肺癌患者化疗前后血清IL-2,SIL-2R检测的临床意义

目的 :分析了 36例肺癌患者化疗前后血清中IL - 2和SIL - 2R水平的变化。方法 :采用放射免疫分析法测定患者血清中IL - 2和使用ELISA法测定SIL - 2R含量 ,并与 35名正常健康人作比较。结果 :化疗前IL- 2活性明显低于正常人 ,SIL - 2R水平明显高于正常人 (P <0 .0 1 ) ,化疗后 6个月复发者IL - 2 /SIL - 2R水平持续异常 ,未复发者IL - 2 /SIL - 2R水平恢复正常。结论 :观察肺癌患者免疫功能的变化与患者的病情和预后密切相关。     

Lack of intermediate-affinity interleukin-2 receptor in mice leads to dependence on interleukin-2 receptor α, β and γ chain expression for T cell growth

An interleukin (IL)-4 dependant mouse T cell clone 8.2 derived from an IL-2-dependent T cell line was characterized. As measured by flow cytometric analysis and Northern blotting, it expresses IL-2 receptor β (IL-2Rβ) and γ (IL-2Rγ) chains, but has lost expression of IL-2 receptor α chain (IL-2Rα). To investigate the properties of the mouse IL-2Rβγ complex and the role of IL-2Rα gene expression, this clone was further studied. T cell clone 8.2 has lost the capacity to bind ¹²⁵I-labeled human IL-2 under experimental conditions able to detect intermediate-affinity IL-2R in human cells. Mouse IL-2 is unable to block the binding of mAb TMβ1 to 8.2 cells. Under the same experimental conditions, mouse IL-2 blocks the binding of TMβ1 to C30-1 cells expressing the IL-2αβγ complex. Since TMβ1 recognizes an epitope related to the IL-2 binding site of IL-2Rβ, these results can be taken as a demonstration that mouse IL-2Rβγ does not bind mouse IL-2. Furthermore, T cell clone 8.2 does not proliferate in response to recombinant mouse or human IL-2. On the other hand, T cell transfectant lines expressing heterospecific receptors made of the human IL-2Rβ and mouse IL-2Rγ chains bind ¹²⁵I-labeled human IL-2 and proliferate in response to IL-2. This establishes the difference between mouse and human IL-2Rβ chains. Transfection of T cell clone 8.2 with human IL-2Rα genes restores their capacity to proliferate in response to IL-2. In addition, all transfectants grown in IL-2 express the endogeneous mouse IL-2Rα chain. When grown in IL-4, the endogeneous mouse IL-2Rα gene remains silent in all these transfectants. These results show that, contrary to the human, the mouse does not express an intermediate-affinity IL-2R. Expression of the IL-2Rα gene is therefore required for the formation of the functional IL-2R in mice.     

Interferon-γ and interleukin-10 inhibit antigen presentation by Langerhans cells for T helper type 1 cells by suppressing their CD80 (B7-1) expression

CD80(B7-1) and CD86(B7-2) co-stimulatory molecules have been reported to activate Th1/Th2 development pathways differentially. It is well known that Langerhans cells (LC), potent antigen-presenting dendritic cells in the epidermis, express several co-stimulatory molecules and that this expression is modulated by several cytokines. Based on the recently reported effect of interferon (IFN)-γ and interleukin (IL)-10 on the expression of CD80 and CD86 by LC, we examined the effects of these cytokines on the expression of CD54 (intercellular adhesion molecule-1) and CD40 in addition to CD80 and CD86 on LC, and correlated the expression of each co-stimulatory molecule with antigen presentation for a Th1 clone by cultured LC (cLC) treated with these cytokines. LC cultured for 72 h significantly up-regulated MHC class II antigen expression and all the co-stimulatory molecules we examined. As previously reported, IL-10 or IFN-γ inhibited the up-regulation of CD80 expression. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) partially restored the suppression of CD80 expression induced by IFN-γ on cultured LC, while it had virtually no effect on the inhibition induced by IL-10. Antigen presentation for the myoglobin-specific syngeneic Th1 clone by cLC, which were pre-incubated with these cytokines, correlated well with their CD80 expression. In addition, among the antibodies for CD80, CD86, CD28 or CD40, the suppression of the Th1 clone stimulation by LC was found to occur only with anti-CD80 and anti-CD28 antibodies. Finally, we studied the effects of IFN-γ and IL-10 on GM-CSF production by epidermal keratinocytes (KC). We could show that only IFN-γ, but not IL-10, suppressed GM-CSF production by KC. These findings suggest that both IFN-γ and IL-10 suppress antigen presentation by LC for Th1 cells by suppressing their CD80 expression. The inhibitory effect of IFN-γ on CD80 expression on LC appears to be partially mediated through the suppression of GM-CSF production by KC.     

Existence of a small population of IL-2Rβhi TCRint cells in SCG and MRL-lpr/lpr mice which produce normal Fas mRNA and Fas molecules from the lpr gene

Mice carrying the lpr gene, SCG and MRL-lpr/lpr mice, were used to characterize the phenotype and lpr gene of abnormally proliferating T cells in these mice. A major population which expanded in these mice were T cells expressing intermediate (int) levels of T cell receptor (TCR) (and CD3) and the phenotype of interleukin-2 receptor (IL-2R)β^lo α^? (possibly abnormal TCR^int cells). The levels of TCR^hi cells of thymic origin (generated through the mainstream of T cell differentiation in the thymus) profoundly decreased after the onset of disease. However, a small population of normal TCR^int cells (i.e. IL-2Rβ^hi α^?) were also found to exist in all tested organs. For example, the majority of abnormal IL-2Rβ^lo TCR^int cells were CD4^?8^? CD2^?, while normal IL-2Rβ^hi TCR^int cells were a mixture of single-positive cells (mainly CD8⁺), CD4^?8^? cells and CD2⁺ cells. Moreover, normal TCR^int cells preferentially produced normal Fas mRNA and Fas molecules from the lpr gene. This phenomenon explains the leaky appearance of normal Fas mRNA and Fas molecules in mice carrying the lpr gene. It is suggested that a small population of IL-2Rβ^hiTCR^int cells are resistant to the lpr genetic abnormality.     

Acute and long-term effects of 17b-oestradiol on agonist-stimulated force in rat tail artery

The effects of 17β-oestradiol on the force responses to KCl and noradrenaline were investigated in rings of the rat tail artery. Incubation with 10 μm 17β-oestradiol for 100–295 min reduced the force amplitude after 5 min in high-K⁺ (140 mm ) to 10% of the control value. The inhibitory effect of the steroid was unaffected by the NO-synthase inhibitor l -NAME. Rings activated by an intermediate degree of depolarization (60 mm K⁺) were less affected by the steroid (58% of control force). The sustained force response to 1 μm noradrenaline was reduced in the presence of 17β-oestradiol to 60% of control value. Lower concentrations of 17β-oestradiol (0.1 and 1 μm ) were without acute effects on force development. However, long-term effects of 17β-oestradiol on vessel reactivity were found at these low concentrations. Rings were cultured for 3–7 days in the absence or in the presence of the steroid before they were stimulated with agonists. Cultured rings developed an increased sensitivity to noradrenaline compared with freshly prepared ones. Cocaine (30 μm) shifted the noradrenaline concentration–response curve to the left in freshly prepared rings while it had no effect in cultured ones, indicating that the increased sensitivity to noradrenaline in cultured rings depends on loss of noradrenaline uptake. Rings cultured for 7 days in the presence of 0.1 μm 17β-oestradiol developed a more pronounced supersensitivity to noradrenaline (EC₅₀ for noradrenaline was 0.13±0.03 μm in steroid exposed rings vs. 0.38±0.09 μm in control rings). Thus, prolonged treatment with 17β-oestradiol results in a potentiation of noradrenaline evoked force, in contrast to the acute effect of the steroid.     

The interleukin-8 receptor B and CXC chemokines can mediate transendothelial migration of human skin homing T cells

We studied the involvement of chemokines that bind to G protein-coupled receptors in the migration of skin homing T cells across a bilayer vascular construct (BVC) consisting of a fibroblast matrix underneath an activated endothelial (EC) monolayer. Based on the expression of the cutaneous lymphocyte-associated antigen (CLA), a skin homing receptor, CD45R0⁺ T cells freshly isolated from blood or HUT-78 cutaneous T lymphoma cells were separated into CLA⁺ and CLA⁻ subpopulations. These T cells were incubated on interleukin (IL)-1β and tumor necrosis factor-α-activated EC, and the number of transmigrated cells was determined. The chemokine IL-8 was selectively involved in the enhanced migration of CLA⁺ T cells across activated EC as demonstrated by blocking antibody to IL-8 but not to GRO-α, MCP-1 and RANTES. Identical results were obtained with both human umbilical vein EC (HUVEC) and microvascular skin EC (HDMEC). Pertussis toxin selectively inhibited the enhanced transendothelial migration (TEM) of CLA⁺ T cells, suggesting that CLA-dependent TEM depends on G_i protein-transmitted signals. Moreover, the IL-8 receptor B (IL-8RB) appeared to be functionally involved in TEM, as demonstrated by receptor desensitization with the CXC chemokines IL-8 and GRO-α and by blocking the IL-8RB with specific monoclonal antibodies. Although only the IL-8RB was involved in CLA-dependent TEM, mRNA encoding IL-8RA and IL-8RB was expressed by both CLA⁺ and CLA⁻ T cells. This correlated with IL-8RA and IL-8RB surface expression on these cells. Thus, the IL-8RB is selectively functional in TEM of T cells expressing the skin homing receptor CLA. Our results demonstrate a critical role for IL-8 and possibly other IL-8RB ligands in addition to the IL-8RB in TEM and suggest the involvement of these molecules in the homing of specific T cells to inflamed skin.     

R24 anti-GD3 ganglioside antibody can induce co-stimulation and prevent the induction of alloantigen-specific T cell clonal anergy

R24 is a monoclonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell clonal anergy. Binding of GD3 by R24 also prevented anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoclonal antibodies for the α and β chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell clonal response.     

Opposite effects of interleukin-13 and interleukin-12 on the release of inflammatory cytokines,cytokine inhibitors and prostaglandin E from synovial fibroblasts and blood mononuclear cells

We examined the effects of interleukin-12 (IL-12) and interleukin-13 (IL-13) on cytokine, cytokine inhibitor and prostaglandin E (PGE) release from synovial fibroblasts and blood mononuclear cells (MNC). In resting synovial fibroblasts, we found that IL-13 is an inhibitor of IL-8 and PGE release. A significant decrease of PGE synthesis caused by IL-13 was also observed in tumor necrosis factor (TNF)-α-stimulated synovial fibroblasts, whereas IL-12 had no regulatory effects on these cells. In resting and cytokine-stimulated MNC, IL-13 markedly inhibited IL-1β, IL-8 and monocyte chemoattractant protein-1 (MCP-1) release and potently stimulated interleukin-1 receptor antagonist (IL-1ra) synthesis. In contrast, IL-12 stimulated the production of IL-1β and MCP-1 in TNF-α-stimulated MNC and inhibited IL-1ra synthesis in cytokine-stimulated cells. These findings identify novel biological actions of IL-12 and IL-13 on connective tissue and on blood mononuclear cells which indicate their regulatory functions as enhancer and suppressor of inflammatory processes, respectively.     

Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen-specific IgE

A number of structurally diverse antigens preferentially stimulate the synthesis of IgE antibodies, but no unifying principle has been proposed that explains the nature of isotype selection. In the present study, we show that common allergens present in bee venom, house dust mite emanations and parasite proteins induce mast cell and basophil degranulation and stimulate interleukin-4 synthesis, and secretion in the absence of antigen-specific IgE. These data point to a linkage between the initial activation of cells of the innate immune system and subsequent adaptive immune responses. They suggest that IgE-independent mast cell and basophil degranulation is predictive of potential allergenicity and can be evaluated by means of a cellular assay. Our study indicates that non-immunological degranulation by prototypic allergens, such as bee venom phos-pholipase A₂ or proteases associated with house dust mite emanations, is critically dependent on enzymatic activity. These findings have potentially important implications for vaccine design in allergic and parasitic disease.