Publications by authors named "Andrey A Kruglov"

16 Publications

  • Page 1 of 1

Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Immunity 2020 11;53(5):1015-1032.e8

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an institute of the Leibniz Association, 10117 Berlin, Germany. Electronic address:

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6 ILC3 via lymphotoxin-β receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2020.10.012DOI Listing
November 2020

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

Gastroenterology 2020 10 22;159(4):1417-1430.e3. Epub 2020 Jun 22.

Georgia Cancer Center, Augusta University, Augusta, Georgia.

Background & Aims: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice.

Methods: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf, Lta, and Ltb mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times.

Results: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC.

Conclusions: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607422PMC
October 2020

Effects of myeloid cell-restricted TNF inhibitors in vitro and in vivo.

J Leukoc Biol 2020 06 10;107(6):933-939. Epub 2020 Feb 10.

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Systemic TNF neutralization can be used as a therapy for several autoimmune diseases. To evaluate the effects of cell type-restricted TNF blockade, we previously generated bispecific antibodies that can limit TNF secretion by myeloid cells (myeloid cell-specific TNF inhibitors or MYSTIs). In this study several such variable domain (VH) of a camelid heavy-chain only antibody-based TNF inhibitors were compared in relevant experimental models, both in vitro and in vivo. Pretreatment with MYSTI-2, containing the anti-F4/80 module, can restrict the release of human TNF (hTNF) from LPS-activated bone marrow-derived macrophage (BMDM) cultures of humanized TNF knock-in (mice; hTNFKI) more effectively than MYSTI-3, containing the anti-CD11b module. MYSTI-2 was also superior to MYSTI-3 in providing in vivo protection in acute toxicity model. Finally, MYSTI-2 was at least as effective as Infliximab in preventing collagen antibody-induced arthritis. This study demonstrates that a 33 kDa bispecific mini-antibody that specifically restricts TNF secretion by macrophages is efficient for amelioration of experimental arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.3AB0120-532RDOI Listing
June 2020

Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

Proc Natl Acad Sci U S A 2018 12 29;115(51):13051-13056. Epub 2018 Nov 29.

Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;

TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (T) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3 cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of T signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished T suppressive function in vitro. Consequently, T-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in T cells that could translate into protective functions in vivo, including treatment of autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1807499115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304938PMC
December 2018

Antibiotic treatment-induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia.

J Clin Invest 2018 08 16;128(8):3535-3545. Epub 2018 Jul 16.

Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Broad-spectrum antibiotics are widely used with patients in intensive care units (ICUs), many of whom develop hospital-acquired infections with Pseudomonas aeruginosa. Although preceding antimicrobial therapy is known as a major risk factor for P. aeruginosa-induced pneumonia, the underlying mechanisms remain incompletely understood. Here we demonstrate that depletion of the resident microbiota by broad-spectrum antibiotic treatment inhibited TLR-dependent production of a proliferation-inducing ligand (APRIL), resulting in a secondary IgA deficiency in the lung in mice and human ICU patients. Microbiota-dependent local IgA contributed to early antibacterial defense against P. aeruginosa. Consequently, P. aeruginosa-binding IgA purified from lamina propria culture or IgA hybridomas enhanced resistance of antibiotic-treated mice to P. aeruginosa infection after transnasal substitute. Our study provides a mechanistic explanation for the well-documented risk of P. aeruginosa infection following antimicrobial therapy, and we propose local administration of IgA as a novel prophylactic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI97065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063483PMC
August 2018

Hypoacylated LPS from Foodborne Pathogen Induces Moderate TLR4-Mediated Inflammatory Response in Murine Macrophages.

Front Cell Infect Microbiol 2018 27;8:58. Epub 2018 Feb 27.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Toll-like receptor 4 (TLR4) initiates immune response against Gram-negative bacteria upon specific recognition of lipid A moiety of lipopolysaccharide (LPS), the major component of their cell wall. Some natural differences between LPS variants in their ability to interact with TLR4 may lead to either insufficient activation that may not prevent bacterial growth, or excessive activation which may lead to septic shock. In this study we evaluated the biological activity of LPS isolated from pathogenic strain of , the most widespread bacterial cause of foodborne diarrhea in humans. With the help of hydrophobic chromatography and MALDI-TOF mass spectrometry we showed that LPS from a strain O2A consists of both hexaacyl and tetraacyl forms. Since such hypoacylation can result in a reduced immune response in humans, we assessed the activity of LPS from in mouse macrophages by measuring its capacity to activate TLR4-mediated proinflammatory cytokine and chemokine production, as well as NFκB-dependent reporter gene transcription. Our data support the hypothesis that LPS acylation correlates with its bioactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2018.00058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835049PMC
March 2019

VHH-Based Bispecific Antibodies Targeting Cytokine Production.

Front Immunol 2017 1;8:1073. Epub 2017 Sep 1.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Proinflammatory cytokines, such as TNF, IL-6, and IL-1, play pathogenic roles in multiple diseases and are attractive targets for biologic drugs. Because proinflammatory cytokines possess non-redundant protective and immunoregulatory functions, their systemic neutralization carries the potential for unwanted side effects. Therefore, next-generation anti-cytokine therapies would seek to selectively neutralize pathogenic cytokine signaling, leaving normal function intact. Fortunately, the biology of proinflammatory cytokines provides several such opportunities. Here, we discuss various applications of bispecific antibodies targeting cytokines with specific focus on selective TNF neutralization targeted directly to the surface of specific populations of monocytes and macrophages. These bispecific antibodies combine an anti-TNF VH with VHs or scFvs directed against abundant surface molecules on myeloid cells and serve to limit the bioavailability of TNF produced by these cells. Such reagents may become prototypes of a novel class of anti-cytokine biologics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585155PMC
September 2017

Structural Relationship of the Lipid A Acyl Groups to Activation of Murine Toll-Like Receptor 4 by Lipopolysaccharides from Pathogenic Strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa.

Front Immunol 2015 23;6:595. Epub 2015 Nov 23.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow , Russia ; Biological Faculty, Lomonosov Moscow State University , Moscow , Russia.

Toll-like receptor 4 (TLR4) is required for activation of innate immunity upon recognition of lipopolysaccharide (LPS) of Gram-negative bacteria. The ability of TLR4 to respond to a particular LPS species is important since insufficient activation may not prevent bacterial growth while excessive immune reaction may lead to immunopathology associated with sepsis. Here, we investigated the biological activity of LPS from Burkholderia mallei that causes glanders, and from the two well-known opportunistic pathogens Acinetobacter baumannii and Pseudomonas aeruginosa (causative agents of nosocomial infections). For each bacterial strain, R-form LPS preparations were purified by hydrophobic chromatography and the chemical structure of lipid A, an LPS structural component, was elucidated by HR-MALDI-TOF mass spectrometry. The biological activity of LPS samples was evaluated by their ability to induce production of proinflammatory cytokines, such as IL-6 and TNF, by bone marrow-derived macrophages. Our results demonstrate direct correlation between the biological activity of LPS from these pathogenic bacteria and the extent of their lipid A acylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2015.00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655328PMC
December 2015

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.

Infect Immun 2015 Sep 29;83(9):3612-23. Epub 2015 Jun 29.

Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland

Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00743-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534677PMC
September 2015

Novel mouse model to study T cell-dependent IgA induction in vivo.

J Immunol Methods 2015 Jun 17;421:54-60. Epub 2015 Mar 17.

German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin 10117, Germany; Belozersky Institute of Physico-Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow 119991, Russia. Electronic address:

Commensal microbiota at the mucosal surfaces controls multiple aspects of body homeostasis. Therefore, regulation of microflora composition by the host is crucial, and one of the mechanisms driving microbiota diversity is the production of large quantities of immunoglobulin A (IgA) at the mucosal surfaces. However, mechanisms of IgA induction in the gut are not completely understood. Here we further characterize a mouse model for studying T cell-dependent IgA production in the gut due to specific genetic ablation of LTβ in RORγt+ cells. Using in utero blockade of the mesenteric lymph node development, we showed that IgA induction in these mice occurs directly in the LP. Furthermore, T cell-dependent IgA inducing mechanism in these mice generates distinct IgA plasma cells producing commensal microflora-binding IgA antibodies. Thus, this model represents a unique in vivo tool for the analysis of T cell-dependent IgA plasma cell generation and their antibody specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jim.2015.03.001DOI Listing
June 2015

Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.

J Virol 2015 May 11;89(9):4748-59. Epub 2015 Feb 11.

Campell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany Department of Molecular Medicine II, Düsseldorf, Germany

Unlabelled: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.

Importance: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.02976-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403498PMC
May 2015

Commensal microbiota influence systemic autoimmune responses.

EMBO J 2015 Feb 19;34(4):466-74. Epub 2015 Jan 19.

Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium VIB Inflammation Research Center Ghent University, Ghent, Belgium

Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance against nuclear self-constituents remain largely unresolved. Using mice deficient in lymphotoxin and Hox11, we report that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies. Interestingly, we find this phenotype is not caused by a defect in central tolerance. Rather, cell-specific deletion and in vivo lymphotoxin blockade link these systemic autoimmune responses to the formation of gut-associated lymphoid tissue in the neonatal period of life. We further demonstrate antinuclear antibody production is influenced by the presence of commensal gut flora, in particular increased colonization with segmented filamentous bacteria, and IL-17 receptor signaling. Together, these data indicate that neonatal colonization of gut microbiota influences generalized autoimmunity in adult life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embj.201489966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331001PMC
February 2015

Cellular sources of pathogenic and protective TNF and experimental strategies based on utilization of TNF humanized mice.

Cytokine Growth Factor Rev 2014 Apr 24;25(2):115-23. Epub 2013 Dec 24.

German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin 10117, Germany; Belozersky Institute of Physico-Chemical Biology, and Biological Faculty, Lomonosov Moscow State University, Moscow 119991, Russia; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia. Electronic address:

Over the years, tumor necrosis factor (TNF) has been implicated in the pathogenesis of various inflammatory conditions and TNF antagonists are highly efficient in treatment of multiple autoimmune diseases. However, it has been shown that various cellular sources of TNF exhibit distinct and non-redundant functions that can be either deleterious or beneficial. This suggests that systemic TNF blockade, in addition to neutralization of pathogenic TNF, may abrogate its protective functions, resulting in adverse effects. Here we review the data on cellular sources of pathogenic and protective TNF and then discuss an experimental system based on humanized mice to study the role of cell-type specific TNF ablation during various disease models for development of cell-type specific TNF blockade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cytogfr.2013.12.005DOI Listing
April 2014

Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis.

Science 2013 Dec;342(6163):1243-6

German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin 10117, Germany.

Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1243364DOI Listing
December 2013

Pathogenic and protective functions of TNF in neuroinflammation are defined by its expression in T lymphocytes and myeloid cells.

J Immunol 2011 Dec 4;187(11):5660-70. Epub 2011 Nov 4.

German Rheumatism Research Center, a Leibniz Institute, Berlin 10117, Germany.

TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1100663DOI Listing
December 2011

Tumor necrosis factor, lymphotoxin and cancer.

IUBMB Life 2010 Apr;62(4):283-9

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Initially TNF has been discovered as an anti-tumor factor, but it is now considered as one of the universal effectors of innate signaling implicating its key role in host defense and inflammation. Other physiological functions of TNF are primarily linked to organization of lymphoid tissues. TNF can exert deleterious effects on the organism when its local or systemic concentrations exceed certain levels. This is the main reason for the failure of TNF therapy in oncology. Moreover, in certain experimental models TNF to TNFRp55 signaling axis was found to play a pro-tumorigenic role. On the other hand, anti-TNF therapy proved to be beneficial in rheumatic and other autoimmune diseases. Taking into consideration the pivotal function of TNF in the immune system, it is obvious that such therapy cannot be entirely free of adverse effects including suppression of host defense and, possibly, predisposition to lymphomas. Lymphotoxins alpha and beta are the two related cytokines that exist in distinct trimeric forms which can signal through TNFR I and TNFR II, as well LTbetaR receptors, depending on the composition of the trimer. These signals have important functions in the development and homeostasis of the immune system. Importantly, there is a recently uncovered link between the LTalpha/LTbeta to LTbetaR signaling axis and cancer. Here we review the current status of the field with the focus on one particular issue: are TNF and lymphotoxins intrinsically anti-cancer or pro-tumorigenic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/iub.309DOI Listing
April 2010