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1.
Nat Immunol ; 16(8): 819-828, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26147686

RESUMEN

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.


Asunto(s)
Inflamación/inmunología , Grasa Intraabdominal/inmunología , Linfocitos/inmunología , Tejido Linfoide/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/inmunología , Quimiocina CXCL13/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Inflamación/genética , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Linfocitos/metabolismo , Tejido Linfoide/citología , Tejido Linfoide/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células del Estroma/inmunología , Células del Estroma/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
2.
Biochemistry (Mosc) ; 89(5): 853-861, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38880646

RESUMEN

Tumor necrosis factor (TNF) is one of many cytokines - protein molecules responsible for communication between the cells of immune system. TNF was discovered and given its grand name because of its striking antitumor effects in experimental systems, but its main physiological functions in the context of whole organism turned out to be completely unrelated to protection against tumors. This short review discusses "man-made" mouse models generated by early genome-editing technologies, which enabled us to establish true functions of TNF in health and certain diseases as well as to unravel potential strategies for improving therapy of TNF-dependent diseases.


Asunto(s)
Factor de Necrosis Tumoral alfa , Animales , Humanos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Edición Génica/métodos , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/terapia
3.
Biochemistry (Mosc) ; 87(7): 590-604, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36154880

RESUMEN

Peptides are widely used for the diagnostics, prevention, and therapy of certain human diseases. How useful can they be for the disease caused by the SARS-CoV-2 coronavirus? In this review, we discuss the possibility of using synthetic and recombinant peptides and polypeptides for prevention of COVID-19 via blocking the interaction between the virus and its main receptor ACE2, as well as components of antiviral vaccines, in particular, against new emerging virus variants.


Asunto(s)
COVID-19 , Enzima Convertidora de Angiotensina 2 , Antivirales/uso terapéutico , Humanos , Péptidos/uso terapéutico , SARS-CoV-2
4.
Immunity ; 32(3): 403-13, 2010 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-20226692

RESUMEN

Epithelial cells provide the first line of defense against mucosal pathogens; however, their coordination with innate and adaptive immune cells is not well understood. Using mice with conditional gene deficiencies, we found that lymphotoxin (LT) from innate cells expressing transcription factor RORgammat, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LTbetaR signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LTbetaR signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LTbetaR signaling in intestinal epithelial cells was required for recruitment of neutrophils to the infection site early during infection via production of CXCL1 and CXCL2 chemokines. These results support a model wherein LT from RORgammat(+) cells orchestrates the innate immune response against mucosal microbial infection.


Asunto(s)
Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Células Epiteliales/inmunología , Inmunidad Innata , Mucosa Intestinal/inmunología , Receptor beta de Linfotoxina/inmunología , Transducción de Señal , Inmunidad Adaptativa , Animales , Células de la Médula Ósea/inmunología , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Receptor beta de Linfotoxina/deficiencia , Receptor beta de Linfotoxina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
5.
Proc Natl Acad Sci U S A ; 113(11): 3006-11, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26936954

RESUMEN

Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.


Asunto(s)
Anticuerpos Biespecíficos/inmunología , Antígenos de Diferenciación/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Macrófagos Peritoneales/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Sustitución de Aminoácidos , Animales , Anticuerpos Biespecíficos/genética , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Especificidad de Anticuerpos , Reacciones Antígeno-Anticuerpo , Antígenos de Diferenciación/genética , Antígenos de Superficie/inmunología , Camelus/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Galactosamina/toxicidad , Genes Sintéticos , Humanos , Células L , Macrófagos Peritoneales/inmunología , Ratones , Mutación , Distribución Aleatoria , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Anticuerpos de Cadena Única/genética , Anticuerpos de Cadena Única/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
6.
Cytokine ; 101: 33-38, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-27624866

RESUMEN

Cytokines are involved in a wide range of functions shaping the normal immune response, yet inflammatory changes in the immune system due to dysregulated cytokine signaling may lead to the induction of autoimmunity. Cytokine inhibitors have revolutionized the treatment of many autoimmune diseases in recent years. Systemic cytokine ablation, however, is often associated with the development of adverse side effects and some patients simply do not respond to therapy. TNF, IL-1 and IL-6 are the best characterized proinflammatory cytokines considered as the main therapeutic targets for the treatment of several autoimmune and inflammatory diseases. But can anti-cytokine therapy become more selective and thus more efficient? This mini-review discusses several recently emerging paradigms and summarizes current experimental attempts to validate them in mouse studies.


Asunto(s)
Autoinmunidad/inmunología , Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Inmunoterapia , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Citocinas/inmunología , Inflamación/terapia , Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Ratones , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
7.
Blood ; 116(18): 3456-64, 2010 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-20634375

RESUMEN

Secondary lymphoid organs provide a unique microenvironment for generation of immune responses. Using a cell type-specific conditional knockout approach, we have dissected contributions of tumor necrosis factor (TNF) produced by B cells (B-TNF) or T cells (T-TNF) to the genesis and homeostatic organization of secondary lymphoid organs. In spleen, lymph nodes and Peyer patches, the cellular source of TNF, and its molecular form (soluble versus membrane-bound) appeared distinct. In spleen, in addition to major B-TNF signal, a complementary T-TNF signal contributed to the microstructure. In contrast, B-TNF predominantly controlled the development of follicular dendritic cells and B-cell follicles in Peyer patches. In lymph nodes, cooperation between TNF expressed by B and T cells was necessary for the maintenance of microarchitecture and for generation of an efficient humoral immune response. Unexpectedly, soluble but not membrane TNF expressed by B cells was essential for the organization of the secondary lymphoid organs. Thus, the maintenance of each type of secondary lymphoid organ is orchestrated by distinct contributions of membrane-bound and soluble TNF produced by B and T lymphocytes.


Asunto(s)
Linfocitos B/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos Agregados/inmunología , Bazo/inmunología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Regulación de la Expresión Génica , Inmunidad Humoral , Ganglios Linfáticos/citología , Ganglios Linfáticos/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ganglios Linfáticos Agregados/citología , Bazo/citología , Bazo/ultraestructura , Factor de Necrosis Tumoral alfa/genética
8.
Plant Biotechnol J ; 9(1): 22-31, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20444206

RESUMEN

Tumour necrosis factor (TNF) is a major pro-inflammatory cytokine involved in multiple inflammatory diseases. The detrimental activity of TNF can be blocked by various antagonists, and commercial therapeutics based upon this principle have been approved for treatment of diseases including rheumatoid arthritis, Crohn's disease and psoriasis. In a search for new, improved anti-inflammatory therapeutics we have designed a single-domain monoclonal antibody (V(H) H), which recognizes TNF. The antibody component (TNF-V(H) H) is based upon an anti-human TNF Camelidae heavy-chain monoclonal antibody, which was linked to an elastin-like polypeptide (ELP). We demonstrate that ELP fusion to the TNF-V(H) H enhances accumulation of the fusion protein during biomanufacturing in transgenic tobacco plants. With this study, we show for the first time that this plant-derived anti-human TNF-V(H) H antibody was biologically active in vivo. Therefore, therapeutic application of TNF-V(H) H-ELP fusion protein was tested in humanized TNF mice and was shown to be effective in preventing death caused by septic shock. The in vivo persistence of the ELPylated antibody was ∼24 fold longer than that of non-ELPylated TNF-V(H) H.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Choque Séptico/prevención & control , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Modelos Animales de Enfermedad , Elastina , Escherichia coli , Galactosa , Expresión Génica , Humanos , Células L , Lipopolisacáridos , Ratones , Péptidos , Plantas Modificadas Genéticamente , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/aislamiento & purificación , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Nicotiana/genética , Factor de Necrosis Tumoral alfa/inmunología
9.
Cytokine Growth Factor Rev ; 19(3-4): 231-44, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18502680

RESUMEN

TNF is an exciting cytokine which has helped to establish many paradigms in immunology. Although TNF itself has found only very limited use in the clinic, anti-cytokine therapy, which targets this single molecule, has enjoyed astounding success in treatment of a growing number of human diseases. However, since TNF mediates unique physiologic functions, in particular those related to host defense, TNF blockade may result in unwanted consequences. Much of our understanding about TNF intrinsic functions in the body, as well as about consequences of its overexpression and ablation, is based on studying phenotypes of various genetically engineered mice. Here we review mouse studies aimed at understanding TNF physiologic functions using transgenic and knockout models, and we discuss additional mouse models that may be helpful in the future.


Asunto(s)
Factor de Necrosis Tumoral alfa/fisiología , Animales , Enfermedades Autoinmunes/metabolismo , Marcación de Gen , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Animales , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética
10.
Eur J Immunol ; 39(10): 2906-15, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19735075

RESUMEN

TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.


Asunto(s)
Atrofia/genética , Expresión Génica/genética , Linfotoxina-alfa/genética , Linfotoxina beta/genética , Timo/patología , Factor de Necrosis Tumoral alfa/genética , Animales , Apoptosis/genética , Apoptosis/inmunología , Atrofia/patología , Trasplante de Médula Ósea , Recuento de Células , Proliferación Celular , Células Epiteliales/patología , Dosificación de Gen/genética , Humanos , Queratina-8/metabolismo , Receptor beta de Linfotoxina/genética , Linfotoxina-alfa/metabolismo , Linfotoxina beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Células Madre/patología , Subgrupos de Linfocitos T/patología , Linfocitos T/patología , Timo/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
12.
Semin Arthritis Rheum ; 49(3S): S39-S42, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31779851

RESUMEN

In spite of successful therapeutic neutralization of proinflammatory cytokines in several autoimmune diseases, such therapy is not entirely free of side effects. The main reason relates to the fact that cytokine signaling may have protective components that need to be spared. Several approaches to achieve a less damaging cytokine inhibition are being explored. In our experimental studies we are using bispecific reagents based on VHH-modules from the heavy-chain-only antibodies to limit bioavailability of TNF and IL-6 produced by myeloid cells. After evaluation of their properties in vitro and in vivo we argue that these types of reagents may have an advantage over systemic blockers.


Asunto(s)
Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Citocinas/metabolismo , Células Mieloides/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Disponibilidad Biológica , Humanos
13.
J Leukoc Biol ; 102(3): 783-790, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28546502

RESUMEN

Cytokine neutralization is successfully used for treatment of various autoimmune diseases and chronic inflammatory conditions. The complex biology of the two well-characterized proinflammatory cytokines TNF and IL-6 implicates unavoidable consequences when it comes to their global blockade. Because systemic cytokine ablation may result in unwanted side effects, efforts have been made to develop more specific cytokine inhibitors, which would spare the protective immunoregulatory functions of a given cytokine. In this article, we review current research and summarize new strategies for improved anti-TNF and anti-IL-6 biologics, which specifically target only selected parts of the signaling cascades mediated by these ligands.


Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Interleucina-6/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Humanos
15.
J Biotechnol ; 142(2): 170-8, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19439388

RESUMEN

Tumor necrosis factor (TNF) plays an important role in chronic inflammatory disorders, such as Rheumatoid Arthritis and Crohn's disease. Recently, monoclonal Camelidae variable heavy-chain domain-only antibodies (V(H)H) were developed to antagonize the action of human TNF (hTNF). Here, we show that hTNF-V(H)H does not interfere with hTNF trimerization, but competes with hTNF for hTNF-receptor binding. Moreover, we describe posttranslational dimerization and multimerization of hTNF-V(H)H molecules in vitro catalyzed by microbial transglutaminases (MTG). The ribonuclease S-tag-peptide was shown to act as a peptidyl substrate in covalent protein cross-linking reactions catalyzed by MTG from Streptomyces mobaraensis. The S-tag sequence was C-terminally fused to the hTNF-V(H)H and the fusion protein was expressed and purified from Escherichia coli culture supernatants. hTNF-V(H)H-S-tag fusion proteins were efficiently dimerized and multimerized by MTG whereas hTNF-V(H)H was not susceptible to protein cross-linking. Cell cytotoxicity assays, using hTNF as apoptosis inducing cytokine, revealed that dimerized and multimerized hTNF-V(H)H proteins were much more active than the monomeric hTNF-V(H)H. We hypothesize that improved inhibition by dimeric and multimeric single chain hTNF-V(H)H proteins is caused by avidity effects.


Asunto(s)
Cadenas Pesadas de Inmunoglobulina/metabolismo , Multimerización de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Transglutaminasas/metabolismo , Factor de Necrosis Tumoral alfa , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Pruebas Inmunológicas de Citotoxicidad , Escherichia coli/genética , Etanercept , Humanos , Inmunoglobulina G/metabolismo , Cadenas Pesadas de Inmunoglobulina/genética , Unión Proteica , Receptores del Factor de Necrosis Tumoral/metabolismo , Rumiantes/inmunología , Espectrometría de Fluorescencia , Streptomyces/enzimología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología
16.
Immunity ; 22(1): 93-104, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15664162

RESUMEN

Tumor necrosis factor (TNF, TNFalpha) is implicated in various pathophysiological processes and can be either protective, as in host defense, or deleterious, as in autoimmunity or toxic shock. To uncover the in vivo functions of TNF produced by different cell types, we generated mice with TNF ablation targeted to various leukocyte subsets. Systemic TNF in response to lipopolysaccharide was produced mainly by macrophages and neutrophils. This source of TNF was indispensable for resistance to an intracellular pathogen, Listeria, whereas T-cell-derived TNF was important for protection against high bacterial load. Additionally, both T-cell-derived TNF and macrophage-derived TNF had critical and nonredundant functions in the promotion of autoimmune hepatitis. Our data suggest that T-cell-specific TNF ablation may provide a therapeutic advantage over systemic blockade.


Asunto(s)
Macrófagos/metabolismo , Neutrófilos/metabolismo , Linfocitos T/metabolismo , Factores de Necrosis Tumoral/fisiología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Comunicación Celular , Cruzamientos Genéticos , Eliminación de Gen , Vectores Genéticos , Listeria/patogenicidad , Hígado/inmunología , Hígado/patología , Ratones , Ratones Transgénicos , Sensibilidad y Especificidad , Linfocitos T/inmunología , Factores de Necrosis Tumoral/inmunología , Factores de Necrosis Tumoral/metabolismo
17.
Eur J Immunol ; 35(5): 1592-600, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15832287

RESUMEN

We generated a novel tumor necrosis factor (TNF) null mutation using Cre-loxP technology. Mice homozygous for this mutation differ from their "conventional" counterparts; in particular, they completely lack Peyer's patches (PP) but retain all lymph nodes. Our analysis of these novel TNF-knockout mice supports the previously disputed notion of the involvement of TNF-TNFR1 signaling in PP organogenesis. Availability of TNF-knockout strains both with and without PP enables more definitive studies concerning the roles of TNF and PP in various immune functions and disease conditions. Here, we report that systemic ablation of TNF, but not the presence of PP per se, is critical for protection against intestinal Listeria infection in mice.


Asunto(s)
Ratones Noqueados/inmunología , Ganglios Linfáticos Agregados/inmunología , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética , Animales , Citometría de Flujo , Hematopoyesis/inmunología , Inmunohistoquímica , Listeriosis/inmunología , Ratones , Ratones Noqueados/genética , Mutación , Ganglios Linfáticos Agregados/patología , Factor de Necrosis Tumoral alfa/inmunología
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