Recruitment Of Immunocompetent Cells Research Articles

Характеристика модели асцитной карциномы Эрлиха и перспективы ее применения в экспериментальной фармакологии ветеринарных препаратов

The article provides an overview of the most significant works of domestic and foreign authors devoted to the Ehrlich ascites carcinoma biological model. The analysis of the available literary sources showed that despite the long history of the existence of this model and its application in biomedical research, it has not yet become widespread in veterinary medicine. It should be noted that the Ehrlich ascites carcinoma model has a number of peculiarities that allow it to be used for the needs of veterinary medicine, in particular, experimental pharmacology at the stage of drug design and its preclinical testing. The high resistance of malignant cells and tumor survival in experimental animals, as well as the ease of its cultivation and relatively rapid tumor growth, make this model a convenient biological object for research. The effect of tumor cells on the body of the animal with a tumor leads to a change in a number of biochemical indicators of various tissues and organs, and a general toxic effect. In this case, an imbalance of the free-radical and antioxidant systems is observed, the body is exposed to oxidative stress. The immune system under the effect of Ehrlich ascites carcinoma also undergoes a number of changes. Thus, in response to the development of tumor-induced pathological processes, recruitment of immunocompetent cells and an antitumor immune response are observed, which at the same time is suppressed as carcinoma cells grow under the action of immunosuppressive physiologically active compounds produced by the tumor, escape of tumor cells from immunological surveillance and remodelling of immune cells in the tumor microenvironment. These processes lead to suppression of the immune system and as a result to the death of animals. These peculiarities make it possible to use the Ehrlich transplantable ascites carcinoma model for testing new veterinary drugs with potential antiblastoma, immunomodulatory, antitoxic properties, as well as medicinal formulations for restoring biochemical indicators and redox homeostasis under conditions of tumor-induced immunosuppression and chronic inflammatory process, and also to study the mechanisms of cell adaptation, including the immune system, under the action of carcinogenesis factors.

Muc2-дефицитные мыши как модель хронического воспаления

The article provides an overview of the most significant works of domestic and foreign authors devoted to the Ehrlich ascites carcinoma biological model. The analysis of the available literary sources showed that despite the long history of the existence of this model and its application in biomedical research, it has not yet become widespread in veterinary medicine. It should be noted that the Ehrlich ascites carcinoma model has a number of peculiarities that allow it to be used for the needs of veterinary medicine, in particular, experimental pharmacology at the stage of drug design and its preclinical testing. The high resistance of malignant cells and tumor survival in experimental animals, as well as the ease of its cultivation and relatively rapid tumor growth, make this model a convenient biological object for research. The effect of tumor cells on the body of the animal with a tumor leads to a change in a number of biochemical indicators of various tissues and organs, and a general toxic effect. In this case, an imbalance of the free-radical and antioxidant systems is observed, the body is exposed to oxidative stress. The immune system under the effect of Ehrlich ascites carcinoma also undergoes a number of changes. Thus, in response to the development of tumor-induced pathological processes, recruitment of immunocompetent cells and an antitumor immune response are observed, which at the same time is suppressed as carcinoma cells grow under the action of immunosuppressive physiologically active compounds produced by the tumor, escape of tumor cells from immunological surveillance and remodelling of immune cells in the tumor microenvironment. These processes lead to suppression of the immune system and as a result to the death of animals. These peculiarities make it possible to use the Ehrlich transplantable ascites carcinoma model for testing new veterinary drugs with potential antiblastoma, immunomodulatory, antitoxic properties, as well as medicinal formulations for restoring biochemical indicators and redox homeostasis under conditions of tumor-induced immunosuppression and chronic inflammatory process, and also to study the mechanisms of cell adaptation, including the immune system, under the action of carcinogenesis factors.

Neurons Are a Primary Driver of Inflammation via Release of HMGB1.

Recent data show that activation of nociceptive (sensory) nerves turns on localized inflammation within the innervated area in a retrograde manner (antidromically), even in the absence of tissue injury or molecular markers of foreign invaders. This neuroinflammatory process is activated and sustained by the release of neuronal products, such as neuropeptides, with the subsequent amplification via recruitment of immunocompetent cells, including macrophages and lymphocytes. High mobility group box 1 protein (HMGB1) is a highly conserved, well characterized damage-associated molecular pattern molecule expressed by many cells, including nociceptors and is a marker of inflammatory diseases. In this review, we summarize recent evidence showing that neuronal HMGB1 is required for the development of neuroinflammation, as knock out limited to neurons or its neutralization via antibodies ameliorate injury in models of nerve injury and of arthritis. Further, the results of study show that HMGB1 is actively released during neuronal depolarization and thus plays a previously unrecognized key etiologic role in the initiation and amplification of neuroinflammation. Direct targeting of HMGB1 is a promising approach for novel anti-inflammatory therapy.

Activation of human macrophages by human corneal allogen in vitro.

PurposeTo study distinct aspects of human monocyte-derived macrophage (MDM) activation by human corneal tissue as a possible initial stage in human corneal allograft rejection.MethodsHuman monocytes were isolated from peripheral blood mononuclear cells (PBMC) and differentiated into MDM. Human corneas with or without endothelium were fragmented using a standardized protocol. MDM were stimulated with human corneal fragments, corneal fragment supernatant, lipopolysaccharide (LPS) or interferon-gamma (IFNγ), and expression profiles for 34 cytokines were determined in MDM-conditioned media using a Luminex bead-based multiplex assay. Data from clinical aqueous humour samples served for comparison and validation. To assess cell recruitment, immunogenicity of corneal endothelial cells (CEC), monocyte survival and differentiation, we applied transwell migration assays, cell viability assays and fluorescence-activated cell sorting, respectively.ResultsCorneal fragments induced MDM to release distinct cytokines into the medium. Media thus conditioned in vitro by stimulated MDM shared cytokine patterns, namely MCP-1, MIP-1α and MIP-1β, with human aqueous humor samples obtained in human corneal allograft rejection. The presence of CEC in tissue fragments used for MDM stimulation attenuated the upregulation of distinct pro-inflammatory chemokines, like MCP-3 and IL-8, reduced the monocyte survival time, and diminished monocyte-to-macrophage differentiation induced by conditioned media. Distinct anti-inflammatory cytokines, like IL-4 and IL-13, were upregulated in the presence of corneal endothelium. Cornea fragment-stimulated MDMs induced recruitment of monocytes from a PBMC pool in a transwell migration model, modulated immune cell viability and promoted further immune cell recruitment and differentiation.ConclusionsHuman macrophages respond to allogenic corneal tissue and generate an inflammatory milieu. This can drive further recruitment of immunocompetent cells and modulate cell survival and differentiation of the cells recruited. These observations are consistent with the hypothesis that macrophages play a significant role in the initiation of corneal transplant rejection. Our data also indicate that distinct aspects of early human corneal transplant rejection can be modelled in vitro.

Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease.

The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand–receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer’s disease.

Regulation of Immune Cell Entry into the Central Nervous System

Regulation of Immune Cell Entry into the Central Nervous System

Intratumoral CC Chemokine Ligand 5 Overexpression Delays Tumor Growth and Increases Tumor Cell Infiltration

Chemokines participate in the antitumor immune response by regulating the movement and positioning of lymphocytes as well as effector functions and may thus be candidates for use in antitumor therapy. To test whether CCL5, a chemokine involved in the recruitment of a wide spectrum of immunocompetent cells, can control tumor growth, we forced its expression at mouse tumor sites. Tumor growth was reduced in mice with s.c. syngeneic CCL5-EL-4 compared with EL-4-injected mice, whereas both reduced tumor growth and incidence were observed in mice with OVA-expressing EG-7 transfected with CCL5 compared with EG-7-injected mice. Significant antitumor effects were observed soon after intratumoral injection of DNA plasmid coding for chimeric CCL5-Ig. Importantly, quantitative RT-PCR assays showed that the amount of CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. This effect was lost in mice deficient for T/B lymphocytes (RAG-2 knockout) or for CCR5 (CCR5 knockout). Together, these data demonstrate the antitumor activity of intratumoral CCL5 overexpression, due to its recruitment of immunocompetent cells, and the potential usefulness of chimeric CCL5-Ig DNA as an agent in cancer therapy.

TNFalpha-induced macrophage chemokine secretion is more dependent on NF-kappaB expression than lipopolysaccharides-induced macrophage chemokine secretion.

The transcription factor NF-kappaB is a pivotal intracellular regulator of many inflammatory responses and it has been proposed that it represents a potential therapeutic target. As chemokines are important for the progress of an inflammatory response by the recruitment of immuno-competent cells, the role NF-kappaB plays in TNFalpha- or lipopolysaccharides (LPS)-induced chemokine secretion by human monocyte-derived macrophages was examined. Secretion of the CXC chemokines IL-8, GROalpha and ENA-78, induced by TNFalpha, was significantly suppressed by inhibiting NF-kappaB, using overexpression of IkappaBalpha. However, when induced by LPS the expression of these chemokines was unaffected. In contrast, expression of the CC chemokines MIP-1alpha, MCP-1 and RANTES inducedby TNFalpha or LPS was significantly inhibited by the overexpression of IkappaBalpha. Therefore, there appear to be different mechanisms regulating CC and CXC chemokine secretion by macrophages, depending on the stimulus and that TNFalpha and LPS can use different signaling mechanisms in macrophages to regulate chemokine synthesis.

Recruitment of immunocompetent cells in a transplanted lung is not impaired despite incompletel reinnervation

It is not clear whether surgical intervention during lung transplantation which includes cutting vegetative nerves, lymphatic vessels and bronchial arteries, leads to alterations in immune responses. Thus, it was studied in an animal model whether an induced pulmonary immune reaction after syngenic lung transplantation was impaired without the influence of immunosuppression and rejection. The recruitment of leukocytes and the status of reinnervation was examined. Syngenic transplantation of the left lung was performed in Lewis rats without rejection and therefore without immunosuppressive therapy. In a subgroup of animals host and donor leukocytes were distinguished. An ovalbumin (OVA)-specific pulmonary immune response was induced four months after transplantation. Bronchoalveolar lavage (BAL) and interstitial leukocytes were examined using flow cytometry and immunocytology, comparing the right lung and the grafted left lung. Immunohistology was performed to detect nerve fibers on cryostat sections. An induced cellular inflammation was observed in the right host lung as well as in the grafted left lung. However, the CD4 T cell numbers in the BAL were increased in the left lung. Single donor-type leukocytes could still be observed four months after transplantation. A partial reinnervation was found. The recruitment of immune cells into the lung interstitium and bronchoalveolar space of grafted lungs is not impaired. The incomplete reinnervation has no influence on leukocyte recruitment.

Intercellular Adhesion Molecule-1 Expression in the Inner Ear of Rats following Secondary Immune Reaction in the Endolymphatic Sac

An immunological aetiology for inner ear diseases has long been proposed. The endolymphatic sac (ES) is the only immunoprivileged site in the inner ear with a resident population of immunocompetent cells. By keyhole limpet hemocyanin (KLH) challenge into the ES of systemically pre-immunized guinea pigs, we previously demonstrated an infiltration of inflammatory cells into the perilymphatic space of the cochlea. In order to understand the mechanisms involved in the recruitment of immunocompetent cells into the inner ear, and their relation to the development of endolymphatic hydrops (EH), we investigated the expression and time-kinetics of intercellular adhesion molecule 1 (ICAM-1) in the inner ear of systemically pre-immunized rats after antigen (KLH) challenge into the ES, its relation to cell infiltration in the cochlea and subsequent development of EH. By immunohistochemistry, strong ICAM-1 expression was detected in the spiral ligament, suprastrial region, spiral prominence, spiral modiolar veins, spiral collecting venules, surface membrane of the perilymphatic compartment, perilymphatic space and ES of immunized rats, but not of control rats. ICAM-1 expression was detected at 5-6 h, peaked at 10-15 h, and gradually reduced by 2 weeks. Cell infiltration into the cochlea started at 6-12 h and peaked at day one. By 6 h, 50% of challenged rats developed EH. This figure rose to 70% at 12 h, and then gradually reduced. However, immunoreactivity for KLH (antigen) was only detected in the ES. These results emphasize that the sac is the central immunological organ of the inner ear, and suggest that ICAM-1 may play a pivotal role in the aetiology of immune-mediated inner ear diseases through the recruitment of immunocompetent cells into the inner ear and subsequent development of EH.

Morphological fate and sequelae of human atherosclerosis: Evaluation of immune mechanisms in atherogenesis through immunohistological and ultrastructural analysis

Modern techniques of investigation have revealed several similarities between atherosclerosis and chronic inflammation, and that immune mechanisms seem to operate in the incipient and subsequent phases of atherosclerosis. In the present study, the fate and morphogenesis of human atherosclerosis was considered, and the immune aspects of atherogenesis were analysed, using fresh human aorta obtained from autopsy cases. One of the earliest changes in the grossly normal, lesion-prone area of the aorta from young cases (prelesional changes) was the infiltration of blood-borne T lymphocytes and monocytes/macrophages beneath the endothelium. Cell-populated lesions abounding in T lymphocytes and macrophages, often bearing signs of activation, with or without cytoplasmic lipids were found in the fatty streaks, cap and shoulder regions of more advanced atheromatous plaques. The ultrastructural observation of cell-rich areas suggested that cognate cell-to-cell interaction plays a pivotal role in atherosclerosis, as well as cytokine-mediated paracrine or autocrine mechanisms. From an immunological perspective, the areas where both cell types are especially numerous and in close proximity are considered to be the areas with an index of disease activeness or progressiveness. Also, the present authors show evidence of clonal expansion of T lymphocytes. It is most likely that the increase of intimal cells was caused by the recruitment of immunocompetent cells from the blood-stream into the intima and by the clonal expansion of T lymphocytes. In addition, dead or dying cells were identified in areas of different stages ranging from prelesional areas to atheromatous plaques. Thus, the initiation and progression of human atherosclerosis appears to be punctuated by brief episodes of immunological events related to cell infiltration, proliferation and death.

The hemolytic-uremic syndrome in siblings: A prospective survey

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The Effect of Antigen Competition on Both the Primary and Secondary Immune Capacity in Mice

Abstract The primary and secondary immune capacity in mice was studied during antigen competition. Three antigens were used: sheep erythrocytes (SRBC), rat erythrocytes (RRBC), and human γ globulin (HGG). The results of these studies demonstrate the following. 1) In both competition systems, SRBC prior to RRBC or HGG, a marked suppression of the secondary immune capacity corresponds to a suppressed primary agglutinin response to the second antigen. 2) The degree of suppression of the secondary agglutinin capacity can be reduced by increasing the dose of the secondary challenge, which suggests that in the secondary immune response there may be participation of both reacting sensitized and uncommitted immunocompetent cells. 3) The entire level of the immune suppression during competition is dependent upon the dose of the first antigen. Further, the experimental results do not support the possibility that the competition can be attributed to either an increased or a decreased rate of antigen elimination. 4) Antigen competition cannot be attributed to a deficiency in the extracellular localization of antigen in reticular cells of splenic germinal centers. 5) The deficiency in a competition system is attributed to an impairment which ultimately affects the immunocompetent cell or unit. One reflection of this lesion on the antigen-sensitive unit is expressed in the competition between SRBC and HGG. A detectable increase in the latent phase of the primary HGG agglutinin response occurs when the HGG is injected at 1 or 3 days after SRBC. The recruitment of immunocompetent cells, and thus priming, is limited by the decreased level of preexisting tissue-associated and/or free antigen. On the other hand, in a condidition where there was limited immune progenitor cell recruitment to RRBC as a result of subsequent competition with SRBC the result was antigen-driven depletion of the existing sensitized immune cell compartment.