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The sequential nature of the process allowing the immune system to learn how to withstand pathogen agents is explored by means of large-scale computer simulation of the Celada-Seiden immunological automaton. In accord with our previous results, it is found that the learning process proceeds via a sequential cascade in affinity space.
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PURPOSE: The use of the CD20-specific antibody rituximab has greatly improved the response to treatment of CD20+ follicular lymphoma. Despite the success of rituximab, resistance has been reported and prognostic markers to predict individual response are lacking. The level of CD20 expression on tumors has been related to response, but results of several studies are contradictory and no clear relationship could be established. Complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) are thought to be important effector mechanisms, but the exact mechanism of rituximab-mediated cell kill is still unknown. Importantly, no data have been reported on the combined contribution of CDC and ADCC. EXPERIMENTAL DESIGN: We have developed a system of clonally related CEM-CD20 cells by retroviral transfer of the human CD20 cDNA (n = 90). This set of cells, with the CD20 molecule as the only variable, was used to study the importance of CD20 expression level on rituximab-mediated CDC, ADCC, and the combination. RESULTS: We show a sigmoidal correlation of CD20 expression level and rituximab-mediated killing via CDC but not ADCC. On both high and low CD20-expressing cells, all CD20 molecules were translocated into lipid rafts after rituximab binding. Furthermore, CDC and ADCC act simultaneously and CDC-resistant cells are sensitive to ADCC and vice versa. CONCLUSIONS: These findings suggest that CDC depends on CD20 expression level and that both CDC and ADCC act complementary. These data give new insights into novel strategies to improve the efficacy of CD20-specific antibodies for the treatment of CD20+ tumors.
Prostaglandins are potent lipid molecules that affect key aspects of immunity. The original view of prostaglandins was that they were simply immunoinhibitory. This review focuses on recent findings concerning prostaglandin E2 (PGE2) and the PGD2 metabolite 15-deoxy-Delta(12,14)-PGJ2, and their divergent roles in immune regulation. We will highlight how these two seminal prostaglandins regulate immunity and inflammation, and play an emerging role in cancer progression. Understanding the diverse activities of these prostaglandins is crucial for the development of new therapies aimed at immune modulation.
Some immunological and parasitological aspects related to the infection of Hymenolepsis nana in mice are summarized in this review, focusing on the immune effector mechanisms involved in this host/parasite relationship. H. nana is a small cestode tapeworm of man and mice. A primary egg-infection determines within few days a strong immunity. Immunity elicited by low-level primary infection is effective as a high-level infection. The protective role of both humoral and cell-mediated immunity is summarized. The histological findings demonstrate that eosinophils and mast-cells are implicated as effector cells. This review is an attempt to re-examine, at low-level infection, the immune mechanisms in H. nana/mouse model.
Immunological data indicate that different subsets of T-helper cells work best against different types of infection. Concomitant infection of a host may thus impose either conflicting or synergistic immune response requirements, depending upon the extent to which the component optimal immune responses differ. Drawing upon empirically-determined optimal responses to single-species infections, an optimality model is here used to generate testable hypotheses for optimal responses to concomitant infection. The model is based upon the principle that the joint immune response will minimize divergence from each of the optima for single-species infections, but that it will also be weighted by the importance of mounting the correct response against each infectious organism. The model thus predicts a weighted average response as the optimal response to concomitant infection. Data on concomitant infection of murine hosts by the parasites Schistosoma mansoni and Toxoplasma gondii will provide the first test of the optimality model. If the weighted average hypothesis holds true, then there are no emergent immunological properties of concomitant infections and we may be able to understand immune responses to concomitant infection directly via our understanding of single-species infections.
AIM: To establish mouse lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice respectively, and to further investigate the immunological mechanisms of anti-tumor effect of melphalan. METHODS: Mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, melphalan of different doses were administered intraperitoneally to treat these wild type C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of melphalan that could cure the tuomr-bearing mice. Then the same amount of EL4 tumor cells were inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, melphalan of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded in these two different types of mice subsequently. RESULTS: A single dose of melphalan (7.5 mg/kg) could cure EL4 tumor-bearing wild type C57BL/6 mice, but could not induce tumor regression in EL4 tumor-bearing nude C57BL/6 mice. CONCLUSION: A single dose of melphalan has obvious anti-tumor effect on mouse lymphoma EL4 tumor-bearing wild type C57BL/6mice, which requires the involvement of T lymphocytes in the host probably related to their killing functions.
NK cells express receptors characterized by opposite functions that finely regulate their activities. Among inhibitory receptors, some are specific for different groups of MHC class I alleles, while others are still orphan receptors. On the contrary, various activating receptors are involved in the triggering of NK-mediated natural cytotoxicity. In general, their engagement induces human NK cells to kill target cells that are either HLA class I-negative or -deficient. Thus, the process of NK cell triggering mediated by Natural Cytotoxicity Receptors can be mainly considered as a non MHC-restricted mechanism. Here, a brief description of the molecular nature of these receptors, as well as, of their 3D-structures and of the implications for ligand recognition, is given.
Many chemicals and drugs can induce a neuroendocrine stress response that can be immunosuppressive. Mathematical models have been developed that allow prediction of the immunological impact of such stress responses in mice on the basis of exposure to the important stress-related mediator corticosterone. The area under the corticosterone concentration vs. time curve (AUC) has been used as an indicator of cumulative corticosterone exposure in these modeling studies. In the present study, an immunotoxicant known to induce a stress response, 3,4-dichloropropionanilide (propanil), was evaluated to determine if corticosterone AUC values are related to suppression of immunological parameters in mice treated with this chemical. Linear relationships between corticosterone AUC values and suppression of the following parameters were noted in B6C3F1 female mice: thymus cellularity and thymus subpopulation percentages, splenic subpopulation percentages, natural killer cell activity, MHC class II protein expression, and IgG1 and IgG2a antibody responses to antigen. Linear models derived in previous studies using mice treated with exogenous corticosterone or with restraint stress effectively predicted the immunological effects of 3, 4-dichloropropionanilide on the basis of corticosterone AUC values. The models derived using immobilization stress were more effective (r(2) for observed vs. predicted = 0.90) than the models derived using mice treated with exogenous corticosterone (r(2) for observed vs. predicted = 0.65). This was expected, because most stressors induce a variety of immunomodulatory mediators, not just corticosterone. These findings have implications for risk assessment in immunotoxicology.
Several immunological processes can be affected by space flight. However, there is little evidence to suggest that flight-induced immunological deficits lead to illness. Therefore, one of our goals has been to define models to examine host resistance during space flight. Our working hypothesis is that space flight crews will come from a heterogeneous population; the immune response gene make-up will be quite varied. It is unknown how much the immune response gene variation contributes to the potential threat from infectious organisms, allergic responses or other long term health problems (e.g. cancer). This article details recent efforts of the Kansas State University gravitational immunology group to assess how population heterogeneity impacts host health, either in laboratory experimental situations and/or using the skeletal unloading model of space-flight stress. This paper details our use of several mouse strains with several different genotypes. In particular, mice with varying MHCII allotypes and mice on the C57BL background with different genetic defects have been particularly useful tools with which to study infections by Staphylococcus aureus, Salmonella typhimurium, Pasteurella pneumotropica and Ehrlichia chaffeensis. We propose that some of these experimental challenge models will be useful to assess the effects of space flight on host resistance to infection.
The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) on type II to IV allergic reactions and immunological functions were investigated in animal models. Types II to IV allergic reactions in rodents were unaffected in vivo by TBX, even at higher doses than those capable of completely inhibiting the type I allergic reaction. However, both complement-mediated hemolysis via the classical pathway and hypotonic shock-induced hemolysis were slightly inhibited in vitro only by a high concentration of the drug (10(-4) g/ml). In the mouse system, TBX had no ability to suppress anti-hapten IgE antibody formation as well as hemagglutinin formation and to inhibit the proliferation of spleen cells induced by non-specific T and B cell mitogens. The results obtained indicate that TBX is an antiallergic drug essentially devoid of inhibitory actions on types II to IV allergic reactions and immunological functions, thus indicating that it is a specific inhibitor of type I allergic reactions.
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A canine model for the comparative study of lower respiratory and systemic immunologic reactions is described. The techniques of bronchopulmonary lavage and percutaneous splenic aspiration were employed to obtain serial samples of pulmonary and systemic lymphocytes. The morphologic features and the yield of cells obtained by these procedures were characterized. The presence of lymphocytes and plasma cells among the cell populations obtained by pulmonary lavage was confirmed by electron microscopy. The effect of serial bronchopulmonary lavage per se on the yield, composition, and functional properties of bronchoalveolar lymphocytes and macrophages was found to be minor. By contrast, the effect of immununization on these parameters was marked and easily detected. Evidence is presented that at least 2 anatomically and functionally different populatons of immunocytes subserve the lower respiratory tract, namely, the hilar lymph node cells and the bronchoalveolar lymphocytes. It is concluded that the canine model is well suited for the investigation of respiratory and systemic immunity and is useful for the study of bronchoalveolar lymphocyte and alveolar macrophage function, either independently or in concert with the study of pulmonary host defense and the pathogenesis of lung disease.
BACKGROUND AND OBJECTIVE: Laboratory stress studies found that acute psychological stresses may elicit changes in leukocyte numbers similar to those occurring in physical stresses. Both types of stress evoke - mainly by release of catecholamines - leukocytosis resulting from a release of natural killer cells (NK-cells), of CD8+ T-cells, of monocytes and of neutrophils. However, there is little proof that laboratory stress models can be applied to daily clinical routines. As a likely inductor of an immunological stress response the setting of retrobulbar anaesthesia prior to intraocular surgery permits the study of a short-term painful anaesthetic procedure under highly standardized conditions. This was examined in 16 female patients. METHODS: Counts of leukocyte subsets, serum cortisol and cardiovascular variables were measured 30 min and 1 min prior to retrobulbar anaesthesia as well as 2, 15 and 45 min afterwards. RESULTS: The setting of retrobulbar anaesthesia induced an increase in total leukocytes [+380 cells microL-1; P < 0.01 (means; significance level)] mainly due to rising counts of neutrophils (+241 cells microL-1, P < 0.01). Of all lymphocyte subpopulations, natural killer cells increased most markedly (+64 cells microL-1; P < 0.01). Furthermore, the retrobulbar block induced an increase in systolic arterial pressure (+15.2 mmHg; P < 0.01). CONCLUSION: These changes in immunological and cardiovascular variables are considered to be elements of a sympatho-adrenal stress reaction; catecholamines are considered to induce a demargination of leukocytes by binding to beta2-adrenoceptors and by modifying the avidity state of adhesion molecules.
The field of Artificial Immune Systems (AIS) concerns the study and development of computationally interesting abstractions of the immune system. This survey tracks the development of AIS since its inception, and then attempts to make an assessment of its usefulness, defined in terms of 'distinctiveness' and 'effectiveness.' In this paper, the standard types of AIS are examined--Negative Selection, Clonal Selection and Immune Networks--as well as a new breed of AIS, based on the immunological 'danger theory.' The paper concludes that all types of AIS largely satisfy the criteria outlined for being useful, but only two types of AIS satisfy both criteria with any certainty.
The heterotopic heart graft was examined as a surgical model for in vivo studies of transplantation immunology. Two innovations previously described distinguish it from an orthotopic heart transplant; its heterotopic, superficial position in the neck, and the use of portex cuffs to facilitate anastomoses of donor aorta and pulmonary artery to recipient common carotid artery and external jugular vein respectively. In this study, few modifications to the original technique were required. However, to ensure a high technical success rate exceeding 95%, it was found that the use of small donors (less than 200 g) and large recipient rats (greater than 230 g) was required. The former minimised the risk of kinking of the venous anastomoses, and the latter ensured an adequate luminal diameter of the carotid artery to facilitate the cuff anastomosis. With the vena cava and pulmonary veins ligated, the transplant served purely as an indicator graft with rhythmic contractions discernible by inspection or palpation. This simplified monitoring of the graft, with no requirement for ECG or biochemical studies. The direction of blood flow was established by angiography as via the aorta to the coronary vessels, returned to the right atrium and ventricle and out through the pulmonary artery to the recipient circulation. As the accessory heart did not provide any life-sustaining function, it could be removed for histological studies once rejection had occurred without compromising the survival of the recipient animal. This allowed the use of the recipient for further studies on its immunological status, including the performance of second grafts.
This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.
Because Mycoplasma pneumoniae is hypothesized to play an important role in reactive airway disease/asthma, a comprehensive murine model of M. pneumoniae lower respiratory infection was established. BALB/c mice were intranasally inoculated once with M. pneumoniae and sacrificed at 0 to 42 days postinoculation. All mice became infected and developed histologic evidence of acute pulmonary inflammation, which cleared by 28 days postinoculation. By contrast, M. pneumoniae persisted in the respiratory tract for the entire 42 days studied. Tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), KC (functional IL-8), MIP-1alpha, and MCP-1/JE concentrations were significantly elevated in bronchoalveolar lavage samples, whereas IL-4 and IL-10 concentrations were not significantly elevated. Pulmonary airflow resistance, as measured by plethysmography, was detected 1 day postinoculation and persisted even after pulmonary inflammation had resolved at day 28. Serum anti-M. pneumoniae immunoglobulin G titers were positive in all mice by 35 days. This mouse model provides a means to investigate the immunopathogenesis of M. pneumoniae infection and its possible role in reactive airway disease/asthma.