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At least 865 records · Page 48Linked to original sources
PubMed1995

In situ analysis of the immune microenvironment of the adenoid in children with and without secretory otitis media.

Using monoclonal antibodies and immunohistochemistry, we compared adenoid tissue from 35 children with or without secretory otitis media. Numerous cells infiltrating the reticular crypt epithelium expressed HLA-DR, as did < 10% of the epithelial cells. Of the antigen-presenting cells, CD1a+ dendritic cells showed intraindividual and interindividual variations; CD68+ macrophages and CD22+ B cells were uniformly distributed. The relative frequencies of CD4+ and CD8+ cells were 6.6 +/- 2.0 versus 2.3 +/- 1.2 (p < .001) in the reticular crypt epithelium and 18 +/- 4.5 versus 1.5 +/- 0.9 (p < .001) in the germinal centers. The IL-2 receptor was expressed on < 0.1% of CD3+ T cells. Over 90% of intraepithelial CD3+ T cells were of the CD45RO+ memory phenotype. The proliferation marker Ki67 was almost exclusively found in the germinal centers. That the analyzed parameters showed a similar pattern in both clinical groups suggests that the presence of secretory otitis media may not correlate to specific alterations in the immune microenvironment of the adenoid.

Adenoids↗
PubMed1998

Laminin-5 expression is independent of the injury and the microenvironment during reepithelialization of wounds.

We examined the expression of laminin-5 and its integrin receptors during reepithelialization of human wounds. We used suction blisters of skin as a model of keratinocyte migration on a basement membrane matrix and mucosal full-thickness wounds as a model in which keratinocytes migrate in a provisional matrix. An animal model, in which human epidermal keratinocytes were injected into the back of athymic mice, was used to follow the deposition of the basement membrane components. In 4-day-old blisters, about 20-50 cells at the leading edge of the migrating tongue showed cytoplasmic laminin-5 immunostaining. Laminin-5 mRNA was detected in 15-30 cells at the leading edge of the migrating epidermis. alpha3beta1 and alpha6beta4 integrins were found in membrane projections of the migrating basal cells and also in suprabasal cell layers, suggesting their combined role in binding laminin-5. In mucosal wounds, laminin-5 was the only basement membrane zone component that was deposited between the clot and the migrating keratinocytes. In the animal model, linear deposition of laminin-5 and alpha6beta4 integrin was already seen on Day 2, whereas the other basement membrane zone components were not yet organized. The results suggest that, regardless of the injury and the microenvironment, laminin-5 plays an essential role in the interaction between wound keratinocytes and the surrounding matrix.

Adult↗
PubMedDate not supplied

Tumor microenvironment: what have we learned studying the immune response in this puzzling battlefield?

Recent developments hallmark the progress in the understanding of tumor immunology and related therapeutic strategies. The administration of interleukin-2 (IL-2) to patients with cancer has shown that immune manipulation can mediate the regression of established cancers. The identification of the genes encoding cancer antigens and the development of means for effectively immunizing against these antigens has opened new avenues for the development of active immunization of patients with cancer. However, an efficient immune response against tumor comprises an intricate molecular network still poorly understood. Only when the code governing immune responsiveness of cancer will be deciphered, new therapeutic strategies could be designed to fit biologically defined mechanisms of immune rejection of cancer. In this review, we propose that the mechanisms regulating tumor rejection in response to vaccination will be more efficiently identified by following the evolution of treatment induced events within the tumor microenvironment taking advantage of recently developed technological tools. As a model, we will discuss the observed immune response to tumor antigen -specific immunization and its relationship with the systemic administration of IL-2.

Animals↗
PubMed2002

What can wound fluids tell us about the venous ulcer microenvironment?

Research into the healing of venous leg ulcers is increasing as they are a common problem. The wound fluid bathing an ulcer is thought to reflect the wound microenvironment, and the properties of wound fluids have been studied in attempts to find ways to promote healing. After a brief summary of normal wound healing, this article reviews some of the research that has been carried out on venous ulcer wound fluid, with respect to its biochemistry, proteolytic nature, growth factor profile, and effects on cell cultures. Some of the problems and pitfalls inherent in performing and interpreting wound fluid studies are discussed. Finally, a proposal is made for standardizing research on wound fluids that would improve comparisons between different studies.

Journal Article↗
PubMed1980

Distribution of H-2 microenvironments in the mouse thymus. Immunoelectron microscopic identification of I-A and H-2K bearing cells.

Antigens coded for by the major histocompatibility complex (MHC) are differentially expressed in the mouse thymus. Immunoperoxidase studies of frozen thymus sections incubated with monoclonal (hybridoma) anti-I-Ak antibodies revealed a dendritic straining pattern in the cortex and a confluent staining pattern in the medulla. Serial sections incubated with monoclonal anti-H-2Kk antibodies showed that H-2Kk antigens were only present at detectable levels in the medulla. Microenvironments expressing H-2Kk antigens also expressed I-Ak antigens. In cortico-medullary regions, relatively large MHC-negative areas were found. These areas appeared to connect to perivascular spaces surrounding blood vessels. Using a new postfixation labeling method for the detection of cell surface associated antigens on cells of the lymphoid system in situ, we have characterized the nature of MHC positive cell types at the ultrastructural level. These studies show that epithelial-reticular cells are the major MHC positive elements in the thymus. Lymphocytes in the medulla and in cortico-medullary bounderies are also MHC positive, however, lymphocytes in the cortex were not detectably labeled. These findings support the contention that epithelial-reticular cells are involved in the H2-restriction process during T cell maturation.

Animals↗
PubMed1991

Extracellular matrix components of the mouse thymus microenvironment: ontogenetic studies and modulation by glucocorticoid hormones.

The present investigation was an ontogenetic study on the distribution of extracellular matrix (ECM) components in the thymic microenvironment of C57BL/6 mice (comprising young and old adults and developing embryos) and NZB mice. In addition, we evaluated the in vivo and in vitro influence of hydrocortisone treatment on basement membrane protein production by a thymic epithelial cell line. In young normal animals, Type I collagen was restricted to the interstitial spaces of the capsule and septa, where Type IV collagen, fibronectin, and laminin could be detected in the basement membranes. In addition, fibronectin-containing fibers were seen within the medulla of the thymic lobules. The ECM distribution pattern in the developing embryos was distinct from that observed in adults, since a fine meshwork of basement membrane-containing proteins was clearly seen throughout the parenchyma. Moreover, aging normal and NZB mice exhibited a denser ECM pattern than young adult normal animals. Treatment with hydrocortisone, both in vivo and in vitro, resulted in enhancement of ECM expression, detected in mice as early as 2 hr post injection and lasting for several days. Considering that the fluctuations of ECM expression parallel important events in thymocyte differentiation, we discuss the possibility that the two phenomena may be associated.

Animals↗
PubMed2003

GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment.

Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.

Bone Marrow↗
PubMed2005

Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment.

Notch receptors are involved in lineage decisions in multiple developmental scenarios, including hematopoiesis. Here, we treated hybrid human-mouse fetal thymus organ culture with the gamma-secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-l-alanyl]-S-phenyl-glycine t-butyl ester) (DAPT) to establish the role of Notch signaling in human hematopoietic lineage decisions. The effect of inhibition of Notch signaling was studied starting from cord blood CD34(+) or thymic CD34(+)CD1(-), CD34(+)CD1(+), or CD4ISP progenitors. Treatment of cord blood CD34(+) cells with low DAPT concentrations results in aberrant CD4ISP and CD4/CD8 double-positive (DP) thymocytes, which are negative for intracellular T-cell receptor beta (TCRbeta). On culture with intermediate and high DAPT concentrations, thymic CD34(+)CD1(-) cells still generate aberrant intracellular TCRbeta(-) DP cells that have undergone DJ but not VDJ recombination. Inhibition of Notch signaling shifts differentiation into non-T cells in a thymic microenvironment, depending on the starting progenitor cells: thymic CD34(+)CD1(+) cells do not generate non-T cells, thymic CD34(+)CD1(-) cells generate NK cells and monocytic/dendritic cells, and cord blood CD34(+)Lin(-) cells generate B, NK, and monocytic/dendritic cells in the presence of DAPT. Our data indicate that Notch signaling is crucial to direct human progenitor cells into the T-cell lineage, whereas it has a negative impact on B, NK, and monocytic/dendritic cell generation in a dose-dependent fashion.

Amyloid Precursor Protein Secretases↗
PubMed2005

Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment.

Hematopoiesis is maintained by specific interactions between both hematopoietic and nonhematopoietic cells. Whereas hematopoietic stem cells (HSCs) have been extensively studied both in vitro and in vivo, little is known about the in vivo characteristics of stem cells of the nonhematopoietic component, known as mesenchymal stem cells (MSCs). Here we have visualized and characterized human MSCs in vivo following intramedullary transplantation of enhanced green fluorescent protein-marked human MSCs (eGFP-MSCs) into the bone marrow (BM) of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Between 4 to 10 weeks after transplantation, eGFP-MSCs that engrafted in murine BM integrated into the hematopoietic microenvironment (HME) of the host mouse. They differentiated into pericytes, myofibroblasts, BM stromal cells, osteocytes in bone, bone-lining osteoblasts, and endothelial cells, which constituted the functional components of the BM HME. The presence of human MSCs in murine BM resulted in an increase in functionally and phenotypically primitive human hematopoietic cells. Human MSC-derived cells that reconstituted the HME appeared to contribute to the maintenance of human hematopoiesis by actively interacting with primitive human hematopoietic cells.

Animals↗
PubMed2005

Keystone symposium: the role of microenvironment in tumor induction and progression, Banff, Canada, 5-10 February 2005.

The first Keystone symposium on the role of microenvironment in tumor induction and progression attracted 274 delegates from 13 countries to Banff in the heart of the Canadian Rockies. The meeting was organized by Mina Bissell, Ronald DePinho and Luis Parada, and was held concurrently with the Keystone symposium on cancer and development, chaired by Matthew Scott and Roeland Nusse. The 30 oral presentations and over 130 posters provided an excellent forum for discussing emerging data in this rapidly advancing field.

Breast Neoplasms↗
PubMed2006

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERalpha-positive breast carcinomas.

INTRODUCTION: Breast cancer is the most frequent malignant disease in women. Exposure to estrogens throughout a woman's life is a risk factor for the development of breast cancer. Organochlorine compounds (OCCs), such as pesticides and polychlorinated biphenyls, are persistent lipophilic chemicals identified as endocrine disruptors, mainly with estrogenic effects. To test the hypothesis that the amount and quality of organochlorine residues in adipose tissue adjacent to breast carcinoma affect the biological behavior of the tumor, we studied biomarker expression in breast carcinoma and the OCC body burden in patients from an urban area adjacent to Paraná fluvial system, Argentina. METHODS: The studied patients were 55 women who had undergone excision biopsies of a breast lesion diagnosed as invasive breast carcinoma. Analysis of OCC residues in breast adipose tissue was conducted by electron-capture gas-liquid chromatography. Estrogen receptor alpha (ERalpha), progesterone receptor (PR) and proliferative activity (Ki-67) levels were measured in paraffin-embedded biopsies of breast tumors by immunohistochemistry. RESULTS: All patients had high levels of organochlorine pesticides in their breast adipose tissue. The most frequently detected compounds were p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and beta-hexachlorocyclohexane. When the whole sample was analyzed, no correlation between ERalpha or PR expression and OCC levels were found. In the subgroup of ERalpha-positive breast carcinoma patients, however, there was a positive correlation between PR expression (an estrogen-induced protein) in the neoplastic cells and OCC levels in adipose tissue surrounding the tumor. More significantly, all the ERalpha-positive breast carcinomas from postmenopausal women exhibited high proliferation when organochlorine levels in the surrounding adipose tissue reached levels higher than 2600 ppb. No associations were found between the organochlorine body burden and any other marker of tumor aggressiveness, such as node involvement or tumor size. CONCLUSION: The present results support the hypothesis that organochlorine residues in adipose tissue adjacent to breast carcinoma generate an estrogenic microenvironment that may influence the biological behavior of the tumor through ERalpha activation and ERalpha-dependent proliferation. These findings may have therapeutic implications, since interference between organochlorine compounds and hormonal therapy could be expected to occur.

Adipose Tissue↗
PubMed2003

Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment.

Growth and progression of breast cancers are accompanied by increased neovascularization (angiogenesis). A variety of factors, including hypoxia and genetic changes in the tumor cells, contribute to increased production of angiogenic factors. Furthermore, cells within the activated tumor stroma also contribute to the increase in production of vascular endothelial growth factor and other angiogenic factors, including basic fibroblast growth factor and platelet-derived growth factor. The contribution of the microenvironment to tumor-induced angiogenesis is underscored by findings that breast tumors implanted into different tissue sites show marked differences in the extent and nature of the angiogenic response. These findings have important implications for designing anti-angiogenic therapies.

Animals↗
PubMed2005

Tumor microenvironments, the immune system and cancer survival.

The study of cancer immunology has recently been reinvigorated by the application of new research tools and technologies, as well as by refined bioinformatics methods for interpretation of complex datasets. Recent microarray analyses of lymphomas suggest that the prognosis of cancer patients is related to an interplay between cancer cells and their microenvironment, including the immune response.

Cell Transformation, Neoplastic↗
PubMed2005

Professional phagocytic granulocytes of the bony fish gilthead seabream display functional adaptation to testicular microenvironment.

It has been shown previously that professional phagocytic granulocytes are present in the testis of the gilthead seabream, a seasonal breeding teleost that offers an excellent model for studying the testicular regression process that occurs in seasonal testicular involution and sex change. It is unexpected that testicular granulocytes produce interleukin-1beta, a regulator for spermatogonia proliferation in mammals, but are not involved in the elimination of degenerative germ cells. Here, we show that phagocytosis and reactive oxygen intermediate (ROI) production were suppressed dramatically in testicular phagocytic granulocytes, compared with their level of activity in the head-kidney, the main hematopoietic organ in fish. Furthermore, testicular-conditioned media modulated migration, phagocytosis, and ROI production of head-kidney phagocytic granulocytes, and the addition of testicular cells impaired their ROI production capacity. Until now, monocytes/macrophages were believed to be the only innate immune cells able to develop into functional subsets, whereas neutrophils only infiltrate the tissues upon infection or inflammation. Our findings demonstrate, however, that fish professional phagocytic granulocytes also display functional adaptation to different microenvironments and strongly suggest a role for these cells in the reorganization of the testis during post-spawning.

Adaptation, Physiological↗
PubMed2006

The dermal microenvironment induces the expression of the alternative activation marker CD301/mMGL in mononuclear phagocytes, independent of IL-4/IL-13 signaling.

Recently, we have shown that mononuclear phagocytes comprise the majority of interstitial cells in the mouse dermis, as indicated by their phenotypic and functional characteristics. In particular, these cells express the mouse macrophage galactose-/N-acetylgalactosamine-specific-lectin (mMGL)/CD301, identified by the monoclonal antibody ER-MP23, as well as other macrophage markers. As expression of mMGL is induced by IL-4 or IL-13 and is therefore a marker of alternatively activated macrophages, we asked whether dermal mononuclear phagocytes are genuinely alternatively activated. We observed that these cells expressed, next to mMGL, two other alternative activation markers, namely, the mannose receptor/CD206 and Dectin-1. Yet, as this expression profile was similar in IL-4 receptor alpha knockout mice, neither IL-4 nor IL-13 signaling appeared to be required for this phenotype. We also found that Langerhans cells (LC), which showed only a low level of mMGL in the epidermis, up-regulated mMGL expression upon migration through the dermis, allowing these cells to internalize limited amounts of mMGL ligands. LC isolated from epidermal preparations did not show this up-regulation when cultured in standard medium, but whole skin-conditioned medium did stimulate mMGL expression by LC. The vast majority of mMGL molecules was present in the cytoplasm, however. LC, which arrived in skin-draining lymph nodes, quickly down-regulated mMGL expression, and dermally derived cells retained significant mMGL levels. Taken together, these data suggest that the dermal microenvironment induces mononuclear phagocyte subpopulations to express mMGL and possibly other markers of alternatively activated macrophages, independent of IL-4/IL-13 signaling.

Animals↗
PubMed2004

Targeting multiple myeloma cells and their bone marrow microenvironment.

Although multiple myeloma (MM) is sensitive to chemotherapy and radiation therapy, long-term disease-free survival is rare, and MM remains incurable despite conventional and high-dose therapies. Direct (cell-cell contact) and soluble (via cytokines) forms of interactions between MM cells and bone marrow stroma regulate growth, survival, and homing of MM cells. These interactions also play a critical role in angiogenesis and in myeloma bone disease. In recent years, several studies have established the biologic significance of cytokines in MM pathogenesis and delineated signaling cascades mediating their effects, providing the framework for related novel therapies targeting not only the MM cell, but also the bone marrow microenvironment.

Antineoplastic Agents↗
PubMed2005

Manipulating the local tumor microenvironment with poxviruses expressing costimulatory molecules.

The identification of tumor-associated antigens and new insights into the molecular and cellular basis of tumor immunology have generated a variety of vaccine strategies. Although promising in animal models, data from early-phase clinical trials have not been encouraging. These studies have documented the ability of vaccines to prime T cells, but these responses have not correlated with therapeutic effectiveness. Because the location of T-cell activation and effector activity may impact T-cell function significantly, attention has been placed on the tumor microenvironment. There is now evidence that T-cell responses may be altered in the setting of established tumor growth. To alter the balance between local immune responses and tumor growth, a vaccine regimen using direct intratumoral delivery of poxvirus vaccines expressing costimulatory molecules was developed. An initial series of clinical trials has documented the safety profile of this approach and has suggested that local and systemic immunity can be induced. Herein, we review the general rationale for this approach, discuss the results of ongoing clinical trials, and highlight critical questions that can be addressed in well-designed preclinical and clinical studies.

Cancer Vaccines↗
PubMed2006

Chemical stabilization of a Delta9-tetrahydrocannabinol prodrug in polymeric matrix systems produced by a hot-melt method: role of microenvironment pH.

This research was conducted in order to fabricate stable polyethylene oxide (PEO)-based transmucosal systems of a Delta(9)-tetrahydrocannabinol (THC) prodrug, a hemisuccinate ester, using a hot-melt method. Since Delta(9)-tetrahydrocannabinol-hemisuccinate (THC-HS) was heat labile, a series of processing aids were evaluated in order to facilitate hot-melt production at lower temperatures, thereby reducing THC-HS degradation. The stability of THC-HS was influenced both by the processing conditions such as heating time and temperature, and the postprocessing storage conditions. The type of formulation additive also affected the extent of degradation. In the presence of polyethylene glycol (PEG)-400, the percentage of relative degradation of THC-HS to THC was 13.5% and 49.4% at 80 degrees C and 120 degrees C, respectively. In contrast, incorporation of vitamin E succinate (VES) reduced processing degradation to 2.1% and 9.2%, respectively, under the same conditions. Severe degradation of THC-HS was observed during storage, even under freezing conditions (-18 degrees C). A VES-Noveon AA-1 combination was observed to best stabilize the prodrug systems both during processing and postprocessing. Stabilization of THC-HS was achieved in these polyethylene oxide matrices at 4 degrees C, with almost 90% of theoretical drug remaining for up to 8 months. Investigation of the pH effect revealed that the pH of the microenvironment in these polymeric systems could be modulated to significantly improve the stability of THC-HS, degradation being the least in a relatively acidic medium.

Dronabinol↗