scholarly journals Biological Response Modifiers and Parasitic Infections: Experimental Aspects of Toxoplasmosis

1994 ◽  
Vol 5 (suppl a) ◽  
pp. 47A-50A
Author(s):  
Miles H Beaman
Keyword(s):  
Critical Role ◽  
Biological Response ◽  
Biological Response Modifiers ◽  
Toxoplasmic Encephalitis ◽  
Current Therapy ◽  
Mouse Strains ◽  
Parasitic Infections ◽  
Ifn Γ

Parasitic infections are important causes of disease in the developing world and, since the advent of AIDS, the developed world. Over the past decade, in vitro and in vivo studies have established the important role that biological response modifiers play in pathogenesis of parasitic disease. These basic studies have resulted in successful clinical trials of interferon gamma (IFN-γ) in human leishmaniasis. Toxoplasmic encephalitis is a major opportunistic infection in patients with AIDS. and current therapy is often problematic. IFN-γ has been shown in in vitro and in vivo animal studies to be critical for host defence against Toxoplasma gondii. Tumour necrosis factor alpha plays a critical role in mediating IFN-γ effect in vitro, but its role in vivo is under further study. lnterleukin (1L)-6 and IL-10 have both recently been shown to enhance T gondii replication in vitro and to antagonize the beneficial effects of IPN-γ. In addition, in certain mouse strains. IL-6 has been shown to worsen mortality from T gondii infection. Future strategies for therapy of T gondii may include administration of exogenous IFN-γ or IL-12 with or without antibody to antagonistic cytokines such as IL-6 (or possibly IL-10).

scholarly journals Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12–IFN-γ

2017 ◽  
Vol 114 (43) ◽  
pp. 11482-11487 ◽  
Author(s):  
Madhuchhanda Kundu ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Cancer ◽  
Critical Role ◽  
Tumor Model ◽  
Cell Mediated Immunity ◽  
Ifn Γ

Cancer cells are adept at evading cell death, but the underlying mechanisms are poorly understood. IL-12 plays a critical role in the early inflammatory response to infection and in the generation of T-helper type 1 cells, favoring cell-mediated immunity. IL-12 is composed of two different subunits, p40 and p35. This study underlines the importance of IL-12 p40 monomer (p40) in helping cancer cells to escape cell death. We found that different mouse and human cancer cells produced greater levels of p40 than p40 homodimer (p402), IL-12, or IL-23. Similarly, the serum level of p40 was much greater in patients with prostate cancer than in healthy control subjects. Selective neutralization of p40, but not p402, by mAb stimulated death in different cancer cells in vitro and in vivo in a tumor model. Interestingly, p40 was involved in the arrest of IL-12 receptor (IL-12R) IL-12Rβ1, but not IL-12Rβ2, in the membrane, and that p40 neutralization induced the internalization of IL-12Rβ1 via caveolin and caused cancer cell death via the IL-12–IFN-γ pathway. These studies identify a role of p40 monomer in helping cancer cells to escape cell death via suppression of IL-12Rβ1 internalization.

scholarly journals Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes

2015 ◽  
Vol 308 (5) ◽  
pp. C362-C371 ◽  
Author(s):  
Konstantinos A. Papadakis ◽  
James Krempski ◽  
Jesse Reiter ◽  
Phyllis Svingen ◽  
Yuning Xiong ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Effector Memory ◽  
Antiviral Immune Response ◽  
Ifn Γ ◽  
Tgf Β1

KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4+ T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8+ T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10−/− CD8+ T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8+ T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8+ T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8+ T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8+ T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10−/− CD8+ T cells and a higher percentage of IFN-γ-producing CD8+ T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8+ T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.

scholarly journals Autocrine TGF-β1 Maintains the Stability of Foxp3+ Regulatory T Cells via IL-12Rβ2 Downregulation

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 819
Author(s):  
Garam Choi ◽  
Hyeongjin Na ◽  
Da-Sol Kuen ◽  
Byung-Seok Kim ◽  
Yeonseok Chung
Keyword(s):  
Treg Cell ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Treg Cells ◽  
Mesenteric Lymph Nodes ◽  
Ifn Γ ◽  
Tgf Β1

Transforming growth factor beta 1 (TGF-β1) is an immunosuppresive cytokine that plays an essential role in immune homeostasis. It is well known that regulatory T (Treg) cells express TGF-β1; however, the role of autocrine TGF-β1 in the development, function, and stability of Treg cells remains poorly understood. We found that Treg cell-derived TGF-β1 was not required for the development of thymic Treg cells in mice, but played a role in the expression of latency-associated peptide and optimal suppression of naïve T cell proliferation in vitro. Moreover, the frequency of Treg cells was significantly reduced in the mesenteric lymph nodes of the Treg cell-specific TGF-β1-deficient mice, which was associated with increased frequency of IFN-γ-producers among Treg cells. TGF-β1-deficient Treg cells were more prone to express IFN-γ than TGF-β1-sufficient Treg cells in a dendritic cell-mediated stimulation in vitro as well as in an adoptive transfer study in vivo. Mechanistically, TGF-β1-deficient Treg cells expressed higher levels of Il12rb2 and were more sensitive to IL-12-induced conversion into IFN-γ-producing Treg cells or IFN-γ-producing exTreg cells than TGF-β1-sufficient Treg cells. Our findings demonstrate that autocrine TGF-β1 plays a critical role in the optimal suppressive activity and stability of Treg cells by downregulating IL-12R on Treg cells.

scholarly journals An Historic Overview of Biological Response Modifiers as Antiviral Agents

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 34-40 ◽  
Author(s):  
Page S Morahan ◽  
Aangelo J Pinto
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Antiviral Agents ◽  
Biological Response ◽  
Natural Resistance ◽  
Biological Response Modifiers ◽  
Protective Effects ◽  
Small Molecular Weight

A wide variety ofimmunomodulators/biological response modifiers (BRMs) has been demonstrated to provide broad spectrum antiviral activity against both RNA and DNA viruses in several animal species. Dramatic decreases in mortality, reduced virus titres in tissues and reduced histopathology can be produced. The antivirally effective agents include microbially derived materials, polyanions, cytokines and chemically diverse small molecular weight chemicals. The greatest protective effects are observed with prophylactic treatment. although early therapeutic treatment can also be effective. Little direct antiviral activity can be observed in vitro. The findings suggest induction by BRMs of antiviral mediators in vivo early in the course of viral pathogenesis, before the virus has become sequestered in a privileged site or too much infectious virus has been produced for natural resistance to have an impact, immunomodulators are pleiotropic in their immunomodulatory effects, and it has been difficult to establish whether one cell type or mediator is critical for the observed broad spectrum antiviral activity. Therefore, the mechanisms of antiviral action of immunomodulators remain unclear for most systems, but probably involve enhancement of natural immune responses. While no unified antiviral mechanism among different immunomodulators has yet emerged, interferon induction remains a major hypothesis.

scholarly journals Effective Induction of Acquired Resistance to Listeria monocytogenes by Immunizing Mice with In Vivo-Infected Dendritic Cells

2003 ◽  
Vol 71 (1) ◽  
pp. 117-125 ◽  
Author(s):  
Hiroshi Sashinami ◽  
Akio Nakane ◽  
Yoichiro Iwakura ◽  
Mutsuo Sasaki
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Listeria Monocytogenes ◽  
Critical Role ◽  
Acquired Resistance ◽  
Interleukin 12 ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Splenic dendritic cells (DCs) obtained from mice at 48 h after Listeria monocytogenes infection exhibited up-regulation of CD80 and produced higher titers of gamma interferon (IFN-γ) and interleukin-12 (IL-12) than did DCs obtained from uninfected mice. Mice immunized with DCs obtained from mice that had been infected with L. monocytogenes 48 h before acquired host resistance to lethal infection with L. monocytogenes at 4 and 8 weeks. Immunization with DCs from heat-killed L. monocytogenes failed to induce resistance. Acquired antilisterial resistance is specific, since the immunized mice could not be protected from Salmonella enterica serovar Typhimurium infection. Infected DCs stimulated proliferation of naive CD4+ and CD8+ cells in vitro, suggesting that in vivo-infected DCs activate CD8+ T cells, which are critical in acquired antilisterial resistance, as well as CD4+ T cells. When wild-type mice were immunized with DCs from IFN-γ-deficient mice, they were protected against a lethal L. monocytogenes challenge. In contrast, when mice were immunized with DCs from anti-IL-12 p40 monoclonal antibody-injected mice, they failed to gain acquired antilisterial resistance. These results suggest that DC-derived IL-12, but not IFN-γ, may play a critical role in induction of acquired antilisterial resistance. Our present results suggest that splenic DCs obtained from mice infected with L. monocytogenes in vivo may be an effective immunogen with which to induce antigen-specific immunity.

scholarly journals The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination

2018 ◽  
Vol 215 (7) ◽  
pp. 1813-1821 ◽  
Author(s):  
Fang Yu ◽  
Suveena Sharma ◽  
Dragana Jankovic ◽  
Rama Krishna Gurram ◽  
Pan Su ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Critical Role ◽  
Molecular Switch ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection

Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)–γ; some Th1 cells can also be antiinflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and antiinflammatory Th1 cells is still elusive. Here, we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild-type Th1 cells both in vitro and in vivo. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection, and blockade of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and antiinflammatory Th1 cells.

scholarly journals Characteristics of Invasive Candidiasis in Gamma Interferon- and Interleukin-4-Deficient Mice: Role of Macrophages in Host Defense against Candida albicans

1998 ◽  
Vol 66 (4) ◽  
pp. 1708-1717 ◽  
Author(s):  
Rita Káposzta ◽  
Peter Tree ◽  
László Maródi ◽  
Siamon Gordon
Keyword(s):  
Candida Albicans ◽  
Host Defense ◽  
Invasive Candidiasis ◽  
Critical Role ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
In Vivo Studies ◽  
Mouse Strains ◽  
Ifn Γ

ABSTRACT Murine models of invasive candidiasis were used to study the in vivo importance of gamma interferon (IFN-γ) and interleukin-4 (IL-4) in host defense against Candida albicans and to characterize the tissue inflammatory reactions, with special reference to macrophages (Mφ). Knockout (KO) IFN-γ-deficient (GKO) and IL-4-deficient (IL-4 KO) and C57BL/6 parental mouse strains were challenged intraperitoneally with 108 C. albicans blastoconidia. Survival of GKO mice was significantly lower (16.7%) than that of C57BL/6 control (55.5%) and IL-4 KO (61.1%) animals, but was not correlated with the extent of organ colonization. Immunohistological analysis with a panel of myeloid and lymphoid markers revealed multiple renal abscesses, myocarditis, hepatitis, meningoencephalitis, and pneumonia in each strain, with a dominant presence of Mφ. In the absence of IFN-γ, C. albicans induced striking changes in the phenotype of alveolar Mφ and extensive perivascular lymphoid infiltrates in the lung. Impairment in nitric oxide production by peritoneal Mφ was shown only in GKO mice, and they produced Candida-specific immunoglobulin G (IgG), IgM, IgA, and IgG subclasses in lower titers. Our in vivo studies with KO mice elucidate a critical role for IFN-γ, but not IL-4, in host defense against C. albicans.

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