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PubMed1996

The cytokine microenvironment of human colon carcinoma. Lymphocyte expression of tumor necrosis factor-alpha and interleukin-4 predicts improved survival.

BACKGROUND: The functional significance of cytokines expressed in situ by tumor cells and tumor infiltrating lymphocytes (TIL) in human colon carcinomas is largely unknown. METHODS: We assessed TIL expression of interleukin-2 (IL-2), IL-4, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-10, and transforming growth factor-beta (TGF-beta), and tumor cell expression of IL-10 and TGF-beta in situ in 49 primary colon carcinomas and 20 metastases using immunohistochemistry. RESULTS: The percentage of primary colon carcinoma samples in which > 20% of TIL expressed each cytokine was as follows: IL-4: 47%; TNF-alpha: 22%; TGF-beta: 10%; IFN-gamma: 6%; IL-2:2%; IL-10: 0%; and GM-CSF: 0%. Lymphocytes more commonly infiltrated colon carcinoma primaries than metastases, and TIL expression of IL-4 and TNF-alpha was more common in primary than metastastatic carcinomas. Expression of TNF-alpha by even a small proportion (> or = 3%) of the TIL in a colon carcinoma specimen was associated with better overall survival (P = 0.01) when compared with patients with little or no TIL TNF-alpha expression (5-year survival 82% vs. 47%). Expression of IL-4 by > or = 20% of colon carcinoma TIL was also associated with improved survival (P = 0.01; 5-year survival 87% vs. 50%). The expression of IL-10 or TGF-beta by colon carcinoma TIL or colon tumor cells themselves was not associated with impaired survival. Benign epithelial cells stained positively for IL-10 and TGF-beta more frequently than tumor cells (P < 0.001). CONCLUSIONS: There are differences between the immune microenvironment of primary tumors and metastases. Although IL-10 is expressed by colon carcinoma cells and TIL, it is unlikely that it plays an important immunosuppressive role. TNF-alpha and IL-4 are commonly expressed by colon carcinoma TIL and both are associated with improved survival.

Carcinoma↗
PubMed2000

Lymph node metastases: the importance of the microenvironment.

BACKGROUND: Although, to the authors' knowledge, no prospective randomized clinical trial has demonstrated improvement in survival following the radical dissection of lymph nodes in the treatment of cancer patients, lymphadenectomy is still routinely performed for curative purposes. For many years, regional lymph nodes (RLNs) in tumor-bearing hosts have been considered anatomic barriers to the systematic dissemination of tumor cells. More recently, the belief has been held that lymph nodes play a completely passive role, by virtue of the observations that many lymphatic and lymphaticovenous shunts bypass RLNs and allow both lymphatic and hematogenous dissemination of malignant cells at an early stage in the vast majority of cancers. Furthermore, surgical removal of RLNs apparently has no effect, deleterious or beneficial, on the well-being of the host. METHODS: A comprehensive and critical review of the scientific literature was conducted to evaluate, from a biologic point of view, the role played by RLNs during the interactions between the tumor and the host's immune system. RESULTS: Recent advances in our understanding of the molecular events of antigen recognition by T cells and T-cell activation have provided strong experimental evidence to demonstrate that these secondary lymphoid organs constitute the primary sites where the specific recognition of tumor antigens and the proper activation of the immune system take place. Indeed, the notion that naive T cells are induced or silenced by tumor cells in the periphery may today be questioned, because effective induction can only occur in these secondary lymphoid organs where cell-to-cell interactions are properly guided and cells can meet in an appropriate cytokine-enriched microenvironment. CONCLUSIONS: Promising results obtained in the human setting with the use of dendritic cells as novel immunotherapeutic tools have recently renewed interest in active immunotherapy for the treatment of solid tumors. However, for accomplishing this goal, the maintenance of the integrity of the immune system remains a crucial issue. Studies showing that radical tumor-draining RLN dissections exert a markedly negative influence on the efficacy of postoperative immunotherapy protocols in mice as well as in humans seem to support adoption of a more conservative approach regarding uninvolved RLNs in the treatment of cancer patients.

Animals↗
PubMed1998

Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment.

Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I Kb antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the Kb autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when Kb- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject Kb-positive grafts no autoaggression against the Kb-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.

Animals↗
PubMed2000

Barrett's mucosa: remodelling by the microenvironment.

Barrett's metaplasia and the associated adenocarcinoma are composed not only of epithelial cells, but also of inflammatory cells and endothelial cells in the lamina propria and around the tumour, respectively. The early incidence of vascular invasion and metastasis is a feature of Barrett's adenocarcinomas. A paper in this issue of The Journal of Pathology shows that vascular endothelial growth factor (VEGF) is expressed in both metaplastic cells and endothelial cells of pre-neoplastic Barrett's epithelium early in the development of neoplasia. It is becoming clearer that the harmful insults of acid and bile reflux alter not only the epithelium, but also the lamina propria. Cytokines such as tumour necrosis factor alpha (TNFalpha) or transforming growth factor (TGFalpha) are implicated in the formation of early Barrett's adenocarcinomas. From current knowledge it is possible to hypothesize that metaplastic cells, perhaps as a consequence of either TNFalpha or TGFalpha stimulation, secrete VEGF. VEGF can promote adjacent endothelial cell growth through phosphorylation of beta-catenin and vascular endothelial cadherin (VE-cadherin) in endothelial cells. In this de novo microenvironment, angiogenesis is therefore accelerated, enhancing the chance of microvascular invasion.

Barrett Esophagus↗
PubMed1987

Reed-Sternberg cells and their cell microenvironment in Hodgkin's disease with reference to macrophage-histiocytes and interdigitating reticulum cells.

Fifty-eight paraffin-embedded lymph node biopsies from patients with Hodgkin's disease (36 nodular sclerosis, 14 mixed cellularity, five lymphocyte depletion, and three lymphocyte predominance) were immunostained with a panel of monoclonal (anti-Leu-M1, antileukocyte common antigen) and polyclonal (to lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin, and S-100 protein) antibodies by using the avidin-biotin immunoperoxidase technique. Both the immunostaining features of the Reed-Sternberg (R-S) cells and their variants, and the numbers of immunostained accompanying cells morphologically corresponding to macrophage-histiocytes (M-H) and to interdigitating reticulum cells (IRC) were analyzed. Variable numbers of R-S cells and their variants were positive for Leu-M1 in 83% of the cases, for alpha 1-antitrypsin in 40%, for alpha 1-antichymotrypsin in 30%, and for leukocyte common antigen in 3.4%; they were constantly negative for lysozyme and S-100 protein. Whereas the average numbers of accompanying cells immunostained for Leu-M1 were very low, the numbers of S-100-positive IRC were relatively high in all the Hodgkin's subtypes. The average numbers of M-H were lower (P less than 0.1 for lysozyme; P less than 0.001 for alpha 1-antichymotrypsin) in the nodular sclerosis than in the other pooled subtypes. In the nodular sclerosis subtype, however, R-S cells and their variants that stained positive for Leu-M1 appeared to express more frequently the lineage markers of M-H (alpha 1-antitrypsin and/or alpha 1-antichymotrypsin). These data appear to suggest that there is not an apparent qualitative correspondence between the immunostaining features of the cellular microenvironment composed of M-H and IRC and the features of the R-S cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2000

The microenvironment of injured and regenerating peripheral nerves.

Local events in the milieu of injured peripheral nerve trunks may have an important influence on the likelihood of regenerative success or the development of neuropathic pain. Injury-related changes in the microcirculation of this milieu have provided some evidence that axonal endbulbs, structures that form at the proximal end of transected axons, dump peptides and other molecules into the injury milieu where they may exert local actions, including those on microvessels. During a later phase of nerve repair, macrophage influx and pancellular proliferative events appear to develop in a coordinated fashion. Nitric oxide is probably an important and prominent player in the injured nerve trunk, both at early and later stages of the repair process. A better understanding of the injured peripheral nerve microenvironment may allow therapeutic approaches that can enhance regeneration and diminish pain.

Animals↗
PubMed2001

Production of IL-4 and leukemia inhibitory factor by T cells of the cumulus oophorus: a favorable microenvironment for pre-implantation embryo development.

The nature and the functional activity of immunocytes present in the cumulus oophorus, a mass of cells surrounding the oocyte, were examined here for the first time. The cumuli oophorus were obtained from women who had taken part in an in vitro fertilization program and were suffering from blocked fallopian tubes. Both macrophages and CD4(+) T cells were detected in all cumuli. CD4(+) T cell clones, generated from T cells of these cumuli, showed higher potential to produce IL-4 and leukemia inhibitory factor (LIF) than CD4(+) T cell clones generated from peripheral blood or ovary specimens from the same women. More importantly, IL-4 and LIF, but not IFN-gamma mRNA was found to be constitutively expressed in vivo by cumulus oophorus cells. Progesterone is highly produced by the cumulus oophorus/oocyte complex. We recently showed that progesterone up-regulates the production of LIF by T cells and that the progesterone-induced LIF production is mediated by IL-4. Progesterone produced by cumulus granulosa cells may favor IL-4 production by T cells, which in turn can produce LIF. As the treatment with LIF enhances the in vitro growth and development of mammalian embryos, our data suggest that T cells present in the cumulus oophorus produce cytokines that may provide a microenvironment suitable for pre-implantation development of the mammalian embryo.

Adult↗
PubMed2002

Galectin-3 modulates carbohydrate-dependent thymocyte interactions with the thymic microenvironment.

The process of thymocyte differentiation occurs within the context of the thymic microenvironment, in which T cell precursors interact with thymic microenvironmental cells and extracellular matrix. Here we studied the expression of galectin-3, a beta-galactoside binding lectin, in the thymus of young adult mice. Galectin-3 was found mainly in the medulla and to a lesser extent in the cortex. We further showed that distinct microenvironmental elements, such as thymic epithelial cells, the epithelial component of thymic nurse complexes and phagocytic cells of the thymic reticulum produce, secrete and accumulate galectin-3 on the cell surface. Functionally, galectin-3-enriched medium inhibited in vitro thymocyte interactions with thymic microenvironmental cells, accelerated the release of thymocytes from thymic nurse cells and inhibited the reconstitution of these lymphoepithelial complexes. These effects were blocked by exogenous lactose (Galbeta1-4Glc), but not melibiose (Galalpha1-6Glc), and by a monospecific anti-galectin-3 antibody. Recombinant galectin-3 also inhibited thymocyte/thymic epithelial cell interactions. Our data indicate that intrathymically produced galectin-3 disrupts thymocyte/microenvironmental cell interactions, thus acting as a de-adhesion molecule.

Animals↗
PubMed1978

Cellular microenvironment in relation to local blood flow.

The investigation was designed to identify microenvironmental factors that might be important in the regulation of local blood flow. Cellular microenvironment in terms of Po2, pH, [K+], [Cl-], [Ca2+] and lactate was measured in rat brain by means of specific microelectrodes. Vascular endothelium was stained in vivo with Thioflavine S. Local blood flow was measured with micro hydrogen electrodes. Some intracellular measurements of pH were made in conjunction with extracellular measurements. The main findings were that local autoregulation responses and blood flow changes in response to imposed hypoxic changes were very rapid (1-1.5 s). Microflow responses to changes in local cell activity were limited to a region not more than 250 micron in diameter. Increased blood flow in acute hypoxia occurred within 1-2 s of the fall in tissue Po2 and was much more rapid than changes in either pH or potassium. Intracellular pH changed within 10 s of the onset of severe hypoxia but in all cases the blood flow followed the Po2 much more closely than any other parameter. It is suggested that changes in capillary endothelium and local membrane transmission may play a part in autoregulatory mechanisms.

Animals↗
PubMed1977

Age-related change in the neuronal microenvironment: penetration of ruthenium red into extracellular space of brain in young adult and senescent rats.

The volume of the extracellular space, which contributes to the microenvironment of neurons, is diminished in the brains of senescent (as compared to adult) rats and an age-related change in its composition has been hypothesized. To test this hypothesis we have compared the penetration of ruthenium red, a polyanion selectively distributed in the extracellular space, into the dentate gyri of young adult and senescent Fischer 344 rats. Slices of hoppocampal formation were fixed by immersion, first in a glutaraldehyde solution containing ruthenium red, then in a solution of osmium tetroxide containind examined by electron microscopy. Dense particles of ruthenium red reaction product were readily localized in intercellular channels and synaptic clefts and the depth of penetration of ruthenium red in 25-month-old rats, as compared with 3-month-old animals, was found. These data indicate an age-related change in the charge density of the intercellular channels in the dentate gyrus of 25-month-old rats. They suggest a primary age-related change in the charg density of extracellular macromoledules, presumed to be primarily glycosaminoglycans, with a consequent change in water binding capacity and volume of the extracellular space.

Aging↗
PubMed1984

Localization of lymphocyte subpopulations in peripheral lymphoid organs: directed lymphocyte migration and segregation into specific microenvironments.

The distribution of lymphocytes in the peripheral lymphoid organs is controlled by recirculatory and microenvironmental factors. Specific interactions between recirculating lymphocytes and high endothelial venules in various lymphoid organs determine the presence and proportions of the various lymphoid sets and subsets in those organs. Separate endothelial determinants on peripheral node and Peyer's patch endothelium along with complementary lymphocyte receptors mediate this organ specificity. B and T cells also exhibit nonrandom organization within lymphoid tissues; after entry via high endothelial venules they segregate into their respective domains, which appear to be determined by distinct types of nonlymphoid stromal cells. Antigenic stimulation results in changes in lymphocyte phenotype as well as in the lymphoid microenvironment. The response to most complex antigens is the formation of germinal centers (GC) composed primarily of proliferating B cells; the phenotype of the few T cells therein is supportive of the GC as a site of B-T interaction. The phenotype of the B cells in GCs suggest a role for GCs in immunoglobulin class switching and the determination of subsequent homing specificity.

Animals↗
PubMed1988

Splenic microenvironment of the CBA/N mouse: immunohistochemical analysis using monoclonal antibodies against lymphocytes and nonlymphoid cells.

CBA/N mice carry an X-linked immune-deficiency gene, leading to a defect in the ability to form antibodies against T-independent type 2 antigens. By using immunohistochemistry, the organization of the spleen of the immune-deficient male (xid) CBA/N F1 and the normal female F1 were compared. Staining with antilymphocyte markers showed that the total number of cells in the various T- and B-cell areas was smaller in the xid mouse, resulting in very small white pulp compartments. Fewer B cells were seen in the marginal zone. When the spleens of the F1 mice were examined for macrophage markers, the rings of marginal-zone macrophages and the ring of marginal metallophilic macrophages were much thinner in the xid mouse. In particular, the marginal-zone macrophages are thought to play a role in the response against thymus-independent type 2 antigens, and their small numbers in the xid mouse are suggestive of a role for the microenvironment in the defects in these mice.

Animals↗
PubMed2002

Macrophage subpopulations in rheumatoid synovium: reduced CD163 expression in CD4+ T lymphocyte-rich microenvironments.

OBJECTIVE: The cell surface glycoprotein CD163 is a member of the cysteine-rich scavenger receptor family, highly specific for leukocytes of the mononuclear phagocyte lineage. In vitro, it is induced by glucocorticoids, interleukin-6 (IL-6), and IL-10 and down-regulated by interferon-gamma (IFNgamma), indicating that it has a role in antiinflammatory or other immunomodulatory pathways. We assessed CD163 expression in microenvironments within rheumatoid arthritis (RA) synovium to clarify the relationships among CD4+ T lymphocytes, IFNgamma, and macrophage function in RA. METHODS: Double immunofluorescence and serial immunoenzymatic studies were performed on normal, osteoarthritic, and RA synovium and tonsil with antibodies to CD163, CD45, CD68, CD14, CD3, CD4, CD8, CD19, and IFNgamma. RESULTS: CD163 was observed on all CD14+ cells in synovium and tonsil with the exception of cells within larger T lymphocyte clusters in synovium and within tonsillar follicles. All brightly CD14+ cells in or around vessel walls (interpreted as immigrant monocytes) were CD163+. CD163 labeled fewer cells than did CD68 in synovial intima, but all CD45+ intimal cells were CD163+. CD4+,IFNgamma+ T lymphocytes in RA synovium were chiefly localized within clusters containing CD68+, CD163- cells. CONCLUSION: Within RA synovium, CD163 has major advantages as a macrophage marker and does not appear to be restricted to "mature" macrophages. CD163 discriminates between synovial macrophages and synovial intimal fibroblasts, which also stain positively for CD68 in diseased tissue.

Antigens, CD↗
PubMed1992

Expression of cell-adhesion molecules in the salivary gland microenvironment of Sjögren's syndrome.

OBJECTIVE: The potential role of cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS) was assessed by examining their expression in salivary gland (SGL) tissue. METHODS: Intercellular adhesion molecule type 1 (ICAM-1), lymphocyte function-associated antigen type 1 (LFA-1), LFA-3, CD2, and CD44 expression were determined using indirect immunofluorescence techniques. RESULTS: In inflamed labial SGL tissue, ICAM-1 expression was evident on infiltrating LFA-1+/CD2+/LFA-3+ mononuclear cells, and to a limited extent on SGL acinar epithelial cells adjacent to sites of intense inflammation. CONCLUSION: In SS, the SGL microenvironment is characterized by only a modest up-regulation of ICAM-1 expression on epithelial cells, despite the presence of T cells bearing an activated phenotype.

Adult↗
PubMed2004

Structural analysis of amyloid beta peptide fragment (25-35) in different microenvironments.

Amyloid beta (Abeta) peptides are one of the classes of amphiphilic molecules that on dissolution in aqueous solvents undergo interesting conformational transitions. These conformational changes are known to be associated with their neuronal toxicity. The mechanism of structural transition involved in the monomeric Abeta to toxic assemblage is yet to be understood at the molecular level. Early results indicate that oriented molecular crowding has a profound effect on their assemblage formation. In this work, we have studied how different microenvironments affect the conformational transitions of one of the active amyloid beta-peptide fragments (Abeta(25-35)). Spectroscopic techniques such as CD and Fourier transform infrared spectroscopy were used. It was observed that a stored peptide concentrates on dissolution in methanol adopts a minor alpha-helical conformation along with unordered structures. On changing the methanol concentration in the solvated film form, the conformation switches to the antiparallel beta-sheet structure on the hydrophilic surface, whereas the peptide shows transition from a mixture of helix and unordered structure into predominantly a beta-sheet with minor contribution of helix structure on the hydrophobic surface. Our present investigations indicate that the conformations induced by the different surfaces dictate the gross conformational preference of the peptide concentrate.

Amyloid beta-Peptides↗
PubMed1992

Effects of the thymic microenvironment on the response of thymocytes to stimulation.

We show that, in vitro, the response of thymocytes to certain stimuli, and their survival largely depend on the nature of the culture environment, i.e. whether thymocytes are stimulated within intact thymus lobes or in cell suspension. Exposure of isolated thymocytes to 12-O-tetra-decanoylphorbol 13-acetate (TPA)+ionomycin rapidly abolishes the expression of recombination-activating gene-1 (RAG-1) mRNA (3 h), down-regulates CD4 surface antigen expression (3 h), and enhances apoptosis (24 h). On the other hand, when thymocytes are cultured in intact lobes, TPA plus ionomycin down-regulate rather than abolish RAG-1 mRNA expression (3 h), have little effect on CD4 expression even following 24-h exposure, and only marginally induce apoptosis (24 h). Differences between the culture systems are less pronounced in response to anti-CD3 antibodies. Therefore, it appears that removing thymocytes from their thymic microenvironment makes the cells more susceptible to certain stimuli, possibly by altering their physiological status. In addition, it has been suggested that termination of RAG-1 expression can be linked to thymocyte selection processes. We found that the down-regulation of RAG-1 expression was not dependent on the induction of apoptosis, supporting a proposed link with positive selection.

Animals↗
PubMed2006

Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface.

The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-gamma and TNF-alpha were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-beta and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.

Adoptive Transfer↗
PubMed2002

Influence of the mucosal epithelium microenvironment on Langerhans cells: implications for the development of squamous intraepithelial lesions of the cervix.

We have addressed the notion that the initiation and progression of human papillomavirus associated cancer of the uterine cervix are associated with alterations of Langerhans cells (LC) within the mucosal squamous epithelium. Since the transformation zone (TZ) of the cervix is the site where the majority of squamous intraepithelial lesions (SIL) are initiated, in contrast to the exocervix, we decided to investigate the influence of the local microenvironment within the TZ on the function and density of LC. We show that the TZ is associated with a significant reduction in the density of immature LC (CD1a/LAG) compared to the exocervix. In contrast, the development of SILs is attributed with a relative increased density of immature LC, compared to the TZ. Furthermore, we show that this variability in LC density is correlated with a differential expression of TNFalpha and MIP3alpha within the micro-environment of the TZ and SILs. Both TZ and SIL epithelium-derived LC, in the presence of allogeneic PBMC, induced lower levels of proliferation and IL2 production and higher levels of the immunosuppressive cytokine IL10 in comparison to the exocervix. Nevertheless, the epithelium-derived LC in SILs exhibits a reduction in their functional activity, relative to the TZ. Together our studies suggest that the immunosurveillance within the epithelium of the TZ may be intrinsically perturbed due to the altered expression of chemokines/cytokines and the concomitant diminished density of LC. Furthermore, following HPV infection and the development of SILs, the function of LC may be further incapacitated by viral associated mechanisms.

Antigen Presentation↗