Cytokine profile in systemic lupus erythematosus,rheumatoid arthritis,and other rheumatic diseases

We investigated serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-gamma" align="MIDDLE" BORDER="0">), and tumor necrosis factor alpha (TNF) from patients with systemic lupus erythematosus (SLE) and its various clinical manifestations of disease and from patients with rheumatoid arthritis (RA) and other rheumatic diseases. The serum levels of IL-6 and IFN-gamma" align="MIDDLE" BORDER="0"> were highly elevated from patients with SLE associated with lymphadenopathy (LN) or nephrotic syndrome (NS). On the contrary, the serum levels of TNF were elevated from most patients with SLE associated with thrombocytopenia (TP). However, serum levels of TNF were in the normal range from patients with SLE associated with NS, LN, or central nervous system disease. Of interest, patients with SLE associated with humoral immunodeficiency disorder, hypogammaglobulinemia, had highly elevated levels of serum IL-6. The concanavalin A-stimulated mononuclear cells (MNC) of patients with SLE associated with TP secreted highly elevated levels of TNF compared to other patient groups. We suggest that abnormal production of various cytokines in SLE is an intrinsic defect of MNC and the immune system that may be the key element for a variety of clinical manifestations of this disease.     

IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells

Although the effect of IL-15 has been described on murine cells in vitro and in vivo, its effect on human memory CD8(+) T cells is not well characterized. We show here that IL-15 preferentially enhances the activation and effector function of human effector-memory CD45RA(-)CD62L(-) and CD45RA(+)CD62L(-) CD4(+) and CD8(+) T cells in both healthy and HIV-infected individuals. We find that IL-15 increases 2- to 5-fold both the activation and secretion of the effector cytokines IFN-gamma and tumor necrosis factor (TNF)-alpha by anti-CD3-stimulated purified CD4(+) and CD8(+) T cells and peripheral blood mononuclear cells from healthy and HIV-infected individuals. Furthermore, IL-15 potently inhibits CD95/Fas-induced apoptosis of the effector-memory CD4(+) and CD8(+) T cells from HIV-infected individuals. These findings suggest that in addition to being a growth and survival factor for memory CD8(+) T cells, IL-15 is also a potent activator of human effector-memory CD8(+) T cells both in healthy and in HIV-infected individuals.     

Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity

Using short term CTL lines derived from HLA A2/K^b transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/K^b molecules. Interestingly, T cell recognition of the naturally processed form of the NS4.1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity.     

Astrocytes and intracerebral immune responses

The astrocyte is the most abundant cell within the central nervous system (CNS). This cell subserves a multiplicity of important functions that contribute to the process of neural development as well as to the integrity of normal brain function. Adding to the already exhaustive list of capabilities, the astrocyte has now been demonstrated to function as an intracerebral antigen presenting cell. These findings are serving to revise our view of the brain as an immunoprivileged site and perhaps will shed some light on the pathogenetic mechanisms involved in a number of CNS disorders of immune dysregulation. In this review we provide some perspective on the regulatory mechanisms that influence astrocyte immune functions. Specifically, we address the role played by the major histocompatibility complex (MHC) antigens as well as adhesion molecules in the initiation of brain immune responses.     

Treatment of atypical leishmaniasis with interferon γ resulting in progression of Kaposi's sarcoma in an AIDS patient

Visceral leishmaniasis (kala-azar) affecting HIV-infected patient is being reported in increasing frequency. A 40-year-old German bisexual patient with full-blown AIDS is described who presented with Kaposi's sarcoma, epigastric pain, diarrhea, and weight loss but without fever.Leishmania amastigotes were initially found in biopsies from stomach, duodenum, and a cutaneous Kaposi's sarcoma lesion but were later also recovered from bone marrow and lymph node. The patient received three courses of a combination of pentavalent antimony and interferon-gamma" align="MIDDLE" BORDER="0">. In addition to the common side effects such as fever, thrombocytopenia, and elevated amylase and lipase, a vivid progression of the Kaposi's sarcoma was noted. Tumor progression was temporally closely associated with treatment with interferon-gamma" align="MIDDLE" BORDER="0">. Because this phenomemon has also been observed in other patients, we advise caution when using interferon-gamma" align="MIDDLE" BORDER="0"> in patients with Kaposi's sarcoma.Abbreviations AIDS acquired immunodeficiency syndrome - HIV human immunodeficiency virus - KS Kaposi's sarcoma Correspondence to: H. Albrecht     

Differential induction of human monocyte transforming growth factorβ1 production and its regulation by interleukin 4

We have previously shown that trauma patients' monocytes which arein vivo activated by multiple injury-induced mediators have elevated transforming growth factor-beta (TGF) bioactivity. Interleukin-4 (IL-4), a Th₂ and B lymphocyte stimulatory factor, has been shown to inhibit monocyte production of a number of mediators both after lipopolysaccharide stimulation and after trauma-induced stimulation. However, IL-4 inhibitory effects appears to vary, depending on the mixture of inducing stimuli. Here we describe thein vitro IL-4 inhibition of human monocyte TGF bioactivity using several stimulation induction protocols: muramyl dipeptide stimulation alone, or after Fc_{gamma" align="MIDDLE" BORDER="0">}RI (CD64) cross-linking induction, interferon-gamma (IFN_{gamma" align="MIDDLE" BORDER="0">}) priming, or trauma-generatedin vivo mediator induction. IL-4 suppressed both muramyl dipeptide-induced TGF bioactivity and TGF mRNA in a dose-dependent fashion and was most effective when IL-4 was administered at initiation of normal monocyte stimulation. Muramyl dipeptide (MDP)-induced increases in trauma patients' monocyte TGF bioactivity were also inhibited by high doses of IL-4 (25 ng/ml). Fc_{gamma" align="MIDDLE" BORDER="0">}RI cross-linking increased MDP-induced normal monocyte TGF bioactivity, but this increase could be consistently inhibited only by very high IL-4 concentrations (50 ng/ml). IL-4 did not consistently downregulate MDP-induced TGF bioactivity in IFN_{gamma" align="MIDDLE" BORDER="0">}-primed monocytes. IL-4 can suppress monocyte TGF production, as well as other monocyte mediators, but its efficiency depends on the stimuli combination present in the microenvironment.     

Stochastic and Coherence Resonance in an In Silico Neural Model

We show that it is possible for chaotic systems to display the main features of stochastic and coherence resonance. In particular, a model of coupled nonlinear oscillators which emulates the transmembrane voltage activities in CA3 neurons, operating in a chaotic regime and in the presence of noise, can exhibit coherence resonance and stochastic resonance. Certain firing frequencies become more "rhythmic" for some optimal values of noise intensity. The effect of noise in different coupling pathways is investigated. We found that the effect of coherence resonance and stochastic resonance are more prominent if noise is presented in either electric field or gap junction coupling pathways. Frequency sensitivity of the model is investigated as a preliminary step in illustrating the principles of possible epileptic seizure control strategies using "chaos control" concepts. Significant effects of stochastic resonance are observed in the 4-8 Hz range. Weaker effects can be found in the 1-4 Hz and 8-10 Hz ranges whereas 0.5 Hz does not exhibit any resonance phenomenon. Our results suggest that: (a) Stochastic resonance could enhance the intrinsic 4-8 Hz rhythms in CA3 neurons more prominently via field coupling pathways. It could also help explain why some reported seizure control strategies using pulse-trains would only be effective at 0.5 Hz. (b) Stochastic resonance-like behavior can occur in the gamma range only if noise is presented via chemical synaptic pathways.     

Isoenzymes of γ-glutamyl transpeptidase in liver diseases

Summary A new method for the separation of isoenzymes ofgamma" align="MIDDLE" BORDER="0">-glutamyl-transpeptidase is described, using electrophoresis on acetate cellulose gel and a developing solution composed bygamma" align="MIDDLE" BORDER="0">-glutamyl-naphthylamide, and a colored diazonium compound.The method permits the separation of up to four different isoenzymes, which we calledgamma" align="MIDDLE" BORDER="0">-GT₁,gamma" align="MIDDLE" BORDER="0">-GT₂,gamma" align="MIDDLE" BORDER="0">-GT₃,gamma" align="MIDDLE" BORDER="0">-GT₄, the first two showing an electrophoretic migration similar to that of ₁- and ₂-globulins and the other two to that of-globulins.The present technique has proved its usefulness in detecting isoenzymes in serum with values of totalgamma" align="MIDDLE" BORDER="0">-glutamyl-transpeptidase higher than 80 U/L.The application of this method in 52 patients with different types of biliary obstruction and hepatocellular damage has shown that it provides new possibilities in differential diagnosis.     

A unique pattern of lymphokine synthesis is a characteristic of certain antigen-specific suppressor T cell clones

We report that the lymphokines (IFN-gamma.gif" ALT="{gamma}" BORDER="0">) and IL-10 are co-syntheslzedby previously described CD3⁺ TCRß⁺, minor antigen-specificsuppressor T cell clones. IFN-gamma.gif" ALT="{gamma}" BORDER="0"> and IL-10 are known to (I) becharacteristically produced by different helper T cell types,T_h1 and T_h2 respectively, and (II) inhibit the function of thereciprocal subset of T cells: IFN-gamma.gif" ALT="{gamma}" BORDER="0"> Inhibits the function ofT_h2 and IL-10 that of T_h1 cells. Although Th0 cells are alsoknown to synthesize cytoklnes of both the T_h1- and T_h2-typeT cells, the suppressor T cells described in this report aredifferent from T_h0 cells in that they produce (I) neither IL-2nor IL-4 molecules and (II) stimulation via their CD3-TCR systemseems independent of both IL-2 and IL-4, the typical autocrinemolecules for T cell proliferation. The lymphokine profile ofthese suppressor T (TJ cell clones, as well as those of humanantigen-specific T. cells reported earlier, suggests that co-synthesisof some T_h1-llke and some T_h2-like cytoklnes may be a characteristicof antigen-specific T, cells as opposed to the type of reciprocalinhibition mediated through IFN-gamma.gif" ALT="{gamma}" BORDER="0"> or IL-10, which is antigennon-specific.     

Conjugation of DNA fragments to protein carriers by glutaraldehyde: immunogenicity of oligonucleotide-hemocyanin conjugates

The practical realization of the concept of specific immunotherapy for systemic lupus erythematosus (SLE) has been hampered, thus far, by an inability to link DNA fragments to carrier protein. In this paper, a novel technique is described, in which glutaraldehyde is the linking agent. A 2-stage method was used to link oligonucleotides to a soluble protein carrier, such as keyhole limpet hemocyanin (KLH) or human gamma globulin (HGG), whereas a 1-stage technique was sufficient to link oligonucleotides to sheep red cells. Both the ultraviolet absorbance spectrum and diphenylamine assay demonstrated that oligonucleotides were coupled to soluble protein. The conjugate of oligonucleotide to protein carrier appears to be recognized by anti-DNA antibody since oligonucleotide linked to either KLH or HGG inhibited the binding of anti-DNA antibody in vitro, and oligonucleotide-coupled sheep cells are agglutinating by seropositve sera from lupus patients. In addition, oligonucleotide-KLH raised hemagglutinating antibody to denatured DNA in C57BL/6, DBA/2 or NZB mice, as well as IgG antibody as detected by SPRIA in C57BL/6 and DBA/2 mice. The significance of this new method for the development of an antigen specific therapy of SLE is discussed.