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PubMed2006

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis.

The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.

Angiogenesis Inhibitors↗
PubMed2004

Natural killer cell activity and sensitivity to positive and negative modulation in uncomplicated obese subjects: relationships to leptin and diet composition.

BACKGROUND: Natural killer (NK) cells are a key component of innate immunity; their activity is modulated by cytokines and hormones and is influenced by diet. In obesity, a higher risk of cancer and infections has been demonstrated. Studies on NK cell activity have yielded inconsistent results; NK cell sensitivity to modulators has not been assessed before. OBJECTIVE: In this case-control study, we assessed both spontaneous NK cell activity and responsiveness to positive (interleukin (IL)-2) and negative (cortisol) modulators in uncomplicated obesity; we searched for correlations between NK cell activity and anthropometric, dietary and metabolic variables. METHODS: In all, 21 obese (six males/15 females) and 21 age- and sex-matched healthy nonobese subjects underwent clinical examination and dietary and laboratory analyses. Spontaneous and modulated NK activities of peripheral blood mononuclear cells were measured by enzyme-release cytotoxicity assay. RESULTS: Spontaneous NK cell activity was not different in obese subjects vs controls. IL-2 stimulated and cortisol inhibited NK cell activity in both populations. Cortisol-dependent inhibition was lower in the obese than in the control group (-24.4+/-2.9 vs -38.6+/-3.3%, P=0.002), but decreased sensitivity was restricted to women (P=0.0007). In obese subjects, cortisol-dependent inhibition negatively correlated with serum leptin levels (r=-0.54, P=0.02) and, in women, with body mass index (r=-0.63, P=0.01); IL-2-dependent stimulation positively correlated with dietary carbohydrates (r=0.61, P=0.005) and serum LDL levels (r=0.55, P=0.009) and negatively correlated with dietary lipids (r=-0.71, P=0.0006). CONCLUSION: Spontaneous and IL-2-inducible NK cell activity is normal in uncomplicated obesity. Sensitivity to IL-2 correlates with fat and carbohydrate intake. Sensitivity to glucocorticoids negatively correlates with serum leptin levels and is significantly diminished in obese women, in whom it correlates with body mass index.

Adult↗
PubMed1980

Alterations in thymus and spleen cell populations and immune reactivity during syngeneic pregnancy and lactation.

Maternal thymus and spleen cell composition and mitogenic responsiveness were examined in the mouse during syngeneic pregnancy and lactation. The results indicated significant changes in thymus cell populations and in thymus cell in vitro mitogen, mixed-leukocyte and in vivo graft-versus-host (GVH) responses during pregnancy and lactation. In the spleen, in vitro mitogen responses were not altered, however, in vivo GVH reactivity was decreased during lactation.

Animals↗
PubMed2000

Gap junctions in cells of the immune system: structure, regulation and possible functional roles.

Gap junction channels are sites of cytoplasmic communication between contacting cells. In vertebrates, they consist of protein subunits denoted connexins (Cxs) which are encoded by a gene family. According to their Cx composition, gap junction channels show different gating and permeability properties that define which ions and small molecules permeate them. Differences in Cx primary sequences suggest that channels composed of different Cxs are regulated differentially by intracellular pathways under specific physiological conditions. Functional roles of gap junction channels could be defined by the relative importance of permeant substances, resulting in coordination of electrical and/or metabolic cellular responses. Cells of the native and specific immune systems establish transient homo- and heterocellular contacts at various steps of the immune response. Morphological and functional studies reported during the last three decades have revealed that many intercellular contacts between cells in the immune response present gap junctions or "gap junction-like" structures. Partial characterization of the molecular composition of some of these plasma membrane structures and regulatory mechanisms that control them have been published recently. Studies designed to elucidate their physiological roles suggest that they might permit coordination of cellular events which favor the effective and timely response of the immune system.

Animals↗
PubMed1989

Modulation of eicosanoid production and cell-mediated cytotoxicity by dietary alpha-linolenic acid in BALB/c mice.

The effects of dietary alpha-linolenic acid (18:3n-3) on fatty acid composition, eicosanoid production, and cell-mediated cytotoxic activity of immune cells before and after challenge with virus or poly I-C from BALB/c mice were studied. Weanling BALB/c mice were fed purified diets containing either 10%-by-weight corn oil or linseed oil providing a ratio of 18:3n-3 to 18:2n-6 of 1/32 or 2/1, respectively, for 6-10 weeks. Fatty acid analysis of splenocyte phospholipids showed an appreciable increase in the percentage of n-3, and a decrease in n-6, fatty acids in splenocytes from mice fed the linseed oil diet. Splenocyte prostaglandin E and peritoneal exudate cell leukotriene C production was significantly lower in the linseed oil-fed mice. In general, cell-mediated cytotoxic activity was similar for immune cells from linseed oil and corn oil-fed mice. However, 6 days after the viral challenge, splenocyte cell-mediated cytotoxic activity was significantly higher in linseed oil mice. This higher activity was associated with nonspecific cytotoxicity rather than that of viral-specific cytotoxic T-lymphocytes. Cell yields from the spleen and peritoneum were frequently significantly higher in linseed oil mice. Interactions between dietary 18:3n-3, eicosanoid production, and immune cell proliferation and/or migration are discussed. In summary, feeding mice a diet rich in 18:3n-3 elevates immune cell n-3 fatty acid content, reduces eicosanoid synthesis and, to a limited extent, enhances the cell-mediated cytotoxic response to a viral challenge.

Animals↗
PubMed1975

[Immunological aspects in EPH gestosis].

On the base of the fundamental knowledge on immunological reactions in the normal pregnancy the disease of the EPH-gestosis is described from the immunological viewpoint. The following facts may be significant: 1. The increased occurence of specific and nonspecific crossreacting antibodies against liver, kidney and placental tissue in the blood of pregnant women and puerperas. 2. The increased occurence of placental infarctions and throphoblastic defects as well as fibrinoid deposits in the placenta, the arteriols and in the kidney. 3. Changes in the protein composition of blood. 4. The changed maternal cell-mediated immunity.

Alkaline Phosphatase↗
PubMed2005

Female Iberian wall lizards prefer male scents that signal a better cell-mediated immune response.

In spite of the importance of chemoreception in sexual selection of lizards, only a few studies have examined the composition of chemical signals, and it is unknown whether and how chemicals provide honest information. Chemical signals might be honest if there were a trade-off between sexual advertisement and the immune system. Here, we show that proportions of cholesta-5,7-dien-3-ol in femoral secretions of male Iberian wall lizards (Podarcis hispanica) were related to their T-cell-mediated immune response. Thus, only males with a good immune system may allocate higher amounts of this chemical to signalling. Furthermore, females selected scents of males with higher proportions of cholesta-5,7-dien-3-ol and lower proportions of cholesterol. Thus, females might base their mate choice on the males' quality as indicated by the composition of their chemical signals.

Animals↗
PubMed1989

Immune cells in a case of postherpetic marginal trophic ulcer.

The corneal surface was examined by means of replica histology, and the excised limbic conjunctiva was examined by routine histological and immunohistochemical methods with monoclonal antibodies directed against major histocompatibility class II antigens, lymphocyte subsets, Langerhans cells (HLA-DR, OKT4-Leu3a, OKT8, BA1, B1, and OKT6) and immunoglobulins A, G, M, and D. The findings were compared with those found in normal conjunctiva. No inflammatory cells were present in the replica of the corneal surface. An inflammatory infiltrate composed of B lymphocytes and null cells, in addition to T lymphocytes, Langerhans cells, and polymorphs, was present in the epithelium as well as in the stroma of the limbic conjunctiva. The composition of the infiltrate points towards the involvement of cell mediated immunity as well as humoral immunity. No immunoglobulins were bound to the conjunctival epithelium.

Aged↗
PubMed1987

Cyclophosphamide-sensitive activity of suppressor T cells during treponemal infection.

When hamsters were infected with Treponema pallidum subspecies endemicum, the composition and activity of the cellular immune components were markedly altered compared to those of sham-infected controls. A population of suppressor T cells (Ts) developed that diminished the ability of the macrophage (M phi) to perform C3b receptor-mediated ingestion (C3bMI) of erythrocytes coated with antibody and complement. Using cyclophosphamide (CY) we examined node and peritoneal cells to determine their role in regulating M phi activity during this infection. In vitro the node and peritoneal T cells from treponemal-infected/CY-treated animals showed considerably less suppressive activity than treponemal-infected/untreated T cells when co-cultured with M phi from infected animals. This response was greater with node T cells compared to peritoneal T cells. Moreover, a quantitative analysis of the mononuclear leucocyte populations from each of these regions showed that CY-treated/uninfected animals had a decreased percentage of node T cells. Despite this reduction of node T cells, peritoneal T-cell populations were only minimally reduced. However, treponemal-infected hamsters concomitantly treated with CY had a significant reduction in the T-cell percentages in both compartments. These results imply that, during this infection, most Ts generated in the node remain there although some are dispersed to supplementary regions. Thus, the development of a suppressor system that effects M phi function may be one way in which treponemes escape total elimination by the host.

Animals↗
PubMed2005

Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation.

We have analyzed the clonotype composition of CD8+ T cells following nonmyeloablative (NMA) conditioning and hematopoietic cell transplantation (HCT), of patients with chronic lymphocytic leukemia (CLL). Consecutive analyses of blood samples taken up to 2 years following HCT, demonstrated that CD8+ T-cell clonality was highly dynamic in the early phases after HCT, but became more stable after 4-5 months. Moreover, donor lymphocyte infusion (DLI) given for disease progression in one of the patients led to establishment of recurrent as well as new T-cell clonotypes. This coincided with disease remission, strongly suggesting that these T cells were engaged with anti-CLL cytotoxicity. To examine the functional capacity of stable clonally expanded T cells after HCT, CD8+ T cells isolated post-transplant from the recipients were stimulated ex vivo with CLL cells and subsequently analyzed by FACS for surface expression of the marker for cytotoxic activity, CD107a. Stimulation with CLL cells indeed led to surface expression of CD107a, and clonotype analyses of sorted cells demonstrated that CD107a positive T cells were stably expanded following HCT. Our data suggest that clonally expanded CD8+ T-cell clones participate in the ongoing T-cell response against CLL cells following HCT with NMA conditioning.

CD8-Positive T-Lymphocytes↗
PubMed1994

Effects of surfactant protein A and surfactant lipids on lymphocyte proliferation in vitro.

We studied the effects of dipalmitoyl L-alpha-phosphatidylcholine (DPPC), Survanta, surfactant protein A (SP-A), and mixtures of these substances on mitogen-induced lymphocyte proliferation using concanavalin A as a mitogen. A concentration-dependent suppression of proliferation was observed with 50-250 micrograms/ml of DPPC or Survanta. However, when SP-A was added to cultures, proliferation was stimulated. The inhibitory effects of DPPC and Survanta were altered in mixtures that contained SP-A. When added to 50 micrograms/ml of Survanta, SP-A reversed the inhibitory influence of Survanta and caused increased proliferation. These findings suggest that surfactant phospholipids cause a suppression of mitogen-induced lymphocyte proliferation, which is reversed somewhat by addition of SP-A. We hypothesize that immune cell function in the lung varies with changes in the relative amounts of surfactant components. Changes in surfactant composition may occur during pulmonary inflammation or infection or with surfactant replacement therapy and may influence immune and inflammatory processes in the lung.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1981

Effect of soluble immune complexes of Fc and C3 receptor-dependent phagocytosis by human monocytes.

The capacity was studied of bovine serum albumin (BSA) rabbit anti-BSA and ovalbumin (OA) rabbit anti-OA immune complexes of different composition to inhibit the Fc receptor-dependent adherence and phagocytosis of sensitized sheep red blood cells by human monocytes. Parallel experiments were performed on the ability of the immune but complement-reacted complexes to inhibit the C3 receptor-dependent phagocytosis of C3-coated yeast particles. The extent of inhibition of both the Fc and C3 receptor-dependent phagocytosis was proportional to the antibody avidity of the complex used. Immune complexes made at equivalence and at moderate antibody excess markedly inhibited both types of phagocytosis, whereas those made at moderate antigen excess had only a weak inhibitory effect. These findings can be explained by the correlation between the Fc receptor-binding and complement-activating capacities of immune complexes of different composition. An alternative explanation, however, is also discussed.

Antigen-Antibody Complex↗
PubMed1991

[Effect of trauma on space-time organization of B-dependent area of the regional lymph node cortex].

In the experiment performed on 238 non-inbred white mice it has been demonstrated that after trauma in the concha auricularis population density (PD) of immune-competent cells in the germinative center (GC) and in the crown of the regional lymph node (LN) changes. The PD of small lymphocytes increases, and the PD of mitotically dividing cells, immunoblasts, plasmoblasts, immature and mature plasmocytes decreases sharply in both zones. The increase of small lymphocytes PD in the regional LN after the trauma is obviously connected with intensification of their inflow from the lesion focus. Inhibition of proliferation and differentiation of the immune-competent cells in the GC of the crown is a response to the operation stress. During the posttraumatic period both spectral composition and parameters of the constituents of rhythmical alteration of the cells PD change both in the GC and in the crown. As a rule, displacement of acrophase and decrease in amplitude of the rhythm take place. Total power of the process for various types of immune-competent cells alters unequally. In the spectral composition of the rhythmicity amount of circadian components increases, their power increases, too. This demonstrates an increase of central hormonal effects during the posttraumatic period. After trauma fluctuations of the cells PD of the plasmacytic line, as well as in mitotically dividing cells with a 7-hour's period, which has been revealed in intact animals before the trauma, are preserved. This demonstrates a relative independence of the given synchronizer of rhythmicity at a tissue level from any influence of the higher regulatory center.

Animals↗
PubMed1986

Suppression of parasite-specific response in Plasmodium falciparum malaria. A longitudinal study of blood mononuclear cell proliferation and subset composition.

The present longitudinal study was designed to characterize immunosuppression during acute Plasmodium falciparum infection, during the treatment and up to 1 month after the acute stage. The proliferative responses of blood mononuclear cells (BMNC) isolated from non-immune and semi-immune malaria patients and controls to mitogens and two Plasmodium-derived stimulators (merozoites, Meroz, and soluble purified antigen, SPag) and non-related antigens were measured by [3H]thymidine incorporation. BMNC isolated before treatment (day 0) from the non-immune patients did not respond to Meroz, whereas those from controls showed a significantly higher response. The SPag responses were also low in BMNC isolated on day 0 and increased in both the non-immune and the semi-immune patients during the observation period. These findings indicate that during malaria there is a depression of the parasite-specific proliferative response. The subset composition of BMNC isolated from non-immune patients was studied in a FACS analyser. The mean cell volumes of both Leu 2+ and Leu 3+ cells were increased during the acute phase of the infection, indicating that malaria infection results in activation of both T-helper and T-suppressor cells. There was no overall reduction of the response to mitogens on day 0. However, 3 days after initiation of the treatment the mitogen response was decreased. This finding indicates that it is important to distinguish between the effects of malaria infection and of drug treatment.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1993

Immunization against tumor and minor histocompatibility antigens by eluted cellular peptides loaded on antigen processing defective cells.

Material eluted from RMA lymphoma or B6 spleen cells under acid conditions was fractionated by reverse phase high-performance liquid chromatography, and tested for ability to restore the sensitivity to cytotoxic T lymphocytes of the processing/presentation defective mutant line RMA-S. This allowed identification of three fractions (termed M1, M2 and M3) carrying B6 antigens recognized by cytotoxic T lymphocytes (CTL) elicited across the minor histocompatibility barrier A.BY anti-B6 (both H-2b) and one fraction (termed T1) carrying a tumor antigen recognized by B6 anti-RMA CTL. By parallel runs of material from cell lysates over major histocompatibility complex class I affinity columns, the M2 and M3 antigens were defined as Kb restricted, and M1 and T1 as Db restricted. Isolated fractions loaded onto RMA-S cells could be used to prime anti-minor histocompatibility antigen and tumor CTL in vivo. They could also be used for in vitro restimulation of spleen cells from mice that had been primed either by antigen-loaded RMA-S, or by wild-type RMA tumor cells and B6 splenocytes. The CTL generated by these methods were specific for the loading antigen, and they also recognized the antigen on the "physiological" target, i.e. RMA or B6 lymphoblasts. This system based on RMA-S as an immunization and target antigen reporter cell may be used for dissection of complex CTL responses, e.g. in studies of clonal composition and epitope dominance, or for studies of tumors that are poor stimulators of immunity.

Animals↗
PubMed1996

In vitro activation of antigen-presenting cells (APC) by defined composition of Quillaja saponaria Molina triterpenoids.

The capacity of adjuvants to stimulate cytokine production by APC is important for the initiation of the immune response. Novel adjuvant formulations based on the iscom technology have been developed using selected triterpenoid components from Quillaja saponaria Molina. Five of these new Quillaja formulations were used to prepare matrix (an antigen-free particle) and tested for their capacity to stimulate IL-1 secretion by murine peritoneal cells in vitro. The formulation denominated QH 7.0.3 was superior to the other matrix formulations, including the original spikoside matrix. The QH 7.0.3 formulation in iscoms containing influenza virus envelope antigens induced IL-1 secretion more efficiently than the antigen-free matrix, or a mixture of matrix and viral antigens, or the free Quillaja components of similar composition. Compared with adjuvants known as IL-1 inducers, QH 7.0.3 flu-iscoms were as efficient as the most prominent IL-1 inducer, i.e. lipopolysaccharide (LPS) and superior to cholera toxin (CT) and muramyl dipeptide (MDP). These results indicate that the composition per se of triterpenoids included in iscoms or matrix has a prominent influence on the level of APC activation which may result in qualitatively different immune responses in vivo.

Adjuvants, Immunologic↗
PubMed1986

Composition of extracts of airborne grain dusts: lectins and lymphocyte mitogens.

Airborne grain dusts are heterogeneous materials that can elicit acute and chronic respiratory pathophysiology in exposed workers. Previous characterizations of the dusts include the identification of viable microbial contaminants, mycotoxins, and endotoxins. We provide information on the lectin-like activity of grain dust extracts and its possible biological relationship. Hemagglutination of erythrocytes and immunochemical modulation by antibody to specific lectins showed the presence of these substances in extracts of airborne dusts from barley, corn, and rye. Proliferation of normal rat splenic lymphocytes in vitro provided evidence for direct biological effects on the cells of the immune system. These data expand the knowledge of the composition of grain dusts (extracts), and suggest possible mechanisms that may contribute to respiratory disease in grain workers.

Animals↗
PubMed1978

[Alteration of the construction and cellular composition of ileo-colonic lymph nodes of rhesus macaques after administration of salmonella vaccine].

In stained histological sections, percentage ratio of areas to different cellular elements in structural components of the ileocolonic lymph nodes was studied in mature Macaca rhesus, normal and after injection of salmonella vaccine. A rather considerable reaction in all structural components and cell composition of the lymph nodes was demonstrated as a response to immunization of the animals. These changes were demonstrated in decreased area occupied by the cortical substance and in increased area occupied by the medullar substance of the lymph node. In the cortical substance, together with decrease in the cortical plateau, total number of folliculi rises with formation of light centers in them. Calculation of cellular elements revealed that in the cortical substance cytopoietic function was inhibited; that was expressed in decreasing mitoses and blast forms in the cells. Most drastic alterations occur in myelin cords of the lymph nodes. Together with increasing area, a considerable reaction of acidophilic leucocytes, premature plasma cells and macrophages is observed. Their number increases notably.

Animals↗