamate (MSG) results in a lesion largely restricted to the neurons of the ARC.

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