Immunosuppressive effect of cyclosporin A on insect humoral immune response

Cyclosporin A suppressed humoral immune response of Galleria mellonella larvae. Insects were immunized with LPS Pseudomonas aeruginosa and then injected with cyclosporin A. Immunosuppressive effects were expressed both, in larvae treated with cyclosporin A at the initial phase of immune response and at the effector phase of antibacterial immunity. Cyclosporin A moderately decreased lysozyme activity and significantly decreased antibacterial activity peptides against Escherichia coli. Immunosuppressive effects of cyclosporin A were observed after immunoblotting with antibodies anti-G. mellonella lysozyme. Tricine SDS/PAGE shown that synthesis of antibacterial peptides of larvae treated with cyclosporin A was considerably inhibited. Insects of impaired immune response by cyclosporin A action lost protective immunity to insect bacterial pathogen P. aeruginosa.     

Immunosuppressive analogues of hexapeptide Tyr-Val-Pro-Leu-Phe-Pro, an immune system stimulant

It was found that substitution of Val2 and/or Leu4 residue in a hexapeptide Tyr-Val-Pro-Leu-Phe-Pro (I) transforms this peptide immunostimulant into analogues possessing the immunosuppressor activity--Tyr-Gly-Pro-Leu-Phe-Pro (II), Tyr-Val-Pro-Gly-Phe-Pro (III), and Tyr-Gly-Pro-Gly-Phe-Pro (IV). Biological effects of peptides I-IV were studied using PFC (plaque forming cell) test, GvH (graft vs host) reaction in mice, and ARFC (autologous rosette forming cell) test. The strongest immunosuppressor activity was observed for III--in this case the immunosuppressor effect was observed even in PFC test in vitro in which II and IV showed no such activity. These results suggest that simultaneous presence of both Val2 and Leu4 residues is necessary for the generation of immunostimulation. The CD study of I-IV in methanol solution suggests that the conformational preferences of II-IV change towards stabilization of the beta-turn structure, whereas in the case of I the gamma-turn on Leu4 and cis' orientation of the Pro3 carbonyl (distorted beta-turn of type I) was found as the preferred conformation. Competition in biological effects observed for I and III in PFC in vitro test suggests that these analogues may interact with the same cellular receptor. Drastic changes in the activity which accompany changes in the sequence are discussed in the terms of our stereochemical hypothesis.     

Tumor immune escape mechanisms: impact of the neuroendocrine system

Tumor cells act upon, and react to both their proximate and more distant environment, the mechanisms by which this is achieved being both autocrine and paracrine in nature. This interaction, however, takes place not only between adjacent malignant cells, but also non-malignant cells such as those of the immune system, the latter also partaking in the modeling of the tumor environment. Although tumor cells descend from normal tissue cells and thus bear in classical immunological terms ‘self signals’, it is evident that the immune system is able to recognize tumor cells as a harassment for the body and in consequence tries to eliminate these cells. On the counterpart, tumor cells acquire various characteristics which allow them to evade this immunological surveillance, and have been collectively coined with the term “tumor escape mechanisms”. This review will describe and summarize current understanding of tumor escape strategies, and also more closely elaborate on the modulatory role of the neuroendocrine system in the immune system–tumor cell interaction.     

Modeling regulation mechanisms in the immune system

We develop a mathematical framework for modeling regulatory mechanisms in the immune system. The model describes dynamics of key components of the immune network within two compartments: lymph node and tissue. We demonstrate using numerical simulations that our system can eliminate virus-infected cells, which are characterized by a tendency to increase without control (in absence of an immune response), while tolerating normal cells, which are characterized by a tendency to approach a stable equilibrium population. We experiment with different combinations of T cell reactivities that lead to effective systems and conclude that slightly self-reactive T cells can exist within the immune system and are controlled by regulatory cells. We observe that CD8+ T cell dynamics has two phases. In the first phase, CD8+ cells remain sequestered within the lymph node during a period of proliferation. In the second phase, the CD8+ population emigrates to the tissue and destroys its target population. We also conclude that a self-tolerant system must have a mechanism of central tolerance to ensure that self-reactive T cells are not too self-reactive. Furthermore, the effectiveness of a system depends on a balance between the reactivities of the effector and regulatory T cell populations, where the effectors are slightly more reactive than the regulatory cells.     

HERVd: database of human endogenous retroviruses

The human endogenous retroviruses database (HERVd) is maintained at the Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, and is accessible via the World Wide Web at http://herv.img.cas.cz. The HERVd provides complex information on and analysis of retroviral elements found in the human genome. It can be used for searches of individual HERV families, identification of HERV parts, graphical output of HERV structures, comparison of HERVs and identification of retrovirus integration sites.     

Budding of retroviruses utilizing divergent L domains requires nucleocapsid

We recently reported that human immunodeficiency virus type 1 (HIV-1) carrying PTAP and LYPX(n)L L domains ceased budding when the nucleocapsid (NC) domain was mutated, suggesting a role for NC in HIV-1 release. Here we investigated whether NC involvement in virus release is a property specific to HIV-1 or a general requirement of retroviruses. Specifically, we examined a possible role for NC in the budding of retroviruses relying on divergent L domains and structurally homologous NC domains that harbor diverse protein sequences. We found that NC is critical for the release of viruses utilizing the PTAP motif whether it functions within its native Gag in simian immunodeficiency virus cpzGAB2 (SIVcpzGAB2) or SIVsmmE543 or when it is transplanted into the heterologous Gag protein of equine infectious anemia virus (EIAV). In both cases, virus release was severely diminished even though NC mutant Gag proteins retained the ability to assemble spherical particles. Moreover, budding-defective NC mutants, which displayed particles tethered to the plasma membrane, were triggered to release virus when access to the cell endocytic sorting complex required for transport pathway was restored (i.e., in trans expression of Nedd4.2s). We also examined the role of NC in the budding of EIAV, a retrovirus relying exclusively on the (L)YPX(n)L-type L domain. We found that EIAV late budding defects were rescued by overexpression of the isolated Alix Bro1 domain (Bro1). Bro1-mediated rescue of EIAV release required the wild-type NC. EIAV NC mutants lost interactions with Bro1 and failed to produce viruses despite retaining the ability to self-assemble. Together, our studies establish a role for NC in the budding of retroviruses harboring divergent L domains and evolutionarily diverse NC sequences, suggesting the utilization of a common conserved mechanism and/or cellular factor rather than a specific motif.     

The effect of ceramic fibers on the immune system

Male Sprague-Dawley rats were treated by intratracheal instillation with 1 mg/animal of refractory ceramic fibers. Intratracheal exposure to ceramic fibers led to significant changes of immune response. Results of proliferative activity of spleen lymphocytes showed significantly decreased proliferative activity of T-cells in response to mitogens phytohemagglutinin and concanavalin A in animals given ceramic fibers in comparison with control rats. Similarly, T-dependent B-cell response to pokeweed mitogen was significantly suppressed. Spontaneous proliferative activity of lymphocytes in non-stimulated spleen cell cultures did not differ in exposed and control rats. No significant changes were found among groups in percentage of phagocytic blood polymorphonuclear leukocytes and percentage of cells with respiratory burst.     

Endogenous retroviruses and the human germline

The human genome is rife with the proviral remains of many ancient retroviruses. The past year has seen significant progress in understanding the structure, distribution and potential function of many of these elements. Although hypotheses concerning the potential effects of these elements are common, however, incisive experiments to test any functions remain much less so.     

HDACi: molecular mechanisms and therapeutic implications in the innate immune system

Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation and apoptosis of tumor cells. In addition, many advances have been made in understanding the immunoregulation of Toll-like receptors, NOD-like receptors and interferons that have recently generated new momentum for the study of HDACi in immunity as a whole, and in the regulation of these innate signaling pathways specifically. HDACi have shown promise as new anti-inflammatory and immunosuppressant agents. They have also demonstrated great potency and relative selectivity in various human/animal models of inflammatory diseases. This review focuses on recent progress and the current state of HDACi knowledge, as well as the molecular mechanisms and therapeutic potential of HDACi for the treatment of inflammatory diseases and cancers.     

Study of the effect of Edikron on the immune system

Using the nucleolar test, the authors investigated the effects of the new Czechoslovak cytostatic agent Edikron (gamma, gamma-bis[4-ethylphenyl]-alpha, beta-dibromisocrotonic acid] on Wistar rats. The test showed that Edikron, administered perorally in the dose of 100 mg/kg BW per day for 5 days, affects neither the number of leukocytes nor the proteosynthetic activity of peripheral lymphocytes. The serum levels of Edikron, assessed with the aid of HPLC method 90 min after its last administration, averaged 14.03 +/- 1.63 micrograms/ml serum. Histological examination of the spleen, lymph nodes and thymus of the experimental and control groups also failed to detect any changes. However, the administration of Edikron elicited a statistically significant rise of erythrocytes in the experimental group, but the reason for that has not so far been ascertained.     

Molecular characterization of the immune system: emergence of proteins,processes, and domains

Many genes and proteins are required to carry out the processes of innate and adaptive immunity. For many studies, including systems biology, it is necessary to have a clear and comprehensive definition of the immune system, including the genes and proteins that take part in immunological processes. We have identified and cataloged a large portion of the human immunology-related genes, which we call the essential immunome. The 847 identified genes and proteins were annotated, and their chromosomal localizations were compared to the mouse genome. Relation to disease was also taken into account. We identified numerous pseudogenes, many of which are expressed, and found two putative new genes. We also carried out an evolutionary analysis of immune processes based on gene orthologs to gain an overview of the evolutionary past and molecular present of the human immune system. A list of genes and proteins were compiled. A comprehensive characterization of the member genes and proteins, including the corresponding pseudogenes is presented. Immunome genes were found to have three types of emergence in independent studies of their ontologies, domains, and functions. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Immunoelectron microscopy of human retroviruses

The ultrastructural detection and identification of human retroviruses--HTLV (human T-cell lymphotropic virus) and HIV (human immunodeficiency virus)--have become an everyday task for pathologists and virologists as well as for cell and molecular biologists. The development of better and conventionally available immunocytochemical techniques, such as pre- or postembedding immunocytochemical methods, cryofixation-variants and low temperature embeddings, have made it possible to use them in this field. With the help of these methods the structural proteins of HTLV-I and HIV have been identified in infected cells. The virus assembly at the cell membrane has also been described in detail. Using these methods the incorporation of human transplantation antigens into the envelope of these viruses can be followed. Future studies should establish the pathological significance of this process.     

Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system

Intestinal mucosa is constantly exposed to environmental AGS: Activation of lamina propria (LP) T cells by luminal Ags may lead to the production of inflammatory cytokines and subsequent mucosal inflammation and tissue damage. However, in normal circumstances, LP T cells do not respond to antigenic stimulation. The mechanisms of this unresponsiveness in healthy subjects are not fully understood. In this study, we found by in vivo analysis that, except for T cells in lymph nodules of the mucosa, 15% of LP T cells underwent apoptosis in normal individuals. In contrast, there was a marked reduction in apoptosis of LP T cells in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and those with specific colitis. Our findings suggest that apoptosis might be a mechanism that turns off mucosal T cell responses to environmental Ags in healthy subjects, and resistance to apoptosis could be an important cause of mucosal immune dysregulation and tissue inflammation in colitis.     

Regulatory T cells and mechanisms of immune system control

The immune system evolved to protect the host against the attack of foreign, potentially pathogenic, microorganisms. It does so by recognizing antigens expressed by those microorganisms and mounting an immune response against all cells expressing them, with the ultimate aim of their elimination. Various mechanisms have been reported to control and regulate the immune system to prevent or minimize reactivity to self-antigens or an overexuberant response to a pathogen, both of which can result in damage to the host. Deletion of autoreactive cells during T- and B-cell development allows the immune system to be tolerant of most self-antigens. Peripheral tolerance to self was suggested several years ago to result from the induction of anergy in peripheral self-reactive lymphocytes. More recently, however, it has become clear that avoidance of damage to the host is also achieved by active suppression mediated by regulatory T (T(reg)) cell populations. We discuss here the varied mechanisms used by T(reg) cells to suppress the immune system.     

The effect of rivanol on the immune globulins of human colostrum

The behavior of immune globulins of colostrum was investigated during fractionation using rivanol and ethanol. It was found that, in contrast with serum immune globulins, a part of these proteins present in colostrum is precipitable with rivanol. It was also observed that the fraction of colostrum immune globulins which yields a heavy precipitation line in the cathode region of the immunoelectrophoreogram precipitated with normal antihuman serum, represents a heterogeneous mixture of proteins, from the point of view both of their electrophoretic mobility and of interaction with rivanol and solubility in dilute ethanol. We are dealing here with at least three types of protein molecules which all display identical antigen relationship to serum γ-and β_2A-globulins. No differences were found between serum β_2M-globulin and the colostrum protein of similar properties.     

Immunosuppressive effect of the decimeter-band electromagnetic field

The action of ultrahigh frequency (UHF) waves on the projection zone of the adrenal glands has been found to suppress both primary and secondary immune response, which is probably due to an increase in the glucocorticoid function of the adrenal cortex. The synthesis of nonspecific immunoglobulins has proved to be more resistant to the suppressive action of UHF than the synthesis of specific immunoglobulins.