Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response

The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1β, TNF-α and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden-1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri-hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood–brain barrier permeability.     

Antitumour immune responses

The role of the immune system in combating tumour progression has been studied extensively. The two branches of the immune response - humoral and cell-mediated - act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells. The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells. Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance. Attempts are being made to trigger the immune system into an early and efficient response against malignant cells, and various therapeutic modalities are being developed to enhance the strength of the immune response against tumours. This review aims to elucidate the tumoricidal role of various components of the immune system, including macrophages, lymphocytes, dendritic cells and complement.     

CD95/CD95 ligand-mediated counterattack does not block T cell cytotoxicity

Expression of CD95 ligand on parenchymal, epithelial, or tumor cells has been suggested to downregulate the immune response and to control lymphocyte activation. Suppression might be mediated by induction of apoptosis or by inhibition of Ca(2+) channels upon CD95 triggering. We, therefore, aimed to employ this model to modify the immune response to an antigen presented to cytotoxic T cells by antigen-presenting MC57 cells. This model would be very useful to specifically downregulate the immune response to autoantigens in autoimmune situations. However, cytotoxic T cell lines tested in the present study were resistant to CD95 ligand expression on antigen-presenting MC57 cells. In addition, coincubation of the lymphocytes with antigen presenting cells failed to block cytotoxicity mediated by the T lymphocytes. We, therefore, conclude that single expression of CD95 ligand on antigen-presenting cells is insufficient to specifically downregulate an immune response by CD8(+-)triggered immune response.     

Direct in vitro evidence for different susceptibilities to 4-hydroperoxycyclophosphamide of antigen-primed T cells regulating humoral and cell-mediated immune responses to sheep erythrocytes: a possible explanation for the inverse action of cyclophosphamide on humoral and cell-mediated immune responses

Suppressor T cells of humoral immune responses, effector T cells mediating DTH, suppressor T cells of DTH, and helper T cells of humoral immune responses, all with specificity to SRBC, were produced in mice. The biologic activity was tested in adoptive transfer experiments. In vitro treatment with different doses of 4-hydroperoxycyclophosphamide (4-HPCy) yielded the result that the various activities tested were not uniformly sensitive to the action of this drug: Suppressor T cells of humoral immune responses and effector T cells mediating DTH were resistant to doses of 4-HPCy that eliminated the activities of suppressor T cells of DTH and helper cells of the humoral immune response. These findings help to explain the various effects cyclophosphamide has on the in vivo immune response and may help to form a basis for the rational manipulation of the immune response by drugs that selectively affect different subgroups of immune cells.     

Analysis of certain mechanisms of antigen-specific suppression of the immune response

CBA mice were immunized with sheep red blood cells (SRBC) to obtain immune spleen cells (ISc) which were used to suppressor cells. Administration of ISC to intact syngeneic recipients on the immunization day led to a more powerful suppression of the immune response as compared to that seen one day after antigen injection. Four days after immunization the animals' immune response was not liable to be suppressed. ISC extract possessed similar effects with respect to the immune response of normal spleen cells which were transplanted to the cyclophosphamide-treated recipients. The immune response of spleen cells from mice immunized with SRBC in a dose of 10(6) was less liable to be suppressed. Hyperimmune spleen cells from donors immunized with SRC in a dose of 10(9) were insensitive to ISC or to the extract. Experiments with the use of adoptive transfer of a mixture of immune and intact T- and B-cells have disclosed that B-cells from hyperimmune donors were resistant to suppression. Therefore, B-lymphocytes are the most probable target cells exposed to T-suppressors in the given system. The mechanism is discussed of the selective effect of T-suppressors on B-cells in the course of the immune response development during immunization with high doses of antigen.     

Effect of allogeneic cell interaction and graft-versus-host reaction on the antibody response to Escherichia coli 0127 antigen.

The influence of allogeneic cell interaction and GVH reaction on the immune response to Escherichia coli antigen was investigated. Addition of CBA/J spleen cells to cultures of nu/nu spleen cells stimulated a significant increase in the nude PFC response to SRBC but had no significant effect on the immune response to E. coli antigen. Similarly, the induction of a GVH reaction in F₁ mice by the injection of parental spleen cells also had no significant effect on the immune response to the bacterial antigen. These results suggest that the immune response to E. coli is not affected by products of thymus-derived cells.     

Functional Switching and Stability of Regulatory T Cells

It is widely accepted that the primary immune system contains a subpopulation of cells, known as regulatory T cells whose function is to regulate the immune response. There is conflicting biological evidence regarding the ability of regulatory cells to lose their regulatory capabilities and turn into immune promoting cells. In this paper, we develop mathematical models to investigate the effects of regulatory T cell switching on the immune response. Depending on environmental conditions, regulatory T cells may transition, becoming effector T cells that are immunostimulatory rather than immunoregulatory. We consider this mechanism both in the context of a simple, ordinary differential equation (ODE) model and in the context of a more biologically detailed, delay differential equation (DDE) model of the primary immune response. It is shown that models that incorporate such a mechanism express the usual characteristics of an immune response (expansion, contraction, and memory phases), while being more robust with respect to T cell precursor frequencies. We characterize the affects of regulatory T cell switching on the peak magnitude of the immune response and identify a biologically testable range for the switching parameter. We conclude that regulatory T cell switching may play a key role in controlling immune contraction.     

The extracorporeal immunostimulating effect of terrilytin in staphylococcal infection]

The intravenous injection of terrilytin-treated lymphocytes into rats infected with staphylococci enhances the formation of staphylococcal alpha antitoxin in the animals and the development of immune response to T-dependent antigen, such as sheep red blood cells (SRBC), but produces no effect on the development of immune response induced by T-independent antigen (lipopolysaccharide). Terrilytin-treated lymphocytes induce the release of the factor promoting the development of immune response to staphylococcal antigens and SRBC by spleen cells, incapable of adherence to plastic, but have no influence on the development of immune response to lipopolysaccharide in rats infected with staphylococci. At the same time in such rats spleen cells adhering to plastic take part in the transfer of signals from terrilytin-treated lymphocytes to nonadhering spleen cells of recipients.     

Role of helper T-lymphocytes in modulating the humoral immune response to cholera enterotoxin

The role of helper T-lymphocytes in the modulation of humoral immune response to sheep red blood cells with choleragen has been studied in vivo, the populations of cooperating marrow cells, formed in mice under the action of hydrocortisone being used as a model. In adoptive transfer marrow cells, taken from mice on day 12 after thymectomy and from mice previously treated with antithymocyte serum, have proved incapable of humoral immune response. Choleragen, similarly to theophylline, normalizes the humoral immune response of marrow cells in thymectomized mice, but inhibits this response in intact ones, while thymosin fraction 2 restores it again, thus abolishing the action of choleragen and theophylline. The opposite effects rendered by choleragen and theophylline on humoral immune response, depending on the hormonal status of the animals and the possibility of influencing these effects by means of thymosin fraction 2 indicate that the population of helper T-lymphocytes are selectively sensitive to changes in the concentration of intracellular cAMP. Their capacity for cooperative interaction in the immune process is regulated by thymic hormones and forms the basis of the mechanism permitting the modulation of humoral immune response with choleragen.     

The immunologic response in mice unresponsive to experimental allergic encephalomyelitis

The suppressor cells that are involved in antigen-induced protection against EAE in mice were investigated with respect to their effect on the immune response. The cellular immune response to the basic encephalitogenic protein (BE) and to PPD were studied in mice with either actively induced or adoptively transferred unresponsiveness to EAE. The results demonstrate that the DTH response to BE, as assayed in the radiometric ear skin test, was suppressed in mice protected against EAE. Moreover, the passive transfer of DTH response to BE by effector lymphocytes was also inhibited by the preinjection of suppressor cells. On the other hand, the suppressor cells did not affect the response to PPD in all these experiments. The results indicate that suppressor cells that mediate unresponsiveness to EAE regulate also the cellular immune response to BE in a specific manner. These suppressor cells are probably active both at the induction and the effector phase of the immune response.     

Adenosine signaling and adenosine deaminase regulation of immune responses: impact on the immunopathogenesis of HIV infection

Infection by human immunodeficiency virus (HIV) causes the acquired immune deficiency syndrome (AIDS), which has devastating effects on the host immune system. HIV entry into host cells and subsequent viral replication induce a proinflammatory response, hyperactivating immune cells and leading them to death, disfunction, and exhaustion. Adenosine is an immunomodulatory molecule that suppresses immune cell function to protect tissue integrity. The anti-inflammatory properties of adenosine modulate the chronic inflammation and immune activation caused by HIV. Lack of adenosine contributes to pathogenic events in HIV infection. However, immunosuppression by adenosine has its shortcomings, such as impairing the immune response, hindering the elimination of the virus and control of viral replication. By attempting to control inflammation, adenosine feeds a pathogenic cycle affecting immune cells. Deamination of adenosine by ADA (adenosine deaminase) counteracts the negative effects of adenosine in immune cells, boosting the immune response. This review comprises the connection between adenosinergic system and HIV immunopathogenesis, exploring defects in immune cell function and the role of ADA in protecting these cells against damage.     

Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth

ABSTRACT: BACKGROUND: The role of the immune system in tumor progression has been subject to discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. METHODS: We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. RESULTS: A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. CONCLUSIONS: Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion.     

Mechanism of the intensification of the immune response to Staphylococcus in mice after the transplantation of primed donor splenocytes

Experiments on CBA, C57Bl/6 mice and (CBA X X C57Bl/6)F1 hybrids were made to study the mechanism of stimulation of the immune response to staphylococci after injection of primed splenocytes. The stimulating action of immune splenocytes was reversed after their in-vitro treatment with anti-immunoglobulin serum and complement. The stimulant effect was also seen in a semi-allogeneic system (adoptive transfer of CBA mice immune cells to (CBA X C57Bl/6)F1 recipients). Preincubation of splenocytes with CBA-anti-C57Bl/6-serum and complement prior to demonstration of antibody-forming cells did not influence their number in the spleen of hybrid recipients injected with immune cells carrying parent genotype but decreased this indicator of the immune response in control mice. It is concluded that stimulation of the immune response to staphylococci after transplantation of primed splenocytes is due to the anamnestic response of donor's cells repeatedly stimulated by antigen in the recipient's host.     

Detection of Th1/Th2 cytokine signatures in yellow fever 17DD first-time vaccinees through ELISpot assay

Immunity to yellow fever (YF) is conferred by the interplay of humoral and cellular immune response. Despite the extensive literature on the humoral immune response to the YF vaccine virus, little is known about its cellular immune response to vaccination. The analysis of cytokine production by ex-vivo antigen-stimulated T cells has been considered as a valuable tool for understanding cellular immune response. Thus, we have analyzed two T(H)1/T(H)2 signature cytokines (IFN-gamma and IL-4) from 12 healthy first-time adults vaccinated with YF17DD virus. The cells, harvested on day 0 (before vaccination) and 7, 15 and 30 days after immunization were antigen-stimulated and analyzed by ELISpot. A significant increase in the number of spot-forming cells during the response to YF 17DD live virus stimulation by ELISpot assay was observed. IFN-gamma-and IL-4-producing cells were significantly increased on the 15th day after vaccination in all volunteers. These results presented herein are important for understanding the role of cytokines in the immune response to YF 17DD virus.     

Physiology of adaptive immunity regulation via signaling pattern-recognition receptors

In the past fifty years, adaptive immune response has been studied from the standpoint of Burnet’s clonal selection theory. Much progress in understanding the mechanisms of specific cellular (T-cell) and antibody (B-cell) immune response has been made. However, it remained unclear why different pathogen types induce principally different types of immune response. Effective immune response in different cases may develop either by cellular or humoral type, and antibodies are produced on the basis of immunoglobulins of different classes. These facts could only be explained by specific regulation of differentiation of immunocompetent cells during the development of adaptive immune response to different pathogens. The discovery of the system of signaling pattern-recognition receptors (PRRs) in immunocompetent cells made it possible to understand these specific physiological mechanisms of regulation of T- and B-cell response to various pathogens. Upon interaction with pathogens, signaling PRRs activate the synthesis of various cytokines in the cells, which then regulate further activation of cells in different directions. Dendritic cells not only provide naive T cells with a processed antigen but also supply them with various cytokines inducing formation of type 1 or 2 T-helpers; as a result, adaptive immune response develops by the cellular or humoral type, respectively. Antigens of pathogens activate PRRs in B lymphocytes, which initiate the synthesis of various cytokines in cells. These are cytokines that determine predominant production by plasma cells of class A, M, G, or E antibodies depending on the pathogen type.     

Contributions of memory B cells to secondary immune response

The secondary immune response is one of the most important features of immune systems. During the secondary immune response, the immune system can eliminate the antigen, which has been encountered by the individual during the primary invasion, more rapidly and efficiently. Both T and B memory cells contribute to the secondary response. In this paper, we only concentrate on the functions of memory B cells. We explore a model describing the memory contributed by the specific long-lived clone which is maintained by continued stimulation with a small amount of antigens sequestered on the surfaces of the follicular dendritic cells (FDC). The behavior of the secondary response provided by the model can be compared with experimental observations. The model shows that memory B cells indeed play an important role in the secondary response. It is found that a single memory cell in a long-lived clone may not be long-lived. In the present note, the influences of relevant parameters on the secondary response are also explored.     

Regulation of tumor infiltrated innate immune cells by adenosine

Cancer has the ability to escape the immune system using different molecular actors. Adenosine is known to be involved in mechanisms which control inflammatory reactions and prevent excessive immune response. This purine nucleoside can be translocated from the cell or produced in the extracellular space by 5′-ectonucleotidases. Once bound to its receptors on the surface of immune effector cells, adenosine activates various molecular pathways, which lead to functional inhibition of the cell or its death. Some tumors are infiltrated by the different cells of immune system but are able to use adenosine as an immunosuppressive molecule and thus inhibit immune anticancer response. This mechanism is well described on adaptive cells, but much less on innate cells. This review outlines major effects of adenosine on innate immune cells, its consequences on cancer progression, and possible ways to block the adenosine-dependent immunosuppressive effect.

     

Plasmodium berghei: Reduction of the mouse's specific lymphoproliferative response in relation to corticosterone and pregnancy

Spleen cells from mice immune to Plasmodium berghei exhibited a significantly increased in vitro proliferative response to parasitized reticulocytes compared to spleen cells from normal mice. The specific response to malaria antigen was decreased in spleen cells from pregnant immune mice in contrast to the nonspecific response to the mitogen phytohemagglutinin. Addition of mouse serum to spleen cell cultures of immune mice depressed both the phytohemagglutinin and the specific proliferative response, whereas serum of pregnant mice exerted an even stronger inhibition than serum of nonpregnant mice. Charcoal adsorption of mouse sera for the elimination of steroid hormones removed the serum dependent immunosuppression from normal as well as pregnant serum. Corticosterone added to the spleen cell cultures depressed also the proliferative response. These findings demonstrate that the response to malaria antigen is decreased in immune mice during pregnancy. The possible effect of serum corticosterone on the depression of the immune response is discussed.     

肠粘膜上皮细胞在天然免疫中的作用

粘膜免疫是机体防御系统的主要成分。致病性细菌侵入机体后,首先遭遇到天然免疫的抵抗,随后产生获得性免疫,两共同执行机体的防御功能,消灭入侵细菌。最近的研究表明上皮细胞对细菌感染有重要的免疫调节作用,在天然免疫与获得性免疫防御机制中起重要作用。本重点介绍肠上皮细胞在天然免疫中的作用。     

Gr-1+ cells play an essential role in an experimental model of disseminated histoplasmosis

Recent studies have shown the participation of Gr-1(+) cells in many types of infections; however, the role played by these cells in the immune response to fungal pathogens is controversial. In this study we determined whether Gr-1(+) cells are involved in the protective immune response in systemic Histoplasma capsulatum infection. Depletion of Gr-1(+) cells using the monoclonal antibody (MAb) RB6-8C5 increased histoplasmosis severity and inhibited the subsequent development of a protective immune response. In addition to the increased fungal burden in lungs and spleens, the Th1 response was found to be unbalanced in these mice and the suppression of the cellular immune response seemed to be associated with increased nitric oxide production. Taken together, these results indicate that Gr-1(+) cell depletion at the beginning of infection allows yeast multiplication and increases mice mortality. This study improves the understanding of the role of Gr-1(+) cells on the protective immunity in histoplasmosis.