移植免疫中T细胞疫苗作用机制的初步分析

为分析Ｔ细胞疫苗同种兔疫抑制作用的机制，在体外观察了Ｔ细胞疫苗免疫小鼠细胞免疫应答能力的改变，分别在ＭＩＣ实验中，观察了免疫小鼠血清和免疫小鼠脾细胞对同种应答细胞反应能力的影响。结果表明：免疫小鼠淋巴细胞ＣｏｎＡ转化反应能力及同种抗原反应能力均显著降低，免疫小鼠血清及其脾细胞不同程度地抑制了同种应答细胞的反应能力，但以上作用并未表现出抗原特异性。     

肿瘤微环境中髓系来源抑制细胞对T细胞免疫活性抑制的分子机制

髓系来源抑制细胞(MDSC)根据其起源和功能而命名,由巨噬细胞、树突状细胞(DC)及粒细胞等细胞的前体细胞组成。肿瘤免疫逃逸与肿瘤微环境中MDSC介导的抗肿瘤免疫抑制相关,肿瘤微环境中的MDSC主要通过抑制T细胞的免疫活性来发挥免疫抑制作用。根据MDSC与T细胞之间的接触方式,肿瘤微环境中的MDSC抑制T细胞免疫功能的分子机制可分为直接抑制和间接抑制两类,其中MDSC通过产生细胞因子影响T细胞功能和细胞之间膜受体配体相互作用发挥抑制T细胞功能的方式为直接抑制,而MDSC通过影响T细胞代谢从而影响T细胞功能及通过其他细胞发挥抑制T细胞功能的方式为间接抑制。制定针对MDSC的治疗策略时,需综合考虑上述多种分子机制共存的可能性。     

免疫抑制药物抑制树突状细胞分化与功能研究进展

免疫抑制药物多应用于防治移植排斥、移植物抗宿主病或宿主抗移植物病、超敏反应引起的疾病和自身免疫性疾病 ,其作用机制的研究以往多偏重于对T、B细胞的影响。随着DC(dendriticcell,DC)功能研究的深入 ,免疫抑制药物作用于DC的研究结果完善了免疫抑制性药物调节免疫应答的作用机制。本文就免疫抑制药物抑制DC分化与功能的研究进展作一综述     

CD4~＋ CD25~＋ Foxp3~＋调节性T细胞与自身免疫性疾病

自身免疫性疾病系由于机体免疫系统失衡,产生针对自身组织的免疫应答并导致自身组织、器官损害的一类疾病。调节性T淋巴细胞（regulatory T cell,Treg）具有免疫应答低下和免疫抑制特性,在维持机体免疫耐受和免疫应答稳态方面具有非常重要的作用,Treg的异常与多种自身免疫性疾病有关[1]。Foxp3特异性表达于CD4＋CD25＋Treg细胞,与其发育、成熟以及抑制功能关系密切。但是目前关于该转录因子的表达调控机制却不清楚。本文拟就CD4＋CD25＋Foxp3 Treg细胞的研究进展及与多种自身免疫性疾病的关系作一综述。     

CD8~+ Treg的免疫生物学特征及其与疾病的关系

CD8~+Treg是一类具有免疫抑制功能的T细胞亚群,根据其来源及作用机制可分为CD8~+nTreg和CD8~+aTreg。CD8~+Treg通过多种机制调控免疫应答,不仅能够抑制自身免疫性疾病的发生,而且可能参与诱导移植耐受、抗感染免疫以及肿瘤免疫的调节,在维持机体内环境的稳态中发挥重要作用。文章旨在探究CD8~+Treg的免疫生物学特征及其与疾病的关系,将可能为疾病的治疗开辟新途径。     

免疫抑制药物抑制树突状细胞分化与功能研究进展

免疫抑制药物多应用于防治移植排斥、移植物抗宿主病或宿主抗移植物病、超敏反应引起的疾病和自身免疫性疾病，其作用机制的研究以往多偏重于对T、B细胞的影响。随着DC(dendritic cell，DC)功能研究的深入，免疫抑制药物作用于DC的研究结果完善了免疫抑制性药物调节免疫应答的作用机制。本文就免疫抑制药物抑制DC分化与功能的研究进展作一综述。     

肿瘤相关免疫抑制细胞的免疫逃逸作用机制

肿瘤能够通过多种机制有效逃避机体免疫系统监视,肿瘤相关树突状细胞（TADC）、髓系来源抑制细胞（MDSC）、肿瘤相关巨噬细胞（TAM）等在肿瘤免疫逃逸过程中能够诱导免疫抑制反应。虽然由TADC、MDSC和TAM介导的免疫抑制机制还不完全明了,但是最近的研究表明肿瘤相关因子激活的细胞内信号传导途径可以调节细胞内代谢、细胞因子的产生和共刺激分子及共抑制分子的表达,由此产生免疫抑制作用。     

Foxp3基因与自身免疫性疾病

自身免疫性疾病系由于机体免疫系统失衡,产生针对自身组织的免疫应答并导致自身组织、器官损害的一类疾病.调节性T淋巴细胞(Regulatory T cell,Treg )具有免疫应答低下和免疫抑制特性,在维持机体免疫耐受和免疫应答稳态方面具有非常重要的作用,Treg的异常与多种自身免疫性疾病有关[1].Foxp3特异性表达于CD4 CD25 Treg细胞,与其发育、成熟以及抑制功能关系密切.本文拟就Foxp3基因的研究进展及与多种自身免疫性疾病的关系作一综述.     

树突状细胞对调节性T细胞的调控作用

树突状细胞(DCs)是目前已知的体内功能最强大的专职性抗原提呈细胞,具有启动免疫应答和诱导免疫耐受的双重特性.近年来树突状细胞对调节性T细胞的调控作用是免疫学领域的一个研究热点.Foxp3+ Tregs是一群同时具有免疫低反应性和免疫抑制性功能两大特征的T淋巴细胞,它在维持机体内环境稳定、预防自身免疫性疾病、抑制移植排斥反应等病理生理过程中发挥着重要作用.越来越多的研究结果证实DCs和Tregs二者在维持外周免疫耐受中存在着紧密联系,DCs可以诱导抗原特异性Tregs的生成并增加后者的抑制活性,其中参与该调节机制的分子主要包括相关细胞因子、Toll样受体、共刺激分子及维甲酸等.对DCs在接触共生和致病微生物时诱导和调控Tregs细胞有了一些新发现.     

局部免疫调节是胎儿不被母体排斥的主要机制

对于作为半同种异体移植物的胎儿能耐受母体的免疫防御而不被排斥的机制的认识目前倾向于局部免疫调节学说。研究集中于母胎界面滋养层、蜕膜及多种具有免疫抑制作用的因子的探讨。滋养层通过其表面的TLX 抗原刺激母体免疫系统产生相应的抗TLX 抗体(ab_1)和独特型抗体(ab_2)建立TLX-ab_1-ab_2网络、分泌多种免疫抑制因子以及滋养层细胞本身对细胞毒T 细胞的固有抵抗力等途径发挥其免疫调节作用;蜕膜组织中的蜕膜细胞、巨噬细胞、颗粒小淋巴细胞及大抑制细胞则具有分泌PGE_2或可溶性因子,抑制IL-2生成,从而抑制局部母体免疫排斥的功能。此外,新近发现的早孕因子(EPF)也认为是通过局部发挥其免疫抑制作用的。     

Involvement of prostaglandins in immunosuppression caused by adenovirus in mice

The effect of intraperitoneally (i.p.) inoculated human adenovirus type 6 (Ad6) was tested for humoral immune response against sheep red blood cells (SRBC) in normal and indomethacin-treated mice, with the aim to elucidate the mode of the virus action in immunosuppression. The results indicate that inhibition of prostaglandin synthesis slightly influences the immunosuppressive effect of the virus. It is very likely that also other mechanisms are involved in the immunosuppression observed.     

Minimally invasive cancer surgery improves patient survival rates through less perioperative immunosuppression

The import of the immune system to cancer survival is paramount. Immune effector cells are intimately involved in the patient's response to cancer. People with decreased immune function develop cancer more frequently. In the early stages of solid organ malignancies, surgery can potentially be curative. Surgical intervention, in and of itself, is immunosuppressive. Surgical resections are traditionally performed through large incisions. Technologic advances have allowed minimally invasive surgery (MIS) to evolve to the point it is now being used for cancer treatment. Recent minimally invasive series have reported improved survival and recurrence rates, as compared with historical data. We hypothesized that outcome differences for cancer patients undergoing open surgery vs. MIS are due to differential inhibition of immune effector cell function, in response to the different surgical stimulus. This increased immunosuppression after open surgery could potentially inhibit immune effector cell tumor surveillance as well as inhibit scavenging of any residual or micrometastatic disease or of tumor cells shed at the time of the operation. The less immunosuppressive MIS may leave immune function above a threshold level where remaining tumor is cleared. This difference would lead to less recurrence and to survival advantages. A deeper understanding of the integral components of the immune response to surgery would open the door for immunomodulation strategies and be of great clinical utility in guiding neoadjuvant, surgical, or adjuvant therapeutic decisions.     

树突状细胞分化成熟障碍在肿瘤免疫逃逸中的研究

大量研究证实，肿瘤病人体内存在广泛的免疫逃逸现象。目前所知肿瘤逃逸的机制很多，其中重要的一个就是树突状细胞的分化成熟异常导致的功能障碍。近来国内外研究发现许多因素能够影响肿瘤内树突状细胞的正常分化成熟和功能，这些因素包括一些免疫抑制性细胞因子（TGF-β，IL-10，IL-6，VEGF），神经节苷脂，吲哚咹-2-3加双氧酶等等。     

Interferon-Gamma Producing Regulatory T Cells as a Diagnostic and Therapeutic Tool in Organ Transplantation

There is increasing evidence that IFNg plays a major role in both induction of Tregs as well as immunosuppression mediated by IFNg-producing Tregs. The present review focuses on a small subset of iTregs that produces IFNg, comprises only 0.04% of all CD4⁺ T lymphocytes in the blood of healthy individuals, and increases strongly during an immune response. IFNg⁺ Tregs are induced by IFNg and IL12, making them sensors for inflammatory cytokines. They develop rapidly during inflammation and represent the first line of Tregs that suppress initial immune responses. The pool of IFNg⁺ Tregs consists of activated stable immunosuppressive thymus-derived nTregs as well as peripherally proliferating iTregs with in part only transient immunosuppressive function, which limits their diagnostic and therapeutic usefulness in organ transplantation. Apparently, a part of IFNg⁺ Tregs dies during the immune response, whereas others, after efficient immunosuppression with resolution of the immune response, differentiate toward Th1 lymphocytes. Goals of further research are the development of appropriate diagnostic tests for rapid and exact determinination of immunosuppressive IFNg⁺ iTregs, as well as the induction and propagation of stable immunosuppressive IFNg⁺ Tregs that establish and maintain good long-term graft function in transplant recipients.     

Molecular effects of cyclosporine and oncogenesis: a new model

Cyclosporine A is the most commonly used immunosuppressive agent during organ transplantation. One of the most feared adverse effects of cyclosporine A is the appearance of de novo cancers. The mechanisms that lead to the genesis of such cancers are thought to be only related to a side effect of cyclosporine A: a depressed immune system. Here, we review different molecular effects induced by cyclosporine A (inhibition of DNA repair, synthesis of TGF Beta, induction of apoptosis of activated T cells, inhibition of apoptosis through the inhibition of the opening of the mitochondrial Permeability Transition Pore) and propose that cyclosporine A can promote the genesis and the spread of cancer not only because of immunosuppression but also because of its ability to facilitate DNA mutations accumulation, to diminish the clearance of altered cells and to transform cancer cells into aggressive cancer cells. This new insights into the mechanisms of genesis of cyclosporine A-related cancers should be taken into account to develop preventive strategies or new immunosuppressive strategies.     

Influence of human immune cells on cancer: studies at the University of Colorado

There will be over half a million cancer-related deaths in the United States in 2012, with lung cancer being the leader followed by prostate in men and breast in women. There is estimated to be more than one and a half million new cases of cancer in 2012, making the development of effective therapies a high priority. As tumor immunologists, we are interested in the development of immunotherapies because the immune response offers exquisite specificity and the potential to target tumor cells without harming normal cells. In this review, we highlight the current advances in the field of immunotherapy and the current work being completed by laboratories at University of Colorado School of Medicine in multiple malignancies, including breast cancer, lung cancer, melanoma, thyroid cancer, and glioblastoma. This work focuses on augmenting the anti-tumor response of CD8 T cells in the blood, lymph nodes, and tumors of patients, determining biomarkers for patients who are more likely to respond to immunotherapy, and identifying additional anti-tumor and immunosuppressive cells that influence the overall response to tumors. These collaborative efforts will identify mechanisms to improve immune function, which may elucidate therapeutic targets for clinical trials to improve patient health and survival.     

Topical and oral retinoids protect Langerhans' cells and epidermal Thy-1+ dendritic cells from being depleted by ultraviolet radiation.

Murine epidermis contains two types of bone marrow-derived cells of the immune system, Langerhans' cells (LC), which are dendritic antigen-presenting cells, and Thy-1+ dendritic cells (Thy-1+ DEC), which express the gamma/delta T-cell receptor for antigen and hence are probably T cells whose function in the epidermis is unknown. Ultraviolet (UV) light greatly reduces the density of both of these cell types, and hence this may be one of the mechanisms by which UV light induces immunosuppression. It is important to develop strategies for protecting these cells from the effects of UV light. In this study we show that topical all-trans-retinoic acid (RA) and an orally administered retinoid, temarotene, protect both LC and Thy-1+ DEC from being depleted by UV light. However, neither retinoid inhibited the development of immunosuppression in response to application of a contact sensitizer. We also compared two congenic mouse strains, one albino, the other lightly pigmented and capable of tanning in response to UV light. There was no difference in the ability of UV light to deplete LC or Thy-1+ DEC in these two strains or of retinoids to inhibit their depletion. These studies demonstrate that retinoids but not melanin are able to inhibit UV light from depleting LC and Thy-1+ DEC; however, there are other immunosuppressive effects of UV light which are not protected by the retinoids.     

Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine

We have previously shown that abrupt withdrawal (AW) from morphine induces greater than 80% immunosuppression in murine spleen cells, as assessed by the capacity to mount an in vitro plaque-forming cell response to sheep red blood cells. Present studies about the mechanisms of immunosuppression following AW showed that addition of highly enriched (CD11b+) splenic macrophages (obtained by cell sorting or magnetic separation) from AW mice to cultures of normal, unfractionated spleen cells suppressed immune responses. Further, addition of highly enriched (CD19+) B cells (but not T cells) from AW mice to normal cells was also immunosuppressive. B cells from AW mice were also able to inhibit the proliferative response of normal spleen cells to concanavalin A but not to lipopolysaccharide. Overall, the data suggest that immunosuppression by AW spleen cells is a result of active suppression by macrophages and B cells.     

The immunology of experimental liver transplantation in the rat.

In many species, the rejection of liver allografts is milder than that of other organs. This is especially so in the rat where, without immunosuppressive treatment, liver grafts between certain strain combinations are accepted permanently, whereas skin, heart and renal allografts undergo acute rejection. Reliable surgical methods, together with the availability of inbred strains and a rapidly developing knowledge of its MHC and immune system in general, have made the rat a prime species in which to study the immunological events which follow liver grafting. In non-rejector combinations, liver allografts possess remarkable properties of tolerance induction and antigen-specific immunosuppression, leading to a state of donor-specific unresponsiveness in which grafts of other organs are also accepted. Moreover, liver transplantation can terminate ongoing rejection reactions in other organs and convert an existing state of sensitization against donor antigens into one of unresponsiveness. This review describes recent progress in understanding the immunological mechanisms behind these phenomena. The topics discussed include the rat MHC (RT1) antigens and their distribution in the liver; the genetic control of rejection and non-rejection, including the role of MHC-linked immune response genes; and cellular and humoral mechanisms involved in tolerance and immunosuppression, such as clonal deletion of alloreactive lymphocytes and antibody-mediated enhancement.