Pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis.

The outcome of immune responses can be predicted by the lymphokine production pattern of the participating cells. Cytokines of the T helper type 1 (Th1) cells mediate inflammatory responses and delayed-type hypersensitivity (DTH), whereas Th2-like T cells predominantly produce cytokines, which stimulate antibody production by B cells. Immunoregulatory therapy of autoimmune diseases with unknown antigens may be achieved by inhibiting the production of inflammatory cytokines and induction of protective cytokines of Th2-like T cells.

Cell-mediated immune response of macaques immunized with low doses of simian immunodeficiency virus (SIV).

Many uninfected people at high risk of HIV infection developed an HIV-specific cellular immune response despite their lack of seroconversion. Therefore, they must have been exposed to HIV without subsequent infection. It has been concluded from these data, that cell-mediated immunity (CMI) rather than humoral immunity might confer protection to HIV infection.

Monocyte/macrophage differentiation in early multiple sclerosis lesions.

Monocyte/macrophage differentiation was studied in biopsy samples of multiple sclerosis (MS) lesions obtained in the early course of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different macrophage-activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products.

Specificity of intrathecal IgG synthesis for HTLV-1 core and envelope proteins in HAM/TSP.

Introduction: In patients with human T-cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), we investigated the significance of HTLV-1 specific antibodies in the cerebrospinal fluid (CSF).

Material And Methods: The quantities of HTLV-1 specific immunoglobulin G (IgG) in paired CSF and serum were evaluated by a sensitive enzyme immunoassay (EIA). The specificity of antiviral IgG was determined by radioimmunoprecipitation of HTLV-1 antigens.

Soluble forms of intercellular adhesion molecule-1 (ICAM-1) block lymphocyte attachment to cerebral endothelial cells.

Serum levels of circulating ICAM-1 are increased in various disorders including inflammatory diseases of the central nervous system (CNS). We recently described an association between high sICAM-1 levels in the serum of patients with multiple sclerosis and disease activity. The functional consequences of increased circulating adhesion molecules are not fully understood.

A soluble form of tumour necrosis factor receptor in cerebrospinal fluid and serum of HTLV-I-associated myelopathy and other neurological diseases.

Paired samples of cerebrospinal fluid (CSF) and serum from 17 patients with human T-cell lymphotrophic virus I (HTLV-I)-associated myelopathy, 5 patients with multiple sclerosis and 11 controls with non-inflammatory disorders (migraine, idiopathic epilepsy and myelopathy of unknown aetiology) were examined by enzyme-linked immunosorbent assay for the presence of the 60-kDa soluble form of tumour necrosis factor receptor (sTNF-R). The results were compared with blood-CSF barrier function, cell count and the intrathecal synthesis of HTLV-I antibodies. No correlation could be demonstrated.

Circulating forms of ICAM-3 (cICAM-3). Elevated levels in autoimmune diseases and lack of association with cICAM-1.

The intercellular adhesion molecule-3 (ICAM-3) has been identified as the third LFA-1 ligand in addition to ICAM-1 and ICAM-2. In this report we have identified circulating forms of ICAM-3 (cICAM-3) in human serum. Using a sandwich ELISA with two monoclonal anti-ICAM-3 Abs, we detected cICAM-3 in concentrations between 40 and 360 ng/ml in all of 112 healthy controls.

Cerebral endothelial cells are a major source for soluble intercellular adhesion molecule-1 in the human central nervous system.

Immunohistological analysis of tissue sections from human brain revealed that intercellular adhesion molecule-1 (ICAM-1) is mainly expressed on endothelial cells of small vessels, including the subependymal vessels of the choroid plexus. In addition, it is expressed on cerebrospinal fluid (CSF) cells in patients with inflammatory diseases of the central nervous system. Stimulation of confluent monolayers of adult human cerebral endothelial cells with lipopolysaccharide (LPS) or recombinant human tumor necrosis factor-alpha (TNF-alpha) could induce expression and secretion of soluble ICAM-1 in a dose dependent manner.

[Pathogenesis and therapy of multiple sclerosis. The role of cytokines].

Multiple sclerosis (MS) is probably caused by multiple factors, but there is evidence that an autoimmunological process is relevant for the pathogenesis. Cytokines can operate in different ways in MS and the animal model "experimental allergic encephalomyelitis (EAE). "Interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 (IL-1) and IL-2 are important inflammation mediators within the MS plaque, whereas IFN-alpha, IFN-beta, transforming-growth-factor-beta (TGF-beta) and IL-10 exert mainly immunosuppressive functions.

Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity.

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 29 patients with relapsing-remitting multiple sclerosis every 4 weeks over a period of 12 months. During this period 27 relapses occurred in 14 patients (48%). Progression of disease activity as assessed by the occurrence of new lesions on nonenhancing T2-weighted magnetic resonance images of the head was detected in 12 (48%) of 25 patients.

Semi-quantitative analysis of cytokine gene expression in blood and cerebrospinal fluid cells by reverse transcriptase polymerase chain reaction.

An easy, reproducible and semi-quantitative, non-radioactive method for the analysis of mRNA expression for various cytokines, (i.e., Interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, lymphotoxin (LT), transforming growth factor (TGF)-beta, interferon (IFN)-gamma and endothelin-1 (ET-1)) in cells from cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) has been established.

Serial analysis of circulating adhesion molecules and TNF receptor in serum from patients with multiple sclerosis: cICAM-1 is an indicator for relapse.

We determined the serum levels for circulating adhesion molecules (circulating intercellular adhesion molecule-1 [cICAM-1], circulating endothelial leukocyte adhesion molecule-1 [cELAM-1], and circulating L-selectin [cL-selectin]) and circulating tumor necrosis factor receptor (cTNF-R) p60 in 29 patients with relapsing-remitting MS serially over a period of 12 months. During this period there were 27 relapses in 14 patients (48%). There was progression of disease activity in 12/25 patients (48%), as assessed by the occurrence of new lesions on nonenhancing, T2-weighted MRIs of the head.

Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis.

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 45 patients with the relapsing-remitting form of MS and 32 patients with other neurologic diseases. Using a semiquantitative polymerase chain reaction method, we detected significantly higher levels of tumor necrosis factor-alpha and lymphotoxin mRNA in patients with relapsing compared to those with stable disease (p < 0.001), but transforming growth factor-beta and interleukin-10 mRNA expressions were higher in patients with stable disease.

Regulation of JC virus expression in B lymphocytes.

The etiologic agent of progressive multifocal leukoencephalopathy, a subacute demyelinating disease of the central nervous system, is the human polyomavirus JC virus (JCV), which causes a lytic infection of myelin-producing oligodendrocytes. In infected individuals the JCV genome can be detected in brain tissue and B lymphocytes isolated from the blood, bone marrow, or lymph nodes. Using mobility shift assays and a radiolabeled oligonucleotide from the JCV promoter-enhancer region (JCV bp 130 to 160), referred to as domain B, we were able to detect specific bands of the same mobility in nuclear extracts from human fetal glial cells, U-251 glioma cells, different B-cell lines, and in vitro-activated tonsillar B lymphocytes but not from T cells.

Soluble intercellular adhesion molecule-1 in cerebrospinal fluid: an indicator for the inflammatory impairment of the blood-cerebrospinal fluid barrier.

A soluble form of the intercellular adhesion molecule-1 (sICAM-1) was measured in paired cerebrospinal fluid (CSF)/blood samples from 123 patients with different neurological diseases. Mean levels of circulating ICAM-1 in the blood were mean +/- SD = 423 +/- 184.6 ng ml-1 (range 44-1115 ng ml-1).

Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120.

Monocytes/macrophages play a critical role in the pathogenesis of HIV infection, both as targets for virus replication and as sources of production of multifunctional cytokines. Endothelins, peptides with potent vasoconstricting activities originally isolated from endothelial cells, are also produced and secreted by macrophages in a manner similar to that of other cytokines. In an attempt to explore the potential role of endothelins in HIV-infection, we investigated the effect of the HIV-1 envelope glycoprotein, glycoprotein 120, on monocytic endothelin-1 production.

Okadaic acid is a potent inducer of AP-1, NF-kappa B, and tumor necrosis factor-alpha in human B lymphocytes.

Treatment of human B lymphocytes with an optimal concentration of okadaic acid, an inhibitor of phosphatases 1 and 2A, resulted in the induction of the transcription factor, AP-1 and a marked increase in NF-kappa B levels. In contrast, no effect on the levels of the octamer binding proteins, Oct-1 or Oct-2, were found. Since both AP-1 and NF-kappa B have been reported to be important in the induction of the tumor necrosis factor-alpha (TNF-alpha) gene we examined the effects of okadaic acid on TNF-alpha mRNA levels.

Lymphokine production by B cells from normal and HIV-infected individuals.

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are both secreted by in vivo-activated normal B cells and by in vivo-activated B cells from patients with polyclonal B-cell activation, including individuals infected with the human immunodeficiency virus (HIV). Furthermore, IL-6 and TNF-alpha are involved in autocrine and paracrine regulation of human B-cell differentiation. Following in vitro stimulation of normal B cells with Staphylococcus aureus Cowan strain I and IL-2, there is a rapid but brief increase in supernatant levels of TNF-alpha.

Analysis of cis-acting elements present in the CD20/B1 antigen promoter.

A genomic clone spanning a large portion of the 5' untranscribed region of the CD20 gene was isolated. Deletion analysis of subcloned fragments identified several regulatory elements. A major positive cis-acting element was localized between base pairs -290/-186.

Recombinant gp120 specifically enhances tumor necrosis factor-alpha production and Ig secretion in B lymphocytes from HIV-infected individuals but not from seronegative donors.

The effect of recombinant protein from the envelope (gp120) of the HIV on B lymphocytes purified from either HIV-infected individuals or healthy seronegative controls was examined. B cells from peripheral blood and lymph nodes of HIV-infected individuals spontaneously secreted TNF-alpha; this secretion was augmented by the presence of gp120, whereas B cells from healthy seronegative donors failed to secrete significant levels of TNF-alpha in the presence or absence of gp120. In a coculture system of B cells and chronically HIV-infected T cells (ACH-2), where viral expression is largely mediated by TNF-alpha, gp120 increased virus expression only if the B cells were obtained from HIV-infected individuals.

Transforming growth factor-beta suppresses human B lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secreted form of Ig mRNA.

Transforming growth factor-beta (TGF-beta) inhibits B cell Ig secretion and reduces B cell membrane Ig expression. The addition of TGF-beta to human B lymphocyte cultures stimulated with Staphylococcus aureus Cowan strain I and IL-2 completely inhibited B cell Ig secretion (greater than 90%) and decreased B cell surface IgM, IgD, kappa L chain, and lambda L chain expression. In contrast, TGF-beta had only minimal effects on two other B cell membrane proteins, HLA-DR and CD20.

IL-6 and tumor necrosis factor-alpha. Autocrine and paracrine cytokines involved in B cell function.

IL-6 and TNF-alpha are synthesized and secreted by normal tonsillar B cells after stimulation with the polyclonal B cell activator Staphylococcus aureus Cowan strain 1 (SAC) and IL-2 as well as spontaneously by in vivo activated B cells from patients with hypergammaglobulinemia. Using specific neutralizing antibodies, both factors were shown to be involved in autocrine and/or paracrine regulation of B cell differentiation. IgG induced by SAC/IL-2 stimulation was reduced 73% with an anti-IL-6 antibody and 40% with an anti-TNF-alpha antibody.