用混合粘合剂碳糊电极测定丁螺环酮

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CD4-positive/heat-stable antigen-positive thymocytes cause graft-versus-host disease across non-major histocompatibility complex incompatibilities

Single-positive thymocytes are the immediate precursors of peripheral recent thymic emigrants (RTE) which develop into mature peripheral T cells. The functional ability of RTE is unclear but their state of differentiation may be relevant to the development of tolerance to peripheral “self” antigens. Since RTE are difficult to analyze, precursor CD4⁺/8⁻ thymocytes were assessed in a model in vivo to determine their functional capability and their susceptibility to tolerance induction. The ability of both heat-stable antigen-positive (HSA⁺) (immature) and HSA⁻ (mature) single-positive thymocytes to cause graft-versus-host disease (GVHD) across non-major histocompatibility complex differences was examined. Both HSA⁻ and HSA⁺ CD4⁺/8⁻ thymocytes from C3H mice caused lethal GVHD in AKR recipients as did CD4⁺ peripheral T cells in controls. Further, neonatal C3H thymocytes also caused lethal GVHD in AKR recipients. Since CD4⁺/8⁻ thymocytes are the precursors of RTE, these results suggest that RTE are not susceptible to tolerance induction to “minor” antigens and may have a normal immune function in vivo. This would suggest that peripheral tolerance may be dependent upon the manner of antigen presentation rather than T cell maturity.     

Viral infections in the mouth

Oral hairy leukoplakia (OHL) and Kaposi's sarcoma (KS) are commonly encountered in the HIV-infected patient. A unique feature of OHL is non-cytolytic high level of replication of Epstein–Barr virus (EBV) in the glossal epithelium. The expression of viral-encoded anti-apoptotic proteins concomitant to replicative proteins probably underlies this phenomenon. The question of whether OHL arises from activation of EBV latent in the tongue, or from superinfection by endogenous EBV shed via non-glossal sites or by exogenous EBV remains unresolved. Human herpesvirus 8 (HHV8) is now seen as necessary but not sufficient cause of KS. Expression of HHV8-encoded oncogenic proteins in endothelial cells probably explains the aberrant proliferation of these cells in KS lesions. Studies into why KS is so commonly observed at the palate in HIV-infected patients may provide important clues to its pathogenesis.     

Regulation of autoimmune response

Recent work on such apparently disparate fields as T-cell receptor peptide-induced regulation, superantigens, antigen-induced tolerance, models of peripheral tolerance, apoptosis, and T-cell receptor antagonists demonstrates a similarity in immune response from a regulatory perspective. In many systems, a ‘tolerance’ pathway is observed, characterized broadly as an initial disturbance in the immune system, with a resulting predominance of effector cells, followed by a homeostatic response (often requiring CD8⁺ cells) which leads the effector population into T-cell receptor downregulation, T-cell inactivation, anergy and, often, eventual apoptotic death. In the regulated immune response, mixed populations of anergized and apoptosing T cells can be found. In some cases, anergy appears to lead to death while, in other instances, cells revert to a functional state. This review focuses on recent papers examining each of these topics in an attempt to obtain a preliminary, integrated picture of immune regulation in autoimmune diseases.     

Inhibition of rat mixed lymphocyte pancreatic islet cultures with anti-Ia immunotoxin

Studies reported here indicate that an anti-Ia immunotoxin can eliminate the allostimulatory subpopulation of cells present within the islets of Langerhans without damaging the hormone-secreting cells. Such studies made use of an in vitro correlate of transplantation rejection, the mixed lymphocyte islet cell (MLIC) reaction. Using the MLIC, it was demonstrated that an anti-Ia immunotoxin removed cells capable of stimulating the MLIC in a dose-dependent fashion without altering the hormone-secreting functions of the remaining cells when challenged with glucose and theophylline. These studies suggest the feasibility of using such anti-Ia immunotoxins in islet allograft transplantation models to circumvent problems inherent in complement-mediated cytotoxicity, a previously documented effective form of inducing islet allotransplantation tolerance.     

Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4

Rheumatoid arthritis (RA) is an autoimmune arthritis, for which treatment options remain limited. This study investigated the potential role of adoptive cellular gene therapy as a novel means for treating the RA animal model collagen-induced arthritis (CIA). Adoptive transfer of antigen-specific T-cell hybridomas retrovirally transduced to express IL-4 1 day before booster immunization significantly reduced the number of inflamed joints. Cell transfer after clinical onset of disease had no therapeutic effect. Bioluminescence imaging showed that the hybridomas migrated to the inflamed joints, thus delivering the regulatory protein locally at the site of inflammation. The homing was, at least in part, due to chemotaxis in response to proinflammatory chemokines that are expressed in inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes, nor in the systemic levels of anti-collagen antibodies in treated mice. We conclude that the beneficial clinical effects observed in our model were most likely based on the local action(s) of IL-4 in the inflamed joints and that the local delivery (and effects) of regulatory cytokines, like IL-4, constitutes a novel and effective method of preventing organ-specific autoimmune disease and of minimizing systemic adverse effects.     

Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz

The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague- Dawley rats were exposed daily to sidestream cigarette smoke in a whole- body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz, starting 1 week prior to initiation of smoke exposure until the end of the experiment. Analysis of lipophilic DNA adducts by the nuclease P1-mediated 32P-post-labeling showed up to five smoke-related adducts. Adduct no. 5 predominated in both the lung and the heart while adduct nos 3 and 2 predominated in the trachea and bladder, respectively. Quantitative analysis revealed that the total adduct level was the highest in lungs (270+/-68 adducts/10(10) nucleotides), followed by trachea (196+/-48 adducts/10(10) nucleotides), heart (141+/-22 adducts/10(10) nucleotides) and bladder (85+/-16 adducts/10(10) nucleotides). High dose oltipraz treatment reduced the adduct levels in lungs and bladder by >60%, while the reduction in lungs in the low-dose group was approximately 35%. In trachea, the effect of low and high dietary oltipraz on smoke DNA adduction was equivocal, while smoke-related DNA adducts in the heart were minimally inhibited by high-dose oltipraz. In a repeat experiment that employed a 3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to inhibit the formation of DNA adducts in rat lungs and trachea by 80 and 65%, respectively. These data clearly demonstrate a high efficacy of oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts in the target tissues.