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PubMed1996

Undersulfation of glycosaminoglycans reduces the proliferation of a leukemia cell line in vitro.

Leukemia represents the clonal expansion of an individual cell lineage of the hematopoietic system at a specific point of its maturation and development. This dysregulated expansion of cells is often accompanied by altered adherence to the bone marrow microenvironment and abnormalities in endogenous cytokine production by neoplastic cells. Proteoglycans (PGs) synthesized by neoplastic cells may interact with extracellular matrix (ECM) molecules and/or locally produced cytokines. It is believed that these events may be mediated by the glycosaminoglycan (GAG) moiety of PGs such as heparan or chondroitin sulfate, and depends on its charge. The strength of GAG-cytokine binding may be determined by the extent of sulfation of the GAG chains. The synthesis, metabolism and biological role of PGs in hematopoietic malignancies have not been clearly defined. In order to study how alterations of GAGs in leukemic cells may alter cellular behavior, we treated the murine myeloid leukemic cell line WeHi-3B with sodium chlorate. This drug reduces the sulfation of GAGs, since chlorate is a potent inhibitor of sulfate adenylyltransferase. The undersulfated GAGs produced by WeHi-3B cells were not efficient in controlling the mitotic rate of the cells, since a decrease in cell proliferation was observed in vitro. These data suggest that the complexes formed by GAGs with ECM components and/or cytokines may have an important role in the induction of leukemic cell proliferation. It is possible that the stimulatory activity elicited by this binding may be dependent upon the organization of these complexes.

Extracellular Matrix↗
PubMed1989

In situ immunologic characterization of cutaneous involvement in Hodgkin's disease.

The current study assesses in situ the antigenic phenotype of cutaneous infiltrate in two cases of Hodgkin's disease affecting the skin. Immunostaining utilized monoclonal antibodies for T-lymphocyte and B-lymphocyte and mononuclear phagocyte markers. The same immunophenotypic pattern of cutaneous infiltrate was observed in both cases, despite a different histopathologic subtype (mixed cellularity in case one, nodular sclerosis in case two). The majority of infiltrating cells expressed T-lymphocyte markers, with a predominance of CD8+ phenotype. Few cells bore B-lymphocyte markers or had DRC-1+ phenotype. No CD1a+ dendritic cell was found in the dermal infiltrate. Variable numbers of cells reacted with mononuclear phagocyte markers. The authors believe that the antigenic phenotype of cutaneous Hodgkin's disease has not previously been reported. The immunophenotypic pattern of skin infiltrate is different from that described in lymphoid tissues. Such findings could be related to the previous therapy or to the possible influence of skin microenvironment.

Adult↗
PubMed1990

Differentiation induction of HL60 cells in a long-term bone marrow culture of acute myeloid leukemia.

Bone marrow stromal cells are critical for the proliferation and differentiation of hemopoietic stem cells. The hemopoietic microenvironment is reproduced in long term bone marrow culture (LTBMC). Normal LTBMC versus leukemic LTBMC and their stroma conditioned medium were compared with respect to their proliferative and differentiation-inducing capacities. Myeloid leukemic cells (HL60) were layered onto LTBMCs derived from normal volunteers and patients with AML. Differentiation was measured with a comprehensive panel of maturation parameters, i.e. morphology, cytochemistry, quantitative enzyme determination, NBT test and immunophenotyping. Inhibition of proliferation occurred in all cocultures. Clear maturation in monocytic direction was obvious in one culture of HL60 cells layered onto a leukemic stroma. As stroma-derived conditioned medium has no effect, a cellular interaction seems involved. These observations support not only the concept that normal stroma influences leukemic cell growth but also that leukemic stroma can modulate cell growth and maturation.

Adult↗
PubMed2004

Synergistic effects of vascular IL-17 and TNFalpha may promote coronary artery disease.

Interleukin (IL)-17 is a pro-inflammatory cytokine originally described in T lymphocytes. Increased production of IL-17 has been linked to the induction of cytokines, chemokines and adhesion molecules in various cell types, effects that likely contribute to a number of inflammatory diseases including rheumatoid arthritis. Importantly, in the same pathophysiological conditions production of TNFalpha is also up-regulated and recent studies suggest that cellular signaling pathways induced by IL-17 and TNFalpha converge. Recent studies showed that vascular endothelial and/or smooth muscle cells also express TNFalpha and IL-17, which can be up-regulated in pro-atherogenic pathophysiological conditions in the coronary arteries. TNFalpha has been shown to exert pro-inflammatory vascular effects (e.g., induction of oxidative stress, endothelial apoptosis, up-regulation of adhesion molecules and chemokines), however, the role of vascular IL-17 and its interaction with TNFalpha is much less understood. We propose that increased vascular IL-17 and TNFalpha levels can act synergistically to create a pro-inflammatory microenvironment promoting the development of atherosclerotic vascular disease.

Animals↗
PubMed1999

Astrocyte line SVG-TH grafted in a rat model of Parkinson's disease.

The present review describes gene transfer into the brain using extraneuronal cells with an ex vivo approach. The mild immunological reactions in the central nervous system to grafts provided the rationale and empirical basis for brain-transplantation, to replace dying cells, of potential clinical relevance. Fetal human astrocytes were genetically engineered to express tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines. These cells were also found to produce constitutively and secrete GDNF and interleukins. Therefore, these cells may prove as a drug-delivery system for the treatment of neurological degenerative conditions such as Parkinson's disease (PD). The field of neuronal reconstruction has reached a critical threshold and there is a need to evaluate the variables that will become critical as the field matures. One of the needs is to characterize the neurochemical alterations in the microenvironment in the context of grafted-host connectivity. This review discusses the functional effects of the pharmacologically-active construct, which consists of astrocytes producing L-DOPA and GDNF. The striatum in PD that lacks the dopaminergic projection from the substantia nigra metabolizes and releases dopamine differently from normal tissue and may react to different factors released by the grafted cells. Moreover, neurochemicals of the host tissue may effect grafted cells as well. An understanding of the way in which these neurochemicals are abnormal in PD and their role in the grafted brain is critical to the improvement of reconstructive strategies using cellular therapeutic strategies.

Animals↗
PubMed1993

Direct innervation of lymphoid organs: substrate for neurotransmitter signaling of cells of the immune system.

The nervous system can generate outflow capable of signaling cells of the immune system via two routes: (1) hormonal influences via hypothalamopituitary-target organ activation, and (2) neurotransmitter influences via direct innervation of the parenchyma of both primary and secondary lymphoid organs. Both noradrenergic and neuropeptidergic nerve fibers are found directly adjacent to cells of the immune system in bone marrow, thymus, spleen, lymph nodes, and other sites. These neurotransmitters can modulate immune responsiveness at several levels, including individual cellular functions, collective cellular interactions and immune responses, and overall host immunological response to a challenge by bacteria, viruses, tumor cells, or other sources. The ability of neural signals to modulate immune responsiveness is influenced by such factors as co-localization with other neurotransmitters, synergistic or dual signaling by neurotransmitters and cytokines, hormonal influences on ligand availability or receptor responsiveness, extent of catabolism and inactivation of the neural signal, and unique chemical and morphological aspects of the specific compartmentation of the lymphoid organ in which signaling is taking place. Thus, neural-immune signaling is a complex and dynamic process, with bidirectional interactions in a complex microenvironment.

Animals↗
PubMed1987

Directed targeting of immunoerythrocytes provides local protection of endothelial cells from damage by hydrogen peroxide.

Red blood cells bearing anti-mouse IgG antibody on their surface (immunoerythrocytes) may provide for local protection of endothelial cells from the action of hydrogen peroxide. Subconfluent cultures of human umbilical vein endothelial cells responded sharply to increasing concentrations of hydrogen peroxide. Permeabilization of cellular membrane occurred at doses of hydrogen peroxide of from 1 to 3 mM, and was assured by incorporation of trypan blue stain immediately after treatment. Latent damage of cells produced by much lower doses of hydrogen peroxide (0.2-0.4 mM) could be observed after 24-hour incubation of treated cells in the normal culture medium with no hydrogen peroxide. The apparently dead cells differed from intact cells in morphology, were poorly attached to the substrate, and were readily incorporated by trypan blue, thus permitting easy visualization. Immunoerythrocytes bound to the antigen-coated surface enzymatically decreased the concentration of hydrogen peroxide in their microenvironment at least fivefold with respect to the total hydrogen peroxide concentration. Erythrocytes deposited on a part of the endothelial monolayer locally protected it from the damage at hydrogen peroxide concentrations ranging from 0.4 to 1.2 mM. Localization of protected zones corresponded precisely to the geometry of the erythrocyte coating. Immunoerythrocytes targeted to the endothelial cells by means of mouse anti-endothelial antiserum did not impair their viability and protected the endothelium from being killed at 0.3-1.2 mM hydrogen peroxide. This approach might be useful for a cell selection in mixed cell populations. The problem of local protection of cells involved in the inflammation focus are discussed.

Animals↗
PubMed1985

Membrane lipid composition and cellular function.

Membrane fatty acid composition, phospholipid composition, and cholesterol content can be modified in many different kinds of intact mammalian cells. The modifications are extensive enough to alter membrane fluidity and affect a number of cellular functions, including carrier-mediated transport, the properties of certain membrane-bound enzymes, binding to the insulin and opiate receptors, phagocytosis, endocytosis, depolarization-dependent exocytosis, immunologic and chemotherapeutic cytotoxicity, prostaglandin production, and cell growth. The effects of lipid modification on cellular function are very complex. They often vary from one type of cell to another, and they do not exert a uniform effect on all processes in a single cell line. Therefore, it is not yet possible to make any generalizations or to predict how a given system will respond to a particular type of lipid modification. Many of the functional responses probably are caused directly by the membrane lipid structural changes, which affect either bulk lipid fluidity or specific lipid domains. The conformation or quaternary structures of certain transporters, receptors, and enzymes probably are sensitive to changes in the structure of their lipid microenvironment, leading to changes in activity. Prostaglandin production is modulated by the availability of substrate fatty acids stored in the membrane phospholipids, but the underlying chemical mechanism still involves a change in membrane lipid structure. While this is the most likely mechanism, the possibility that the membrane lipid compositional change is an independent event that occurs concurrently but is not causally related to the functional perturbations also must be considered.

Animals↗
PubMed1986

Metabolism of benzene and phenol in macrophages in vitro and the inhibition of RNA synthesis by benzene metabolites.

Benzene may affect hemopoiesis by damaging the bone marrow stroma that provides the microenvironment for hemopoiesis. A possible target of benzene toxicity in the stroma is the macrophage, which is a major source of protein factors required for the proliferation and differentiation of progenitor cells. As an initial approach towards understanding whether benzene inhibits hemopoietic factor production in bone marrow stroma, the metabolism of benzene and phenol has been studied and the effect of benzene and its metabolites on macrophage RNA synthesis has been examined. Benzene is not metabolized in macrophages but phenol, the major metabolite of benzene in bone marrow, is converted by peroxidase in the macrophage to both free metabolites and species which covalently bind to cellular macromolecules. Benzene and its metabolites inhibited RNA synthesis in a dose-dependent manner, with 50% inhibitory concentrations of 5 X 10(-3) M for benzene, 2.5 X 10(-3) M for phenol, 2.5 X 10(-5) M for hydroquinone, and 6 X 10(-6) M for p-benzoquinone; this inhibition was not attributable to loss of cell viability. Benzene, possibly by an inhibition of uridine transport into macrophages, and phenol, by its conversion to covalently binding species, inhibit RNA synthesis in macrophages and thus may inhibit the synthesis of colony stimulating factors required for hemopoiesis.

Animals↗
PubMed1993

Cellular pharmacology of quinone bioreductive alkylating agents.

The cellular pharmacology of the mitomycin bioreductive alkylating agents is complex. This reflects in part the chemical characteristics of these quinones, which have multiple sites of reactivity and the capacity to produce a large number of different lesions of biological importance. Moreover, at least six different enzymes are capable of activating these compounds; the nature of the active species and the resultant biological lesions can vary with the activating enzyme. The relative activities of these reductases vary in different cell lines and can be modulated by pH and oxygenation. The effects of a quinone bioreductive alkylating agent therefore depend upon both the cell line and the microenvironment. DNA damage appears to be critical to the cytotoxic effects of these compounds. Both monoadducts and bis-adducts (forming interstrand and intrastrand cross-links) have been identified in DNA from drug-treated cells. The pattern of adduct formation varies with the compound and the environment. Alkaline elution studies suggest a correlation between DNA cross-linking and cytotoxicity, both in air and in hypoxia. The rate of production of oxygen radicals and the importance of radical reactions in producing cytotoxic damage vary for different quinones and for different environments. While the potency of the bioreductive quinones varies with their redox potential, the direction and magnitude of the oxic/hypoxic differential cannot yet be predicted from the structures.

Alkylating Agents↗
PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗
PubMed2004

Immortalization of hepatic progenitor cells.

Development of cell therapy-based strategies for the treatment of liver failures and of inherited metabolic diseases has become a necessity because of the limitations of orthotopic liver transplantation, including shortage of donor livers. This shortage limits also the availability for hepatocytes and these terminally differentiated cells cannot be expanded in vitro. Thus, other alternative sources of hepatocytes have to be explored such as hepatic stem cells. Foetal hepatic cells have specific intrinsic properties compared to adult hepatocytes that should overcome some of their limitations. Thus, the availability of in vitro expandable progenitor cells by means of immortalization and without inducing a transformed phenotype and disrupting their differentiation potential would facilitate studies on cell engraftment and differentiation within the hepatic parenchyma. A temporally controlled expression of the immortalizing transgene would also permit to revert the immortalized phenotype prior to cell transplantation. Since characteristics of murine stem cells cannot readily be extrapolated to their human or other primate counterparts, we have immortalized one clone of primate hepatic progenitor cells using a retroviral vector expressing SV40 Large T flanked by lox P sites. These hepatic cells were bipotent, expressing markers of both hepatocytic and biliary lineages. After transplantation into athymic mice, approximately 50% of immortalized cells engrafted, stopped proliferating after a few days and differentiated in adult hepatocytes, suggesting that the hepatic microenvironment plays an important role in such regulations. Upon infection with a retrovirus expressing the CRE recombinase, immortalized cells stopped growing and died, showing that immortalization was dependant on SV40 Large T. These studies suggest new approaches to expand hepatic progenitor cells, analyse their fate in animal models aiming at cell therapy of hepatic diseases.

Adult↗
PubMed2005

Evolving concepts in bone tissue engineering.

The field of tissue engineering integrates the latest advances in molecular biology, biochemistry, engineering, material science, and medical transplantation. Researchers in the developing field of regenerative medicine have identified bone tissue engineering as an attractive translational target. Clinical problems requiring bone regeneration are diverse, and no single regeneration approach will likely resolve all defects. Recent advances in the field of tissue engineering have included the use of sophisticated biocompatible scaffolds, new postnatal multipotent cell populations, and the appropriate cellular stimulation. In particular, synthetic polymer scaffolds allow for fast and reproducible construction, while still retaining biocompatible characteristics. These criteria relate to the immediate goal of determining the ideal implant. The search is becoming a reality with widespread availability of biocompatible scaffolds; however, the desired parameters have not been clearly defined. Currently, most research focuses on the use of bone morphogenetic proteins (BMPs), specifically BMP-2 and BMP-7. These proteins induce osteogenic differentiation in vitro, as well as bone defect healing in vivo. Protein-scaffold interactions that enhance BMP binding are of the utmost importance, since prolonged BMP release creates the most osteogenic microenvironment. Transition into clinical studies has had only mild success and relies on large doses of BMPs for bone formation. Advances within the field of bone tissue engineering will likely overcome these challenges and lead to more clinically relevant therapies.

Animals↗
PubMed1999

A comparative study of the cell cycle status and primitive cell adhesion molecule profile of human CD34+ cells cultured in stroma-free versus porcine microvascular endothelial cell cultures.

Porcine microvascular endothelial cells (PMVECs) plus cytokines support a rapid proliferation and expansion of human CD34+CD38- cells that are capable of multilineage engraftment within the bone marrow of a secondary host. CD34+CD38- cells contain the self-renewing, long-term culture-initiating cells (LTC-IC) that are ideal targets for retroviral gene transfer experiments. Previous experiments attempting retroviral infection of CD34+CD38- cells have failed partly because these cells do not enter cell cycle in response to cytokine combinations. In this study, we determined the cell cycle status and the cell adhesion molecule profile on purified CD34+ cells and the CD34+CD38- subset before and after ex vivo expansion on PMVECs. Purified human CD34+ cells were cocultured with PMVECs for 7 days in the presence of optimal concentrations of granulocyte/macrophage-colony-stimulating factor (GM-CSF) + interleukin (IL)-3 + IL-6 + stem cell factor (SCF) + Flt-3 ligand. The total CD34+ population and the CD34+CD38- subset increased 8.4- and 67-fold, respectively, with absolute increases in the number of colony-forming unit-granulocyte macrophage (CFU-GM) (28.2-fold), CFU-Mix (8.7 fold), and burst-forming unit-erythroid (BFU-E) (4.0-fold) progenitor cells. After 7 days of coculture with PMVECs, 44% of the CD34+CD38+ subset were found to be in G1, and 51% were in G2/S/M phase of the cell cycle. More remarkably, 53% of the CD34+CD38- subset were in G1, and 17% were in G2/S/M phase after 7 days of PMVEC coculture. In contrast, only 22% of the CD34+CD38- subset remaining after 7 days of stroma-free culture were in G1, and 6% were in G2/S/M phase. Despite the high level of cellular activation and proliferation induced by PMVEC coculture, the surface expression of adhesion molecules CD11a (LFA-1), CD11b, CD15s (sialyl-Lewis x), CD43, and CD44 (HCAM) on the total CD34+ population was maintained, and the surface expression of CD49d (VLA-4), CD54 (ICAM), CD58, and CD62L (L selectin) increased after ex vivo expansion. In contrast, CD34+ cells expanded on stroma-free cultures showed lower and more variable expression of CD62L and CD15s. These findings demonstrate that the primitive CD34+CD38- subset of marrow progenitor cells can be induced to enter cell cycle and can be significantly expanded ex vivo on a hematopoietic supportive microenvironment (PMVECs) while preserving the expression of cell adhesion molecules that may be important in stem cell homing and engraftment.

ADP-ribosyl Cyclase↗
PubMed2003

Interleukin-2 and cancer: critical analysis of results, problems and expectations.

The cancer process in a combination of two kinds of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.

Cytokines↗
PubMed2002

GM-CSF-based cancer vaccines.

The crafting of genetic and biochemical techniques to identify cancer antigens yielded the unexpected discovery that immune recognition of tumors regularly accompanies cancer development. The failure of the host to suppress tumor formation or attenuate disease progression may thus reflect the limited immunogenicity of nascent tumors. One critical determinant of host immunity is the mixture of cytokines produced in the tumor microenvironment. We have compared a large number of secreted and surface molecules for their relative abilities to augment tumor immunity following gene transfer into cancer cells. In multiple murine models, granulocyte-macrophage colony stimulating factor (GM-CSF) proved to be the most potent immunostimulatory product. Vaccination with irradiated tumor cells engineered to secrete GM-CSF involves enhanced tumor antigen presentation by recruited dendritic cells (DCs) and macrophages; the coordinated functions of CD4+ and CD8+ T cells, CD1d-restricted NKT cells and antibodies mediate protective immunity. The evaluation of this vaccination strategy in patients with advanced melanoma revealed the consistent induction of cellular and humoral antitumor responses capable of effectuating substantial necrosis of distant metastases. The formulation of simplified methods for manufacturing autologous, GM-CSF-secreting tumor cells has enabled more extensive clinical testing in diverse patient settings.

Adjuvants, Immunologic↗
PubMed2005

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs.

Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.

Angiogenesis Inhibitors↗
PubMed2003

The blood-brain barrier and its role in immune privilege in the central nervous system.

The blood-brain barrier (BBB) provides both anatomical and physiological protection for the central nervous system (CNS), strictly regulating the entry of many substances and blood borne cells into the nervous tissue. Increased understanding of how the unique microenvironment in the CNS influences the BBB is crucial for developing novel therapeutic approaches to CNS diseases. In this review, we discuss those characteristics of the BBB that play an important role in maintaining immune privilege in the CNS, as well as factors that regulate immune cell invasion through the BBB and thereby modulate immune responses in the nervous tissue. In general, immune cell invasion across the BBB is highly restricted and carefully regulated. A florid invasion of activated white blood cells can create a predominantly proinflammatory local environment in the CNS, leading to immune-mediated diseases of the nervous tissue. Recent developments in cellular and molecular biological methods have allowed closer analysis of BBB function, and led to an improved understanding of the active role of the BBB in immune-mediated diseases of the CNS.

Animals↗