Common and small molecules as the ultimate regulatory and effector mediators of antigen-specific transplantation reactions

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin(IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase(i NOS), arginase, heme oxygenase-1(HO-1) or indoleamine-2,3-dioxygenase(IDO), the bioavailability of their substrates(L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products(NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as i NOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules(NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

Effect of Early Intensive Insulin Therapy on Immune Function of Aged Patients with Severe Trauma

This study examined the effect of intensive insulin therapy on immune function and inflammatory factors at the early phase after severe trauma. At day 1, 3, 5, 7 after admission, subsets of CD4＋ helper T lymphocytes （Th1/Th2） and human leukocyte antigen （HLA）-DR expression on CD14＋ monocytes were flow cytometrically measured. Levels of cytokines, including tumor necrosis factor-alpha （TNF-α）, interleukin-6 （IL-6）, interleukin-10 （IL-10） and other immunity markers, such as IgA, IgG, IgM, C3, C4 and C reaction protein （CRP） were examined in two groups. The results showed that TNF-α, IL-6 and CRP levels in the intensive insulin therapy group were significantly lower than those in the conventional therapy group, whereas IL-10 levels were substantially increased after intensive insulin therapy. C3 level at day 3, 5, 7 and C4 levels at day 5, 7 were lower in the intensive therapy group than in the conventional therapy group. Th1/Th2 ratios decreased gradually over time in both groups, and were much lower at day 3, 5, 7 in intensive therapy group. There were significant differences among day 3 to day 7 after admission in HLA-DR expression in CD14＋ monocytes. It was concluded that the intensive insulin therapy could decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines in the elderly suffering from severe trauma, at the same time, with complement recovery being delayed. Moreover, intensive insulin therapy promoted immune suppression and, therefore, measures need be taken to address the issue.

Effects of antigen presentation of eosinophils on lung Th1/Th2 imbalance

Background Antigen loaded eosinophils (EOSs) instilled intratracheally into mice were capable of inducing Th2 type cytokine production in the draining lymph nodes The aim of the present study was to evaluate whether EOSs within the tracheobronchial lumen can stimulate Th2 cell expansion in the lung tissues Methods Airway EOSs were recovered from ovalbumin sensitized and challenged BALB/c mice, these EOSs were then cocultured with CD4 + cells isolated from sensitized mice in the absence or presence of anti CD80 or/and CD86 monoclonal antibodies Airway EOSs were instilled into the trachea of sensitized mice. At the day 3 thereafter, the lung tissues were removed and prepared into cell suspensions for culture Cell free culture supernatants were collected for detection of cytokines Results Airway EOSs functioned as CD80 and CD86 dependent antigen presenting cells to stimulate lung CD4 + lymphocytes to produce interleukin 4, interleukin 5 and interleukin 13, but not interferon γ in in vitro assay When instilled intratracheally in sensitized recipient mice, airway EOSs primed lung Th2 cells in vivo for interleukin 4, interleukin 5 and interleukin 13, but not interferon γ, production during the in vitro culture that was also CD80 and CD86 dependent Conclusion EOSs within the lumina of airways could process inhaled antigen and function in vitro and in vivo as antigen presenting cells to promote expansion of Th2 cells in the lungs

The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation

The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation.However,the role of PU.1 in alternatively activated macrophage(AAM)and asthmatic inflammation has yet been investigated.Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation.In response to the challenge of DRA(dust mite,ragweed,and Aspergillus)allergens,conditional PU.1-deficient(PU/ER(T)^(+/-))mice displayed attenuated allergic airway inflammation,including decreased alveolar eosinophil infiltration and reduced production of IgE,which were associated with decreased mucous glands and goblet cell hyperplasia.The reduced asthmatic inflammation in PU/ER(T)^(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type(WT)macrophages.Moreover,after treating PU/ER(T)^(+/-) mice with tamoxifen to rescue PU.1 function,the allergic asthmatic inflammation was significantly restored.In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3(Ym-1)and resistin-like molecule alpha 1(Fizz-1),two specific markers of AAM polarization.In addition,PU.1 expression in macrophages was inducible in response to IL-4 challenge,whichwas associated with phosphorylation of signal transducer and activator of transcription 6(STAT6).Furthermore,DRAchallenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)^(+/-) mice compared with WT mice.These data,all together,indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.

Graves病血清sCTLA-4与Th_1/Th_2细胞因子平衡偏离的关系

探讨Graves病 (GD)血清可溶性细胞毒性T淋巴细胞相关抗原 4(sCTLA 4)与Th1/Th2 细胞因子失衡的关系。结果显示sCTLA 4升高 ,IL 4明显降低 ,IFN γ无明显改变 ,IFN γ/IL 4升高 ,sCTLA 4与IL 4呈直线负相关。提示GD血清Th1/Th2 细胞因子失衡 ,呈Th2 低下型 ,与sCTLA

Effect of short- and long-term immunization of recombinant disorganized muscle protein-1(rDIM-1) against human filarial parasite Brugia malayi in rodents

Objective: To evaluate the effect of short-term and long-term immunization of recombinant disorganized muscle protein-1(r DIM-1) in rodents against human filarial parasite Brugia malayi.Methods: Recombinant Brugia malayi DIM-1(rDIM-1 bm) protein was cloned, expressed and purified using a Ni-NTA affinity column. Mastomys coucha were immunized with rDIM-1 bm in three immunization schedules: short-term(3-dose of rDIM-1 bm), and long-term(booster doses till 3-and 6-week) and subsequently challenged with infective third-stage larvae of filarial parasite Brugia malayi(L3). Microfilaraemia was monitored in L3 exposed groups on day 90 post larval inoculation(p.l.i.) and continued till day 205 p.l.i. On day 205 p.l.i. all the infected animals were killed and total worm burden was estimated. Cellular proliferative response, macrophage activity, nitric oxide(NO) release, specific IgG and its subtypes, IgE, IgA and Th1(IFN-γ, TNF-ααand IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release were determined. Results: Of the 3 different immunization schedules, shortterm immunization(3-dose schedule) showed better reduction in microfilarial burden(36%-63%) in the peripheral circulation, adult worm load(52%), whereas long-term immunization(3-and 6-week schedule) exerted less effect on peripheral microfilariae count(9%-58%), and adult worm burden(9%-12.5%). Short-term immunization resulted in upregulation of cellular proliferation, macrophages activity, NO release, specific IgG, IgG1, IgG2 a, Ig G2 b, IgE and IgA levels and both Th1(IFN-γ, TNF-α and IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release whereas long-term immunization(3-and 6-week schedule) exerted less effect on parasite burden and showed mixed immunological responses. None of the rDIM-1 bm administration schedules induced any pathology in lymphoid tissues, or alteration in mast cell number and granularity. Conclusions: The short-term immunization with rDIM-1 bm(3-dose schedule) induces robust immune responses and protects the host from filarial parasite infection.