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PubMed1992

Bone biochemistry and physiology from the perspectives of the vitamin D endocrine system.

Vitamin D plays an indispensable role in the dual processes of bone formation (mediated by osteoblasts) and bone resorption (mediated by osteoclasts). More recently, researchers have confirmed the existence of a vitamin D endocrine system, which is responsible for describing the "sphere of biological influence" of vitamin D3. In that system, the kidney serves as the endocrine gland that produces 1,25-dihydroxyvitamin D3. This hormonally active form of vitamin D3 generates many, if not all, of the biologic responses attributed to the parent vitamin D3, including its role in bone formation and bone resorption. In addition, 1,25-dihydroxyvitamin D3 is able to generate biologic responses via both genomic and nongenomic pathways. The classic nuclear receptor for 1,25-dihydroxyvitamin D3 is present in more than 30 target tissues. This paper reviews evidence for the critical role of 1,25-dihydroxyvitamin D3 in cell differentiation, particularly of hematopoietic cells, as well as in the generation of the bone resorptive cell--the osteoclast. In the past year, much evidence has been accumulated supporting the claim that 1,25-dihydroxyvitamin D3 tightly regulates differentiation of osteoclast progenitors into osteoclasts. Osteoclast progenitors are believed to be derived from the monocyte-macrophage lineage. However, the generation of new osteoclasts is modulated by osteoblastic stromal cells, which are one of the target cells for the nuclear actions of 1,25-dihydroxyvitamin D3.

Bone and Bones↗

PubMed1989

Biological role of different antibody classes.

Antibodies are divided into different classes and subclasses (isotypes) according to structural differences in the constant region of the heavy polypeptide chains. The different isotypes mediate specific biologic functions that are important for the response to pathogens and in the pathogenesis of immunological diseases such as allergies. The numbers of different isotypes vary in different species, humans have 9 different Ig classes and subclasses. Of these 9, only IgM, IgG1, IgG2 and IgG3 activate the classical pathway of complement. All four IgG and both IgA subclasses, but not IgM, IgE and IgD, bind to Fc receptors on neutrophils, and induce the release of granule enzymes. All four IgG subclasses but no other Ig isotype induce serotonin release from platelets. In man, only IgE binds to the high-affinity Fc receptors (Fc epsilon RI) on mast cells and basophils and induces histamine and leukotriene release. IgE also binds to low-affinity Fc receptors (Fc epsilon RII) on lymphocytes, monocytes and eosinophils; however, the functions of Fc epsilon RII on these cells are not fully established. Monocytes from patients with atopic dermatitis that express more Fc epsilon RII than monocytes from normals do not release more LTC4 than monocytes from nonallergic healthy humans after activation with aggregated IgE. IgG and IgA are more efficient than IgE in inducing the release of mediators of inflammation from monocytes. The antibody response to certain antigens such as carbohydrates and allergens are often restricted to IgG2 and IgG1, IgG4 and IgE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Transcription of the unique ruminant class II major histocompatibility complex-DYA and DIB genes in dendritic cells.

Dendritic cells (DC) constitute the most effective immune cell population for priming and recalling T cell responses to foreign antigens. DC patrol the peripheral tissues collecting foreign antigen for subsequent presentation by classical class II MHC molecules to T cells in the draining lymph nodes. Since the description of the DYA and DIB class II MHC genes, which are unique to ruminants, no transcript or protein have been reported. Here we provide evidence that these genes are transcribed in cattle and that paired transcription is restricted in afferent lymph to a functionally distinct population of DC. Analysis of lymph node, lung and thymus suggests that tissue DC also transcribe both genes. Cytokine-induced differentiation of cultured monocytes to a DC phenotype is linked with induction of both DYA and DIB transcription. This is consistent with an association of their products with the potent antigen presenting capacity of these cells in cattle.

Animals↗

PubMed2002

Anti-inflammatory effects of cerebrocrast in a model of rat paw edema and on mononuclear THP-1 cells.

Cerebrocrast (IOS 1.1212; 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di(2-propoxyethyl) diester) is a novel derivative of 1,4-dihydropyridine, which does not antagonize Ca(2+) influx in neuronal tissues. Since several classical dihydropyridines possess anti-inflammatory properties, we first studied the effects of cerebrocrast in a model of rat paw edema induced by carrageenan. Cerebrocrast had a preventative effect in this model of inflammation, with maximal activity (32-45% inhibition) in the 0.1-0.25 mg kg(-1) range. It was ineffective when added after the injection of carrageenan. Subsequent in vitro experiments showed that cerebrocrast in the micromolar range inhibited secretion of interleukin-1 beta, interleukin-6 and neurotoxic products by cells of the human monocytic THP-1 line while failing to affect secretion of tumor necrosis factor (TNF-alpha). It also lacked any direct neuroprotective effect against toxic secretions from stimulated THP-1 cells. The data obtained suggest that cerebrocrast may be useful not only in various inflammatory disorders of peripheral tissues, but also in treating neurodegenerative diseases, where inflammatory mechanisms in general and microglial activation, in particular, are thought to play an important role.

Animals↗

PubMed1986

Cellular and vascular manifestations of cell-mediated immunity.

The studies reviewed here emphasize both the complexity and the heterogeneity of cell-mediated immunity. In addition to the round cell infiltrate of the classic descriptions, cell-mediated immunity includes reactions that feature many types of inflammatory cells, that exert profound effects on the blood microvasculature, and that initiate extravascular clotting and, possibly, angiogenesis. The common denominator of all of these reactions is a subset or subsets of sensitized T lymphocytes that, on exposure to specific antigen, recruit and collaborate in other ways with one or more populations of circulating bone marrow-derived cells. Although the reactions generally resemble chronic inflammation by virtue of the lymphocytes and monocytes present, cell-mediated immunity may also take the guise of acute or subacute inflammation when neutrophils or eosinophils predominate and an entirely different morphologic pattern when basophils predominate, as in CBH. Tissue mast cells undergo changes (activation, proliferation) that are generally observed at later stages of delayed hypersensitivity, but no convincing evidence has been presented that these cells play an essential role in the elicitation of cell-mediated immunity. The concept that an essential prerequisite for the elicitation of delayed hypersensitivity is the mast cell-dependent generation of microvascular gaps, favoring inflammatory cell diapedesis, is clearly incorrect. First, lymphocytes fail to traverse certain of the vessels that exhibit such gaps (i.e., those of the SCV) in delayed hypersensitivity reactions in humans. Second, there is no diminution in the cellular infiltration associated with cell-mediated immunity reactions in mast cell-deficient mice. Cell-mediated immunity does not consist of an inflammatory cell infiltrate alone. The local microvasculature is rendered hyperpermeable to varying extents, with resulting extravasation of plasma proteins, including fibrinogen. The majority of extravasated fibrinogen is clotted to cross-linked fibrin, presumably as the result of the actions of procoagulants associated with fixed connective tissue cells and perhaps also because of the activity of infiltrating cells, such as monocytes/macrophages. Clotted fibrin forms a water-trapping gel, which accounts for the induration seen in many delayed hypersensitivity reactions. The microvasculature may also be affected in other ways. Endothelial cells may undergo hypertrophy and cell division or, alternatively, may exhibit profound and progressive injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

DNA damage and stress protein synthesis induced by oxidative stress proceed independently in the human premonocytic line U937.

Heat shock proteins (HSPs) function as stress-inducible molecular chaperones and exert protective effects against cellular injury. The induction of the HSPs is considered to be mediated by the presence of abnormal proteins within the cell and/or by classical second messengers. Several lines of evidence have however suggested a relationship between DNA damage, HSP induction and thermotolerance. We investigated whether DNA alterations could represent a common signal for the induction of stress protein synthesis during heat shock or exposure to reactive oxygen species in the human premonocytic line U937. We measured, in parallel, DNA damage (both strand breaks and fragmentation) and HSP synthesis (by biometabolic labeling and Western blotting) after exposure to heat shock, hydrogen peroxide, bleomycin, cadmium or erythrophagocytosis. Heat shock induced DNA alterations along with HSP synthesis. In contrast, exposure to hydrogen peroxide or bleomycin induced DNA damage, but no HSP synthesis, suggesting that oxidation-induced DNA damage and HSP synthesis proceed independently in U937 cells. Erythrophagocytosis and cadmium induced the classical HSPs but no detectable DNA damage. Since these latter stresses also induced the oxidation-specific stress protein heme oxygenase, we suggest a protective role for heme oxygenase against oxidative DNA damage.

Bleomycin↗

PubMed1982

Immunocompetence after incidental splenectomy.

Of 377 patients with chronic duodenal ulcer undergoing highly selective vagotomy, 13 were splenectomized peroperatively because of capsular tear. 12 of these patients were alive at the time of the subsequent investigation and each was matched with a non-splenectomized patient. The postoperative interval was almost 5 years (median). The splenectomized patients were characterized by their longer hospitalization, and increased blood counts of lymphocytes, monocytes and platelets. Analysis of lymphocyte subsets revealed increased numbers of both T and B lymphocytes after splenectomy Among the T cells, those with receptors for Fc of IgG were significantly more numerous in the splenectomized group. It is a matter of controversy whether or not this population contains T suppressor cells. Hence further functional investigations are needed to clarify whether our observations bear any relation to the low level of plasma IgM found by us and others in splenectomized individuals. Screening for complement activation by the classical and alternative pathways did not reveal any defects resulting from splenectomy.

Adult↗

PubMed1986

Decreased response of human milk leukocytes to chemoattractant peptides.

To test the hypothesis that neutrophils and macrophages in human milk may not defend by classical inflammatory mechanisms, experiments were conducted to ascertain whether adherence, orientation, and directed motility of these leukocytes would be enhanced by exposure to chemoattractant peptides including N-formyl-L-methionyl-L-phenylalanine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine and C5a generated from zymosan activated human serum. Adherence and spatial orientation were tested on coverglasses and in Zigmond chambers, and chemotaxis was examined by Boyden chambers and a subagarose technique. Whereas, the adherence, orientation, and directed movement of adult peripheral blood neutrophils and monocytes were significantly enhanced by those chemotactic agents, human milk leukocytes failed to respond. The failure of the response of human milk leukocytes was not due to alterations in maternal peripheral blood leukocytes but appeared to be due partially to inhibitors in human milk. The experiments suggest that human milk leukocytes may be modified in the mammary gland to protect by noninflammatory mechanisms.

Adult↗

PubMed2000

Pathogenesis of heroin-associated glomerulonephritis. Correlation between the inflammatory activity and renal deposits of immunoglobulin and complement?

Renal specimens from 19 autopsies of persons known to be intravenous heroin-addicts and with severe lympho-monocytic glomerulonephritis were investigated to correlate the inflammatory activity and deposits of immunoglobulin and complement. In all sections, there were 10 or more LCA-positive cells/glomerulum, counted in 20 glomerula but only up to 3 LCA-positive cells in a control-group of 10 autopsied persons without drug addiction and any renal diseases. In some cases diffuse granular deposits of immunoglobulin were found together with deposits of Clq. Although these changes cannot be demonstrated in all cases, deposits of Clq point to an activation of the classical way of the complement binding system in heroin-associated glomerulonephritis. The underlying process, activation of the complement binding system by heroin/morphin itself and adulterants or by hepatitis B and C infection, which are frequent in heroin-addicts, is still unclear.

Adolescent↗

PubMed1999

Delivery of liposome-encapsulated HIV type 1 proteins to human dendritic cells for stimulation of HIV type 1-specific memory cytotoxic T lymphocyte responses.

An important aspect of vaccine development involves delivery of antigens to antigen-presenting cells for the induction of potent antigen-specific T lymphocyte responses. We investigated the effect of a cationic liposome, lipofectin, on delivery of whole proteins to human dendritic cells (DCs) derived from blood mononuclear cells by culture in interleukin 4 and granulocyte-monocyte colony-stimulating factor for stimulation of human immunodeficiency virus type 1 (HIV-1)-specific memory cytotoxic T lymphocyte (CTL) responses. Delivery of HIV-1 Gag, Pol, and Env proteins to DCs by lipofectin stimulated greater anti-HIV-1 memory CTL responses in cells from HIV-1-infected subjects than those induced by DCs loaded with protein alone. The CTLs were CD8+ and HLA class I restricted. Antigen presentation was enhanced by chloroquine, but blocked by brefeldin A and peptide aldehyde inhibitors of proteasomes, indicating that the classic MHC class I cytosolic pathway was used for processing and presentation of HIV-1 protein by the DCs. Stimulation of anti-HIV-1 CTLs by this safe, inexpensive, and broadly applicable approach may be used in DC-based therapies for HIV-1 infection.

Adult↗

PubMed1999

Direct vascular antiatherogenic effects of oleic acid: a clue to the cardioprotective effects of the Mediterranean diet.

Atherosclerosis, the main cause of ischemic heart disease, is a process with relevant inflammatory components, in which LDL-cholesterol, largely emphasized in the last years as a "causal" factor following the improvement in prognosis with cholesterol-lowering agents, is only one of the culprits. Despite the use of new cholesterol-lowering drugs, atherosclerotic vascular disease will likely continue to be the main cause of death in Western countries. Furthermore, the statistical relationship between cholesterol and cardiovascular mortality only explains a relatively minor component of differences in mortality among diverse countries. For these reasons, the interest in preventive approaches complementary or alternative to cholesterol reduction should be one of the main objectives of cardiovascular research in the years to come. Already in the '70s the very low incidence of atherosclerotic diseases in Mediterranean countries (Greece and Southern Italy) and the importance of the "dietary factor" in such protection were noticed. Diets for people in these countries are, among other components, very rich in oleic acid, the main constituent of olive oil, with about 29% of daily caloric intake derived from monounsaturated fatty acids. Oleic acid, besides exerting relatively minor effects on the quantitative and qualitative regulation of cholesterol levels, appears to interfere directly with the inflammatory response that characterizes early atherogenesis. The endothelial expression of adhesion molecules for circulating monocytes, induced by inflammatory cytokines, minimally oxidized LDL and the advanced glycation end-products present in diabetes, substantially contributes to the onset and early progression of atherosclerosis. In an in vitro model of early atherogenesis based on cultured endothelial cells stimulated by cytokines, we observed that the incorporation of oleic acid in total cell lipids--mostly at the expenses of saturated fatty acids--decreases the expression of several endothelial leukocyte adhesion molecules, among which vascular cell adhesion molecule-1, involved in the selective monocyte recruitment in the arterial intima. Oleic acid also determines a parallel reduction in messenger RNA for this molecule, interfering with the activation of the most important transcription factor controlling endothelial activation, nuclear factor-kappa B. Thus, possibly in concert with other more highly unsaturated fatty acids, oleic acid may contribute to the prevention of atherosclerosis also through a modulation of gene expression for endothelial leukocyte adhesion molecules. This series of investigations emphasizes the possibility of preventive interventions in atherosclerosis based on the modulation of vascular response to classical "triggers" (cholesterol, advanced glycation end-products of diabetes), an intervention strategy fundamentally different from--and thereby complementary to--those now more in fashion.

Arteriosclerosis↗

PubMed2001

Consequences of dendritic cell (DC)-immunodeficiency virus interactions: chemically inactivated virus as a model for studying antigen presentation and virus transmission by primate DCs.

We have established a model approach to study DC-virus communication, in which classically immature and mature DCs can be compared. The striking observation that macropinocytically poor mature DCs capture and then internalize whole virus particles has substantial implications for both antigen processing and presentation as well as cell to cell transmission of virus from DCs to nearby T cells (as well as other cell types). Studies are ongoing using this system to determine what molecules and mechanisms are involved in virus binding and internalization by immature versus mature DCs. Discerning the consequences of the differential fates of virus in immature versus mature monocyte-derived DCs should provide important information on how virus captured by DCs is processed for immune activation versus virus dissemination. While there are many features shared by monocyte-derived DCs and DCs directly isolated from blood or tissues, there are some important distinctions between these DC subsets and their activation stage. These traits have considerable influence on immune activation by DCs as well as how the individual DC subset handles an immunodeficiency virus. Thus, this approach is ultimately being applied to specific DC subsets, especially those found at the body surfaces where the first DC-virus interactions most frequently occur in vivo. Utilizing this system, we hope to better comprehend the initial events of DC-virus communication to (i) facilitate the development of strategies to block these events and prevent the onset of infection and (ii) identify how to augment the generation of broad anti-viral immunity.

Animals↗

PubMed1987

Mononuclear cells in human lung parenchyma. Characterization of a potent accessory cell not obtained by bronchoalveolar lavage.

Human alveolar macrophages from bronchoalveolar lavage are usually poor accessory cells for antigen-induced T-lymphocyte proliferation and poor stimulators of allogeneic mixed leukocyte reactions (MLR) when compared to peripheral blood monocytes. In contrast, cells harvested from minced lungs are good stimulators of a MLR. We have characterized the accessory cells obtained after enzymatic digestion of human lung tissue. Pulmonary mononuclear cells were separated from the dissociated lung cell mixture on Ficoll-Hypaque. Loosely adherent cells (LAM) were obtained after an overnight incubation on plastic culture dishes of initially adherent mononuclear cells. LAM were significantly more effective than were pulmonary mononuclear cells (p less than 0.05), firmly adherent cells (p less than 0.05), alveolar macrophages obtained by bronchoalveolar lavage (p less than 0.05), or monocytes (p less than 0.05) in stimulating allogeneic resting T-cells. Addition of indomethacin and catalase markedly improved T-cell proliferation induced by LAM. Enrichment for Fc receptor negative or for nonphagocytic cells further enhanced the MLR-stimulating capacity of LAM. Phase-contrast studies demonstrated an enrichment in cells compatible with dendritic cells in LAM as compared to firmly adherent cells. We conclude that there are potent accessory cells in human lung that are loosely adherent, Fc receptor negative, and poorly phagocytic, and thus are dissimilar from classic macrophages. We hypothesize that cells similar to dendritic cells might play a role in the initiation of immune responses in lung parenchyma.

Antibodies, Monoclonal↗

PubMed2001

Heterogeneity within tissue-specific macrophage and dendritic cell populations during cutaneous inflammation in atopic dermatitis.

BACKGROUND: Macrophages and dendritic cells may play a role in chronicity of atopic dermatitis (AD); however, so far only limited data are documented on the distribution of these cells in the skin during cutaneous inflammation. OBJECTIVES: To gain better insight into the presence and distribution of macrophage and dendritic cell (sub)populations in acutely and chronically inflamed skin of AD patients. METHODS: Chronic inflammatory reactions were studied in lesional AD skin biopsies; the atopy patch test was used as a model for the initiation of AD lesions, representing acute inflammation. To determine the number and phenotype of different dermal macrophage and dendritic cell populations immunohistochemistry and digital imaging were used. RESULTS: There was an increase in macrophage numbers in acutely and chronically inflamed AD skin, whereas absolute dendritic cell numbers were unchanged, compared with non-lesional AD skin. Furthermore, phenotypically heterogeneous and overlapping macrophage and dendritic cell populations were present in inflamed AD skin. The classic macrophage marker CD68 and prototypic dendritic cell marker CD1a could bind to the same cell subpopulation in the dermis of inflamed AD skin. Mannose receptors were expressed mainly by macrophages in inflamed AD skin. CONCLUSIONS: In this study we observed changes in macrophage number and phenotype during cutaneous inflammation in AD. Dendritic cell numbers did not change; however, phenotypically dendritic cell and macrophage subpopulations showed increasing overlap during inflammation in AD skin. We show for the first time that within tissue-specific macrophage populations further subpopulations are present, and that monocyte-derived cells may express markers for both dendritic cells and macrophages. Our results point to the existence of a heterogeneous pool of macrophage/dendritic cell-like cells, from which subpopulations of dermal macrophages and dendritic cells arise.

Acute Disease↗

PubMed1987

Macrophage-like cells of the pannus area in rheumatoid arthritic joints.

Frozen sections of pannus tissue taken from the joints of patients with rheumatoid arthritis have been investigated using immunohistological methods to determine the distribution of subsets of macrophage-like cells in this area. A panel of monoclonal antibodies including reagents specific in normal tissue for interdigitating cells (RFD1), macrophages (RFD7), epithelioid cells, (RFD9), monocytes (UCHMI), and osteoclasts (263C), were used. Indirect immunoperoxidase and combination indirect immunofluorescence procedures revealed the phenotypes of macrophage-like cells in four histologically distinct areas of the tissue: the synovial lining layers, the deeper stroma, areas of perivascular infiltration, and the articular cartilage junction where degeneration was occurring. It was discovered that 80% of the lining cells and a majority of macrophage-like cells of the stroma, express the phenotype RFD1+ RFD7+ UCHMI+. Cells with a typical 'dendritic cell' phenotype (RFD1+ RFD7-) were only present in the perivascular infiltrates, while 'classic macrophages' (RFD7+ RFD1-) were the cells accumulating at the cartilage junction. No significant numbers of RFD9+ epithelioid cells were seen. 263C+ osteoclasts were present in small numbers distributed throughout the stroma but did not appear to be involved in areas of cartilage degradation. This cellular distribution in the pannus is compared with previous studies on the rheumatoid synovium proper. It is concluded that a distinct inflammatory reaction occurs in the pannus and that classic activated macrophages are the cells involved in cartilage degradation.

Acid Phosphatase↗

PubMed2006

Synthetic triacylated lipid A derivative activates antigen presenting cells via the TLR4 pathway and promotes antigen-specific responses in vivo.

Triggering the maturation of dendritic cells (DC) with toll-like receptor (TLR) agonists is a favored strategy for the development of vaccine adjuvants. The triacyl pseudo-dipeptidic agent OM-197-MP-AC mimicking the lipid A structure of endotoxin induces the maturation of human monocyte-derived DC. In this study we investigated the signaling pathway by which this molecule activates DC. The ability of OM-197-MP-AC to induce maturation of human and mouse DC and macrophages was dependent on TLR4, not TLR2. Ovalbumin-specific humoral and T helper cell responses were significantly augmented by OM-197-MP-AC treatment. Taken together these results indicate that OM-197-MP-AC is a TLR4 agonist inducing DC maturation and represents a novel class of vaccine adjuvants devoid of the known pyrogenic effects associated with classical LPS derivatives.

Acylation↗

PubMed2004

Comparison of the effects of RNase-negative and wild-type classical swine fever virus on peripheral blood cells of infected pigs.

Elimination of the RNase activity of classical swine fever virus (CSFV) glycoprotein E(rns) was previously shown to result in virus attenuation. Specific reduction of B cell numbers in the peripheral blood, a typical symptom of CSFV infection in pigs, was not detected on infection with the RNase-negative mutant C-H346Delta [Meyers et al. (1999). J Virol 73, 10224-10235]. The present report shows that this feature is restricted to this specific virus mutant, and does not represent a general property of RNase-negative CSFV. The effects induced by infection with two other RNase-negative and wild-type (wt) CSFV strains on the composition of peripheral blood cells have been further analysed. For all viruses, not only general leukopenia but also a reduction of different subsets of leukocytes (T-lymphocytes, monocytes and granulocytes) was detected. Similar to the results with B-cells, no significant differences with regard to changes in cell number were determined for RNase-negative mutants and wt virus during the initial phase of infection. Later, the values returned to pre-infection levels for the mutants, but stayed at low levels in the wt virus-infected animals. A major difference was reflected in the virus load of the infected animals, which was dramatically higher for pigs infected with wt CSFV, so that reduction of the virus load represents a further marker for attenuation resulting from RNase destruction. Attenuation was also detectable for the RNase-negative mutant C-W300G, which showed rapid reversion to the wt sequence within the infected pig. The prevention of fatal disease after infection with C-W300G is apparently determined during the short time between infection and reversion, as the virus revertant reisolated from infected pigs was shown to be virulent when used for infection in a follow-up study. Reversion of C-W300G was also detected in tissue culture during passage on swine testis epithelioid cells and porcine transformed kidney (MAX) cells, whereas the mutation was stable when SK6 or 38A1D cells were tested.

Amino Acid Substitution↗

PubMed1999

Characterization of the sigma ligand panamesine, a potential antipsychotic, by immune response in patients with schizophrenia and by sleep-EEG changes in normal controls.

Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.

Adjuvants, Immunologic↗