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PubMed2003

Osteopontin: roles in implantation and placentation.

Osteopontin (OPN) is an acidic member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of extracellular matrix proteins/cytokines that undergoes extensive posttranslational modification, including phosphorylation, glycosylation, and cleavage, yielding molecular mass variants ranging in size from 25 to 75 kDa. The result is a versatile protein(s) with multiple functions arising from its role as a mediator of cell-cell and cell-extracellular matrix (ECM) communication that encompass both normal and tumorigenic developmental processes, immunological responses during inflammation and wound healing, and biomineralization. Studies in primates, pigs, sheep, and rodents have revealed that OPN is a major constituent of the uterine-placental microenvironment with influence as 1) a component of histotroph required for adhesion and signal transduction at the uterine-placental interface throughout pregnancy, 2) a gene product expressed by uterine stroma contributing to a decidualization-like transformation that correlates with the degree of conceptus invasiveness, and 3) a product of resident uterine and placental immune cells that may regulate their behavior and cytokine production. This minireview summarizes information regarding uterine and placental expression of OPN that has accumulated over the past 15 yr, and we briefly describe structural/functional properties of this protein that are likely relevant to its role(s) during pregnancy. Comparative studies have offered insights into the potential hormonal/cytokine, cellular, and molecular mechanisms underlying OPN-mediated adhesion, remodeling, and cell-cell/cell-ECM communication within the uterus and placenta. OPN has the potential to profoundly impact pregnancy, and investigators are now challenged to focus on the mechanistic nature of the functions of this multifaceted and major component of the uterine-placental microenvironment.

Animals↗
PubMed1989

Studies on the thymus in Chagas' disease. I. Changes in the thymic microenvironment in mice acutely infected with Trypanosoma cruzi.

Previous observations demonstrated severe thymocyte depletion in mice undergoing acute Chagas' disease. These data led us to investigate the status of the thymic microenvironment in these animals. Young adult C57BL/6 and C3H/HeJ mice were infected i.p. with 10(5) blood-derived trypomastigote forms of Trypanosoma cruzi (CL strain) and killed 7-14 days after infection. Sera were then analyzed for thymic hormone (thymulin) levels, and frozen thymus sections were studied by immunohistochemistry for the expression of functional antigens (thymulin and Ia), the distribution of distinct thymic epithelial cell subsets and extracellular matrix components. Infected mice exhibited a transient decrease in thymulin production and those with severe thymic atrophy showed a denser Ia-bearing cellular network. In addition, an abnormal localization of the TR5 and CK18 antigens restricted to the medullary and cortical TEC subsets, respectively, was observed. Furthermore, an increase in the basement membrane proteins was detected within thymic lobules. We suggest that the thymic microenvironment is also affected during T. cruzi infection, extending the concept that the thymus should be regarded as a target in Chagas' disease.

Animals↗
PubMed1998

A subchronic exposure to trichloroethylene causes lipid peroxidation and hepatocellular proliferation in male B6C3F1 mouse liver.

The common groundwater contaminant trichloroethylene (TCE), when given by oral gavage, can produce free radical species during metabolism. Furthermore, TCE end-stage metabolites, trichloroacetic acid and dichloroacetic acid, cause lipid peroxidation in mouse liver. The time courses of lipid peroxidation, free radical generation, and 8-hydroxydeoxyguanosine (8OHdG) formation were used to assess the level of oxidative stress in the liver of B6C3F1 mice dosed orally once daily, 5 days a week for 8 weeks at 0, 400, 800, and 1200 mg/kg TCE in corn oil. Peroxisomal proliferation, cell proliferation, and apoptosis were evaluated at selected times during the study. Lipid peroxidation, as measured by thiobarbituric acid-reactive substances (TBARS), was significantly elevated at the two highest dose levels of TCE on days 6 through 14 of the study. 8OHdG levels were statistically significant in the 1200 mg/kg/day group on days 2, 3, 10, 28, 49, and 56 only. The highest measured free radical load, 307% of oil control, occurred at day 6. A significant increase in cell and peroxisomal proliferation was observed during the same time period in the 1200 mg/kg/day group. Necrosis or an increase in apoptosis was not observed at any dose. The temporal relationship between oxidative stress and cellular response of proliferation, both of which occur and resolve within the same relative time period, suggests that TCE-induced mitogenesis may result from alteration in the liver microenvironment which offers a selective advantage for certain hepatocyte subpopulations.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2025

How Have Massively Parallel Sequencing Technologies Furthered Our Understanding of Oncogenesis and Cancer Progression?

Massively parallel sequencing technologies have been a boon to many fields of biological science, including oncology. Cancer is an umbrella term for many diseases featuring abnormal cellular growth due to genetic and epigenetic aberrations. Advances in sequencing technology allow for interrogation of the DNA and RNA of cancer cells and other cells in the tumor microenvironment down to a single-base resolution. However, these strides come after a rich history of ground-breaking biological assays, like the discovery of the Philadelphia chromosome in the context of leukemia. Many specific genetic and epigenetic modifications have been implicated in oncogenesis, cancer progression, and response to treatment. Sequencing technologies have also helped to associate populations of bacteria in the microbiome to cancer development and prognosis. However, all this new information, especially when procured via high-throughput methods, comes at the cost of being more computationally and staff-resource intensive. There is also more risk to the privacy of the individuals with sequenced genomes. Notwithstanding, the overall benefit of sequencing technologies can greatly outweigh the risks with careful advancements and continued focus on the goal: helping those affected by cancer via precision medicine. Cancer biology has been and will continue to be elucidated by sequencing innovations in ways unimaginable without it.

Humans↗
PubMed2003

Chemokines in the systemic organization of immunity.

Directed cellular migrations underlie immune system organization. Chemokines and their receptors (along with surface-adhesion molecules) are central to these migrations, targeting developing and mature leukocytes to tissues and microenvironments suitable for their differentiation and function. The chemokine CXCL12 and its receptor CXCR4 play a central role in the migration of hematopoietic stem cells, and several chemokine receptors are transiently expressed during distinct stages of B- and T-cell development. In the periphery, mature naïve B and T cells utilize the receptors CCR7, CXCR4, and CXCR5 to recirculate through specialized microenvironments within the secondary lymphoid tissues, while effector and memory lymphocytes express bewildering patterns of adhesion molecules and chemokine receptors that allow them to function within microenvironments and non-lymphoid tissues inaccessible to naïve cells. Here, we summarize the role of chemokines and their receptors in the spatial organization of the immune system and consider the implications for immune function.

Animals↗
PubMed2002

The influence of pH on charged porphyrins studied by fluorescence and photoacoustic spectroscopy.

We have studied the influence of solvent acidity on the aggregation/protonation behaviour of two charged tetraphenylporphyrins: positively charged tetrakis(N,N,N-trimethylanilinium-4-yl)porphyrin (TAP) and negatively charged tetrakis(4-sulfonatophenyl)porphyrin (TPPS4). Spectroscopic measurements (absorption, fluorescence, excitation and photoacoustic) have been made to follow the radiative and nonradiative relaxation processes of excited dye molecules at various pH values. The ability of these porphyrins to exist in aggregated and protonated forms was also investigated. It has been shown that TPPS4 exists in at least three spectroscopic forms: monomer (M1), dication (D1) and aggregated dication (AD), whereas TAP exists in two forms: monomer (M2) and dication (D2). These forms are characterised by different absorption and fluorescence properties. The short wavelength forms of the dyes (M1 and M2) were assigned to the monomeric forms and D1 and D2 were assigned to the protonated forms of TPPS4 and TAP, respectively; AD was identified as the aggregate of the protonated form of TPPS4. Each form shows deactivation of its excited state by nonradiative pathways-particularly high thermal deactivation was observed for the aggregates of the protonated form. Energy transfer between the monomeric form and the dication form has been demonstrated and Förster radii have been estimated (R0 = 31 and 44 A for TAP and TPPS4, respectively). Since protonation and aggregation of photoreceptors can strongly affect their photosensitizing effects (e.g. cellular uptake, singlet oxygen production) the results presented here may be important in the study of the function of photosensitizers in tumour tissues because, as is already known, the microenvironment in cancerous tissue is more acidic than in healthy cells.

Acoustics↗
PubMed2003

The tumor microenvironment: a critical determinant of neoplastic evolution.

Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular 'diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies.

Animals↗
PubMed2007

Nitric oxide in physiologic concentrations targets the translational machinery to increase the proliferation of human breast cancer cells: involvement of mammalian target of rapamycin/eIF4E pathway.

Nitric oxide (NO) in nanomolar (nmol/L) concentrations is consistently detected in tumor microenvironment and has been found to promote tumorigenesis. The mechanism by which NO enhances tumor progression is largely unknown. In this study, we investigated the possible mechanisms and identified cellular targets by which NO increases proliferation of human breast cancer cell lines MDA-MB-231 and MCF-7. DETA-NONOate, a long acting NO donor, with a half-life of 20 h, was used. We found that NO (nmol/L) dramatically increased total protein synthesis in MDA-MB-231 and MCF-7 and also increased cell proliferation. NO specifically increased the translation of cyclin D1 and ornithine decarboxylase (ODC) without altering their mRNA levels or half-lives. Critical components in the translational machinery, such as phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets, phosphorylated eukaryotic translation initiation factor and p70 S6 kinase, were up-regulated following NO treatment, and inhibition of mTOR with rapamycin attenuated NO induced increase of cyclin D1 and ODC. Activation of translational machinery was mediated by NO-induced up-regulation of the Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK (Raf/MEK/ERK) and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt signaling pathways. Up-regulation of the Raf/MEK/ERK and PI-3 kinase/Akt pathways by NO was found to be mediated by activation of Ras, which was cyclic guanosine 3',5'-monophosphate independent. Furthermore, inactivation of Ras by farnesyl transferase inhibitor or K-Ras small interfering RNA attenuated NO-induced increase in proliferation signaling and cyclin D1 and ODC translation, further confirming the involvement of Ras activation during NO-induced cell proliferation.

Alkyl and Aryl Transferases↗
PubMed2000

Excessive apoptosis in low risk myelodysplastic syndromes (MDS).

The paradox of peripheral cytopenias despite a normo/hypercellular marrow in MDS has been ascribed to excessive intramedullary hematopoietic cell apoptosis. Programmed cell death (PCD) in early disease might be triggered by the BM microenvironment, mediated either through inhibitory cytokines such as tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or through a relative deficiency in hematopoietic growth factors. Intrinsic cellular defects giving rise to abnormalities in cell-cell or cell-stromal interaction, cell signaling or cell cycling may also underlie hematopoietic progenitor apoptosis. Alternatively, an early 'hit' in the multistep pathogenesis of MDS may result in a higher proliferative rate of the neoplastic clone. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a role for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic progenitor cell apoptosis might be circumvented.

Apoptosis↗
PubMed2026

Single-cell and spatial transcriptomic technologies for lung cancer tumor microenvironment analysis.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide; beyond its rising incidence, its marked molecular heterogeneity and complex tumor microenvironment (TME) hinder treatment response and drive resistance, contributing directly to its high mortality rate. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) provide complementary approaches for dissecting these features. scRNA-seq enables high-resolution analysis of cellular diversity and transcriptional states but requires tissue dissociation and therefore loses spatial context. In contrast, ST preserves tissue architecture and provides insights into how gene-expression programs within the TME are organized, although no currently available spatial platform combines whole-transcriptome coverage with true single-cell resolution over large tissue areas. Together, these technologies have enabled detailed mapping of tumor, immune and stromal populations and of their spatial interactions, revealing functionally distinct cellular niches that contribute to immune evasion, metastasis and response to therapy. In this narrative review we organize the primary literature around a single question, how spatially structured cellular ecosystems, rather than individual cell types, determine therapeutic response and resistance in lung cancer - and we explicitly separate observations that are reproducible across independent cohorts and platforms from those that remain confined to single studies. We further summarize the technical, analytical and logistic barriers that currently prevent spatially resolved signatures from entering routine diagnostic pathology. Understanding dysregulated pathways and spatially constrained intercellular communication within the TME helps identify candidate biomarkers and may support the identification of therapeutic approaches directed at tumor-intrinsic programs as well as at microenvironment-driven resistance mechanisms.

Cell-cell communication↗
PubMed1997

Purkinje cell survival and axonal regeneration are age dependent: an in vitro study.

Purkinje cells are among the most resistant neurons to axotomy and the most refractory to axonal regeneration. By using organotypic cultures, we have studied age- and environment-related factors implicated in Purkinje cell survival and axonal regeneration. Most Purkinje cells taken from 1- to 5-d-old rats, the period in which these neurons are engaged in intense synaptogenesis and dendritic remodeling, die 1 week after plating, whereas if cultured before or after this period, Purkinje cells survive, even in the absence of deep nuclear neurons, their postsynaptic targets. Cerebellar slices taken from 10-d-old rats and kept in vitro for 1 week acquire a cellular composition resembling mature cerebellum. Their Purkinje cells are resistant to axotomy, but even when confronted with permissive environments (sciatic nerves or fetal cerebellar slices), their axons do not regenerate. In contrast, fetal rat and mouse Purkinje cells are able to regenerate their axons on mature cerebellar slices. This regeneration is massive, and the regrowing axons invade all cerebellar regions of the apposed mature slices, including white matter. These results show that Purkinje cell survival and axonal regeneration are age-related and independent from environmental constraints. Moreover, our observations suggest strongly that the onset of synaptogenesis of Purkinje cell axons could provide a signal to turn off their growth program and that, thereafter, permissive microenvironment alone is unable to reestablish such a program.

Animals↗
PubMed2026

Region-Resolved Integrative Multi-Omic Characterization Reveals Diverse Tumor and Microenvironment Features of Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors are frequently invasive, with cavernous sinus invasion leading to poor treatment outcomes and high recurrence. Regional differences within these tumors remain poorly understood, hindering targeted therapy development. Here, we present the first integrative multi-omics analysis combining proteomics, metabolomics and single-cell transcriptomics to characterize tumors from the cavernous sinus and saddle regions. Our results reveal profound regional and cellular heterogeneity: cavernous sinus tumors exhibit significantly enhanced cell proliferation, driven by cancer-associated fibroblasts through the IGF1-IGF1R-MAPK1 axis. Cancer-associated fibroblasts in the cavernous sinus secrete IGF1 under regulation of the transcription factor FOXO1, which binds to receptors on tumor cells to activate proliferation. Metabolomic profiling identifies proline as a key enriched metabolite that stimulates cancer-associated fibroblasts to produce collagen fibers, reinforcing a pro-tumorigenic microenvironment. Single-cell transcriptomics further delineates a distinct subpopulation of receptor-positive malignant cells and a high abundance of cancer-associated fibroblasts in the cavernous sinus. These findings establish core mechanisms underlying the aggressive behavior of cavernous sinus-invading tumors, providing novel actionable targets for precision therapeutic strategies tailored to distinct tumor regions.

Humans↗
PubMed2005

An emerging role for comprehensive proteome analysis in human pregnancy research.

Elucidation of underlying cellular and molecular mechanisms is pivotal to the comprehension of biological systems. The successful progression of processes such as pregnancy and parturition depends on the complex interactions between numerous biological molecules especially within the uterine microenvironment. The tissue- and stage-specific expression of these bio-molecules is intricately linked to and modulated by several endogenous and exogenous factors. Malfunctions may manifest as pregnancy disorders such as preterm labour, pre-eclampsia and fetal growth restriction that are major contributors to maternal and perinatal morbidity and mortality. Despite the immense amount of information available, our understanding of several aspects of these physiological processes remains incomplete. This translates into significant difficulties in the timely diagnosis and effective treatment of pregnancy-related complications. However, the emergence of powerful mass spectrometry-based proteomic techniques capable of identifying and characterizing multiple proteins simultaneously has added a new dimension to the field of biomedical research. Application of these high throughput methodologies with more conventional techniques in pregnancy-related research has begun to provide a novel perspective on the biochemical blueprint of pregnancy and its related disorders. Further, by enabling the identification of proteins specific to a disease process, proteomics is likely to contribute, not only to the comprehension of the underlying pathophysiologies, but also to the clinical diagnosis of multifactorial pregnancy disorders. Although the application of this technology to pregnancy research is in its infancy, characterization of the cellular proteome, unearthing of functional networks and the identification of disease biomarkers can be expected to significantly improve maternal healthcare in the future.

Female↗
PubMed1987

Influence of the mesenchymal microenvironment on myocardial and endocardial cell behaviour in experimental interaction with chick limb mesenchyme.

In an attempt to clarify the possible influence of the mesenchymal microenvironment in the differentiation of myocardial and endocardial cells, an "in vivo" transplantation experiment was performed in which the ventricular region of the heart (chick or quail) was placed in close association to the mesenchyme of the anterior chick limb to create an experimental interaction between myocardium and foreign mesenchyme. The results showed that after 48 h of tissue interactions the ventricular myocardium is incorporated into the mesenchyme of the anterior chick limb, changing its organization and cytological appearance. The myocytes tend to dissociate, exhibiting a less organized myofibrillar pattern. In addition, abundant extracellular matrix components made up of granular and fibrillar material were observed associated with the myocardial and the mesenchymal cell membranes as well as distributed in their surrounding microenvironment. The endocardium became discontinuous, due to detachment of the cells and emitted multiple pseudopodia and filopodia. These observations indicate that the mesenchyme from the anterior chick limb modifies the cellular behaviour and organization of the neighbouring myocardium and endocardium with which it interacts. We suggest that this might occur through participation of extracellular matrix components such as glycosaminoglycans, fibronectin and collagen which are known to act as macromolecular mediators in cell to cell interactions, cell migration and differentiation.

Animals↗
PubMed1990

Observations on the haemopoietic response to critical illness.

Peripheral blood cytopenias are common in patients receiving intensive care, particularly in those with multiple organ failure. To assess the contribution of bone marrow hypoplasia in such patients 44 bone marrow samples from 24 patients under intensive care were studied by standard morphological techniques and by the granulocyte-macrophage colony forming cell (GM-CFC) assay. Frequently observed morphological abnormalities in the bone marrow included the following: (i) a reduction in overall cellularity in seven patients, with a progressive decrease in most patients studied sequentially; (ii) an increase in the number of actively phagocytic macrophages; and (iii) a disruption of normal bone marrow architecture with the accumulation of intercellular hyaluronic acid glycosaminoglycan. Mean GM-CFC growth was significantly reduced when compared with that in a group of normal controls. In four of five patients studied sequentially GM-CFC growth became subnormal in association with a reduction in bone marrow cellularity. Inhibitory serum factors were not identified. These morphological abnormalities are similar to the changes observed in gelatinous degeneration of the bone marrow. In both situations disruption of the haemopoietic microenvironment, with the accumulation of hyaluronic acid proteoglycan, may be an important factor in the inhibition of haemopoietic progenitor cell growth. The proliferation of macrophages, by the release of a variety of cytokines or reactive oxygen intermediates, may also be implicated in impaired haemopoiesis and the development of disordered erythropoiesis.

Adolescent↗
PubMed2005

Costimulatory pathways in rheumatoid synovitis and T-cell senescence.

The pathogenesis of rheumatoid arthritis (RA) is determined by a complex interaction of genetic and environmental factors. Of all risk factors, age has the largest impact. RA occurs most often during the postmenopausal period of life, with incidence rates peaking in the eighth decade. While age is generally accepted as an etiologic factor for failure of immunocompetence, much less is understood about the role of T-cell senescence in autoimmunity. We have hypothesized that senescent T cells are particularly prone to be activated in specialized microenvironments, such as the synovial membrane. CD4 T cells in the senescence program were identified by the loss of CD28. Gene expression profiling documented that CD28- T cells have acquired a spectrum of regulatory receptors that are usually seen only on NK cells. Such regulatory receptors include stimulatory and inhibitory members of the killer immunoglobulin-like receptor (KIR) family, the stimulatory c-type lectin receptor NKG2D, and CX3CR1, the receptor for the chemokine fractalkine. Synovial fibroblasts express the relevant ligands, thus providing stimulatory signals to tissue-infiltrating T cells. The signaling pathways of these regulatory receptors are complex and dependent on the individual T cells, some of which express important adapter molecules such as DAP10 and DAP12. Inhibitory KIRs on T cells are often only partially functional. Our data suggest that, by virtue of altered receptor profiles, conventional tolerance mechanisms can be evaded in the aging host. By acquiring a new set of regulatory receptors, senescent CD4 T cells become responsive to novel environmental cues and find ideal stimulatory conditions in the synovial microenvironment.

Arthritis, Rheumatoid↗
PubMed1981

Stromal colony-stimulating activity production and myeloid colony-forming cells in human hemopoietic and nonhemopoietic bone marrow.

In order to evaluate the role of the stromal bone marrow microenvironment in regulating granulopoiesis, we have examined the capacity of adult human proximal hemopoietic (PH) and distal nonhemopoietic (DNH) long bone to produce colony-stimulating activity (CSA), characterized the cellular sources of CSA, and quantitated the colony-forming cells (CFU-GM) of marrow from these sites. Stromal elements were obtained from slices of cancellous bone. PH bone marrow stroma contained CFU-GM concentrations similar to aspirated PH marrow and significantly more CFU-GM than DNH bone marrow: 20.7 +/- 4.8/10(5) cells and 25.8 +/- 12.0/mg bone versus 0.81 +/- 0.34/10(5) cells and 0.02 +/- 0.01/mg bone (p less than 0.001). Conditioned media prepared from PH and DNH bone were quantitated for CSA by their ability to promote in vitro granulocyte colony formation of nonadherent human marrow cells. Stromal CSA production was destroyed by freeze--thawing and was radioresistant (4400 rad). Of DNH stromal cells, 15%--30% were monocyte-macrophage, but the slow absolute numbers of these cells suggested alternative CSA cellular sources in distal bones. PH stroma produced significantly more CSA than DNH bone stroma: 0.72 +/- 0.10 versus 0.30 +/- 0.06 U/mg bone (p less than 0.01). The CSA concentration gradient between PH and DNH bones may contribute to the regulation of granulopoiesis in marrow and to the absence of hemopoiesis distally.

Bone Marrow Cells↗
PubMed1999

Activated eosinophils are the major source of Th2-associated cytokines in the schistosome granuloma.

Eosinophils are a numerically dominant cell population within the schistosome granuloma. These granuloma eosinophils can produce a variety of cytokines, including IL-2, IL-4, IL-5, and IFN-gamma. Therefore, eosinophils may play a key role in the determination of the unique cytokine microenvironment within the granuloma milieu. These studies investigated the potential role of eosinophils in the regulation of granuloma immunopathology. We have characterized spleen- and granuloma-derived eosinophils based on cellular activation and cytokine production during the development of murine schistosomiasis. Based on the criteria of hypodensity and CD69 expression, granuloma eosinophils were highly activated and very homogeneous at 7 and 11 wk postinfection. Splenic eosinophils were also activated at 7 wk postinfection, but were much more heterogeneous than their granuloma counterparts. By 11 wk postinfection, few hypodense splenic eosinophils were observed. Eosinophils represented the majority of cytokine-producing cells in the granuloma and were a dominant source of IL-4. Eosinophils also produced IL-2, IL-5, and IFN-gamma, using the criteria of mRNA in situ hybridization and intracellular cytokine staining by FACS. Granuloma eosinophil activation and cytokine production were greatest at the time of maximum granuloma formation, i.e., 10-12 wk after initial cercarial exposure. Therefore, locally activated eosinophils, not Th2 lymphocytes, produce the majority of Th2 cytokines in the granuloma milieu and may be important determinators of immunopathology in schistosomiasis.

Animals↗