CTLA4Ig对NK细胞功能调节及其在大面积烧伤治疗中作用的实验研究
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摘要
大面积烧伤后,患者免疫应答低下(1, 2),容易发生感染,另一方面机体却对皮肤移植物产生强有力的排斥反应,因此在不增加患者感染几率的前提下提高异体皮的存活时间(即所谓免疫耐受的诱导),是大面积烧伤治疗的核心问题。
NK细胞作为天然免疫系统最重要的细胞在机体杀伤肿瘤细胞和抵抗病原体(病毒、细菌等)感染中发挥着重要作用。NK细胞的活化与否受控于NK细胞表面表达的抑制性受体(如NKG2A)和激活性受体(如NKG2D)的状态。然而,在大面积烧伤后,患者NK细胞毒性功能显著下降(26, 27),是机体容易发生感染的重要原因之一。研究发现,院内获得性绿脓杆菌感染是烧伤感染和败血症发生的重要原因(3)。绿脓杆菌分泌的外毒素可抑制NK细胞毒性和IFN-γ的分泌(4),且对现在临床使用的大部分抗生素均耐药(5)。激活性受体NKG2D在NK细胞清除肺绿脓杆菌感染中起了关键作用(6, 7),那么NK细胞功能的增强是否会降低机体播散性感染发生的几率呢?
在免疫耐受诱导的研究中,20年前发现的CTLA4以及在此基础上制备的重组融合蛋白CTLA4Ig最令人瞩目。由于CTLA4Ig能高亲和力地结合抗原递呈细胞上的CD80/CD86,阻断了共刺激信号,使T细胞不能接受第二信号,从而导致T细胞不应答,所以CTLA4Ig是T细胞活化中重要的负调节分子(8)。目前,CTLA4Ig的衍生物-Abatacept和Belatacept分别被用于治疗自身免疫性疾病和控制器官移植免疫排斥反应(9-12)。我们的前期研究结果(13)和文献报道(14)也证实注射CTLA4Ig或创面局部应用CTLA4Ig重组腺病毒均可延长异体皮移植存活期,因此,CTLA4Ig如果可以应用于烧伤患者将会抑制移植物排斥反应,延长移植物的存活时间。那么,在烧伤情况下使用CTLA4Ig会加重烧伤后的病情和增加并发症及死亡率吗?
Abatacept是被美国FDA批准用于临床治疗类风湿关节炎的药物,由人CTLA4分子胞外区和突变的IgG1 Fc段融合而成。奇怪的是,这一T细胞强有力的抑制剂应用于人体后,其肿瘤形成、病毒及细菌感染等副作用的发生率却比预期大大降低(15-17)。亦有研究证实,小鼠全身应用两倍剂量于人的药物浓度时,并不影响其抵抗肺结核感染的能力,但这一有悖于常理的现象的机制和意义还是未知数(18)。Ursula Grohmann发现,CTLA4Ig与DCs表面B7分子结合后,向DCs胞内传递激活信号(19)。该研究说明,CTLA4Ig对表达CD80/CD86分子的细胞有调节作用。另有报道,天然免疫系统中最重要的细胞-NK细胞表面也表达CD86分子,且在某些条件下可表达CD80分子(20, 21)。Beissert S发现,长期暴露于紫外线中的CTLA4Ig转基因小鼠,其皮肤肿瘤结节数量明显少于野生型小鼠(22),事实上,NK细胞在皮肤癌细胞杀伤中发挥中重要作用(23)。综上所述,CTLA4Ig可通过阻断T细胞激活的共刺激信号通路抑制皮肤移植免疫排斥反应.其全身应用并不会显著增加机体感染和肿瘤形成的风险.同时,CTLA4Ig可能对表面表达CD80/CD86分子且在控制感染和肿瘤形成的其重要作用的细胞(如NK细胞)有调节作用(23).因此,我们提出如下科学问题:CTLA4Ig是否因为与NK细胞表面B7分子结合增强NK细胞毒性而造成机体清除皮肤癌细胞(或其他肿瘤细胞)能力的增强?其机制如何?这些作用可否解释CTLA4Ig在活体内使用后并不显著降低整体抵抗力的现象?
本实验通过体内、体外试验验证CTLA4Ig对NK细胞功能是否具有调节功能,通过小鼠感染、烫伤和肿瘤模型验证上述调节作用,并初步探讨其分子机制。从而深化对CTLA4Ig免疫调节作用的认识,并为CTLA4Ig应用于大面积烧伤治疗提供理论基础。我们将本研究获得的主要结果和结论归纳如下:
一、CTLA4Ig及其衍生物Abatacept是NK细胞强有力的激活剂:
1、CTLA4Ig在体外可明显增强人PBMC和NK细胞功能:
为了研究CTLA4Ig体外对人PBMC和NK细胞功能有无调节作用,我们利用流式细胞技术检测加入不同浓度的CTLA4Ig后的人PBMC和NK细胞毒性。在本实验系统中,我们发现:1)浓度大于1μg/ml的CTLA4Ig作用于人PBMC和NK细胞后,其杀伤K562细胞的能力(即NK细胞毒性)明显增强;2)加入CTLA4Ig与加入IL-2后对人PBMC和NK细胞毒性调节无明显差异;3)在本实验浓度范围内,人PBMC和NK细胞毒性并没有随CTLA4Ig浓度增加而发生明显变化。上述结果说明CTLA4Ig在体外可明显增强人PBMC和NK细胞毒性,CTLA4Ig与IL-2激活NK细胞毒性的能力相当,且在我们的实验体系中CTLA4Ig对NK细胞毒性调节作用与其浓度无关。
2、CTLA4Ig(Abatacept)在体内可显著增强小鼠NK细胞毒性:
为了研究Abatacept在抑制T细胞活化的同时却并未显著增加肿瘤或感染发生的几率的现象是否与Abatacept对NK细胞功能调节有关,我们将高于临床治疗类风湿关节炎剂量的Abatacept经小鼠尾静脉注射入小鼠体内,比较其脾脏NK细胞毒性与未注射小鼠是否有差异。结果显示注射Abatacept 24h和48h后小鼠脾脏NK细胞毒性较未注射小鼠脾脏NK细胞毒性明显上升。这一结果说明,Abatacept注射小鼠体内后,CTLA4分子可显著增强小鼠NK细胞的毒性。这可能是Abatacept应用并未显著增加肿瘤或感染发生的几率的重要原因。
3、CTLA4Ig增强人NK细胞毒性的作用是CTLA4分子依赖的:
为了明确CTLA4Ig对NK细胞毒性增强的效应是否全部由ADCC引起,我们进行如下实验:首先在体外实验系统中引入可溶性hIgG1或模拟膜表达的hIgG1作为对照,通过比较加入CTLA4Ig与引入FcR信号后的NK细胞毒性,明确ADCC作用在CTLA4Ig对NK细胞调节中的作用。结果显示加入CTLA4Ig后NK细胞毒性增加的比率远高于引入FcR。因此,CTLA4Ig对NK细胞毒性的增强效应主要是由CTLA4分子介导的;为了进一步说明上述问题,我们选用表面仅表达少量低亲和力FcR-CD16,且无CD32和CD64的表达(25)的NK92细胞株作为效应细胞。在NK92细胞和K562共培养体系中加入CTLA4Ig后,NK92细胞的毒性仍然明显增强,证实CTLA4分子在增强NK细胞毒性作用中起绝对的主导作用。因此我们认为体外实验中CTLA4Ig增强人NK细胞毒性的作用是CTLA4分子依赖的。
二、CTLA4Ig(Abatacept)可增强机体抗肿瘤的能力:
NK细胞在机体抗肿瘤形成中起着至关重要的作用,因此本实验探讨CTLA4Ig对NK细胞毒性增强作用是否有利于机体控制肿瘤形成。我们的实验发现注射超过临床剂量的Abatacept不仅没有因为抑制T细胞激活促进肿瘤形成和生长,相反地,极大地减少了B16细胞肺转移。不仅如此,荷瘤小鼠的生存时间亦明显延长。提示Abatacept可增强机体抗肿瘤(B16)的能力。
三、我们对CTLA4Ig(Abatacept)在大面积烧伤治疗中的新认识:
我们的前期研究结果(13)和文献报道(14)都证实注射CTLA4Ig或创面局部应用CTLA4Ig重组腺病毒均可延长异体皮移植存活期,这就意味着CTLA4Ig如果可以应用于烧伤患者将会抑制移植物排斥反应,延长移植物的存活时间。因此,我们利用绿脓杆菌感染模型和烫伤模型评价CTLA4Ig用于烧伤患者治疗皮肤移植排斥反应的安全性,我们的研究首次发现使用Abatacept不仅可以显著提高Balb/c小鼠清除绿脓杆菌的能力而且还能增强烫伤小鼠脾脏细胞的毒性,与体外的实验结果一致。这一研究发现提示CTLA4Ig未来可用于大面积严重烧伤患者以诱导对皮肤移植物的免疫耐受,增强机体天然免疫力。这将是严重烧伤疾病治疗的重大突破。
四、CTLA4Ig通过与NK细胞表面CD80/CD86分子结合上调激活性受体NKG2D和NKp44表达,增强NK细胞毒性功能:
1,CTLA4Ig通过与NK细胞表面CD80/CD86分子的结合促进NK细胞的毒性功能:本实验研究抗CD80抗体和抗CD86抗体对NK细胞有无调节作用。结果发现:抗CD80抗体和抗CD86抗体在体外可明显增强人PBMC对K562细胞的毒性,且与CTLA4Ig组NK细胞毒性无明显差异。结合上述实验结果我们认为,CTLA4Ig通过与NK细胞表面CD80/CD86分子的结合促进NK细胞的毒性功能。
2,CTLA4Ig可上调NK细胞表面激活性受体NKG2D、NKp44的表达:我们采用流式细胞技术探讨CTLA4Ig对NK细胞表面NKG2D和NKp44表达的调节作用。结果发现体外加入CTLA4Ig后,人NK细胞表面激活性受体NKG2D、NKp44表达明显上调,且程度与IL-2相似。FcR受体与NK细胞结合不会导致NKG2D、NKp44表达上调。这一结果说明NK细胞表面激活性受体NKG2D、NKp44的在CTLA4Ig增强NK细胞毒性功能的调节作用中可能发挥了重要作用。
总结:
一、CTLA4在体内、体外均可增强NK细胞毒性;
二、CTLA4Ig通过与NK细胞表面CD80/CD86分子结合上调NK细胞表面NKG2D和NKp44的表达,增强NK细胞功能;
三、CTLA4Ig及其衍生物(如Abatacept)在全身应用,可增强小鼠抗肿瘤和抗感染的能力,不增加患者罹患肿瘤及感染的几率,扩大了其临床应用的适应症;
四、CTLA4Ig全身应用不仅可治疗皮肤移植物排斥反应,且可增加烫伤小鼠NK细胞毒性,减少播散性感染的发生,为CTLA4Ig应用于治疗烧伤患者提供了新思路;
五、我们发现CTLA4对于获得性免疫系统(T细胞)和天然免疫系统(NK细胞)截然不同的作用,这对我们深入了解免疫系统的调节和内环境的稳定具有重大意义,将为临床肿瘤生物治疗和大面积烧伤救治提供全新的理论基础和研究方向。
Patients who suffer from massive burn injury are hyporesponsive and susceptible to infection (1, 2), while the rejection towards skin graft is severe. Therefore, maintenance of long-term skin graft survival without increasing incidence of disseminated infection is the key problem to be solved in treatment of massive burn patients.
NK cells, as the most important cells in innate immune system, play a considerable role in tumor surveillance and anti-infection. Whether NK cells are activated or not is mostly dependent on the balance between the inhibitory (i.e.NKG2A) and activated (i.e.NKG2D) receptors expressed on the cell surface. However, NK cell function is proved to be severely suppressed after massive burn, which leads to susceptibility to infection. It is believed that nosocomially-acquired resistant Pseudomonas aeruginosa infection is the major cause of infection and sepsis after burn injury(3). Pseudomonas aeruginosa exotoxin A is found to be able to inhibit NK cell-mediated cytotoxicity and IFN-gamma synthesis (4). Furthermore, it has been 10 years since Pseudomonas aeruginosa was identified, while unfortunately, it became multidrug resistance (5). However, it is demonstrated that NKG2D is critical for NK cell activation in host defense against Pseudomonas aeruginosa respiratory infection (6, 7). Accordingly, we are very interested in the question that whether the enhancement of NK cell-mediated cytotoxicity can decrease the incidence of disseminated infection.
Recombinant protein CTLA4Ig has been shown to be able to induce immune tolerance. The necessary co-stimulatory signal for T cell full stimulation is provided by ligation of CD28 with either B7-1 or B7-2 molecules expressed on antigen-presenting cells and can be blocked by a soluble form of CTLA4Ig which binds with high affinity to both B7-1 and B7-2(8). Recently, selective immunomodulatory agents such as Belatacept and Abatacept have shown great promise in treatment of rheumatoid arthritis and promoting allograft survival (9-12). Additionally, not only our previous research (13), but also other work(14) have proved that systemic or local administration of recombinant adenovirus CTLA4Ig can promote skin allograft survival. Nonetheless, CTLA4Ig utilization in promoting skin allograft survival in massive burn patients is rarely because of the consideration of the side-effects, especially disseminated infection.
Abatacept is a fusion protein composed of a mutant immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. It is licensed by FDA for the treatment of rheumatoid arthritis. One interesting aspect of CTLA4Ig is that patients treated with this fusion protein experience much lower incidence of tumors and infectious episodes than the prediction (15-17). Meanwhile, Abatacept does not impair the ability of mice to control a chronic M tuberculosis infection(18). However, the corresponding mechanism of these phenomenons has not yet been determined. Grohmann et al. found that CTLA4Ig could influence on the antigen presenting cell function via the interaction with B7 molecules on APC (19), which means CTLA4Ig is possibly able to regulate all the cells that expressed CD80/CD86 molecules. Moreover, recent studies demonstrated that resting NK cells can express CD86, and activated NK cells express both CD80 and CD86 receptors(20, 21), which prompted us to study the possibility role of CTLA4Ig in NK cell function. Beissert S et al. found that Chronic UV exposure of CTLA4Ig transgenic mice resulted in significantly reduced numbers of skin tumors, when compared to control mice (22). Taken together, previous data showed that CTLA4Ig could inhibit immune rejection of skin grafts without increasing the infection morbidity via blocking co-stimulatory pathway, meanwhile,CTLA4Ig might regulate the functions of CD80/CD86 positive cells such as NK cells that play an important role in control of infections and in tumor cell clearance (23). Thus it prompts us to determine the questions as to: 1,whether the ligation of CTLA4Ig and B7 molecules expressed on NK cell surface leads to the enhancement of NK cell-mediated cytotoxicity and clearance of tumor cells and bacteria.2, what the underlying mechanisms are. 3, whether the regulation of CTLA4Ig on NK cell-mediated cytotoxicity can explain CTLA4Ig systemic administration does not increase the morbidity of infections and tumorogenesis.
In the present study, we detected the possible roles of CTLA4Ig in the regulation of NK cell function both in vitro and in vivo, and in the models of Pseudomonas aruginosa infection, scald injury and B16 melanoma metastasis. The corresponding molecular mechanisms were also been examined. Our main findings and conclusions of this study are summarized as follows:
1. CTLA4Ig and Abatacept are strong activator of NK cells:
1) CTLA4Ig could enhance PBMC or purified human NK cell function in vitro:
In order to determine that whether CTLA4Ig can regulate PBMC or purified human NK cell function in vitro, we used FACS to detect the cytotoxicity after administration of different concentrations of CTLA4Ig. In our study, we found that:Ⅰ.CTLA4Ig significantly enhanced PBMC or purified human NK cell cytotoxicity to NK cell-sensitive target cells (K562 cell line) in vitro when its concentration was more than 1μg/ml.Ⅱ.The enhanced cytotoxicity was comparable to IL-2 that has long been identified as the T cell and NK cell stimulator.Ⅲ.PBMC or purified human NK cell cytotoxicity did not change significantly with the increase of CTLA4Ig concentration in our experiment. These data indicated that CTLA4Ig can enhance NK cell-mediated cytotoxicity in vitro, which is comparable to IL-2 and the enhancement did not change significantly with the increase of CTLA4Ig concentration in our experiment.
2) CTLA4Ig (Abatacept) could augment NK cell-mediated cytotoxicity of mice in vivo
To determine that whether the augmentation of Abatacept on NK cell-mediated cytotoxicity was related to the phenomenon that systemic administration of Abatacept did not significantly increase the incidence of tumor and infection, we injected Abatacept into mice via tail vein at a dose higher than clinical utilization and then detected the splenetic NK cell-mediated cytotoxicity. It was demonstrated that administration of Abatacept via mouse tail vein could significantly increase NK cell cytotoxicity as compared with PBS at 24 and 48 hours after injection. These data indicated that CTLA4 molecule could significantly enhance NK cell-mediated cytotoxicity in vivo. It might be the major reason that administration of Abatacept did not significantly increase the incidence of tumor and infection.
3) The augmentation of CTLA4Ig on NK cell-mediated cytotoxicity is mainly CTLA4 dependent:
NK cell cytotoxicity could be activated via FcR signaling as referred as antibody-dependent cellular cytotoxicity (ADCC)(24). To test whether the enhanced cytotoxicity of NK cells is ADCC-dependent in the presence of the Fc portion of CTLA4Ig, IgG1 containing the same Fc portion was added into the co-culture system in the form of either soluble human IgG1 or plate-bound human IgG1. Either soluble human IgG1 or plate-bound human IgG1 could significantly affect NK cell cytotoxicity, which, however, was much lower than that in the presence of CTLA4Ig. These data suggested that the CTLA4 portion rather than the Fc portion was the main part of CTLA4Ig that was responsible for enhancement of NK cell cytotoxicity. To further determine whether CTLA4Ig mediated NK cell cytotoxicity was mainly CTLA4 dependent, we chose human NK cell-line (NK92) as the effective cells that only express minimal low-affinity FcR CD16 and are lack of CD32/CD64(25). We found that CTLA4Ig could also significantly increased NK92 cell cytotoxicity. These data strongly argued that CTLA4Ig-mediated NK cell activation is mainly CTLA4 dependent.
2. CTLA4Ig(Abatacept)could strengthen host defense against tumors:
As is known that NK cells are very important in tumor surveillance in the body, we then tested whether this enhanced NK cell cytotoxicity could favor the control of tumor formation. In the B16 melanoma bearing-mice, injection of Abatacept significantly decreased the melanoma formation in the number of tumor nodules on the lung surface and finally prolonged the survival of B16 melanoma bearing-mice as compared with PBS control. Experiment in vivo model of B16 melanoma showed that Abatacept could significantly retard B16 melanoma metastasis. These date indicated that Abatacept could strengthen host defense against tumors (B16 melanoma).
3. CTLA4Ig(Abatacept)application in massive burn:
It was reported that systemic or local administration of CTLA4Ig both in our(13) and other work(14) could promote allogenic skin graft survival. Take account of disseminated infection, we valued the safety of CTLA4Ig utilization in massive burn patients via Pseudomonas aeruginosa infectious model and scald mice model. We for the first time found that systemic administration of Abatacept could not only strengthen host defense against Pseudomonas aeruginosa but also enhance splenetic NK cell-mediated cytotoxicity of scald mice in vivo, which was coincidence with in vitro experiments. These data prompted that CLTA4Ig might be safety when utilized in massive burn patients in order to induce immune tolerance and promote skin graft survival.
4. CTLA4Ig enhanced NK cell-mediated cytotoxicity by up-regulation of activated receptors (NKG2D and NKp44) via ligation of CD80/CD86 molecules:
1) CTLA4Ig enhanced NK cell-mediated cytotoxicity via ligation with CD80/CD86 molecules expressed on NK cell surface: To test whether CD80/CD86 contributed to the activation of NK cell cytotoxicity induced by CTLA4Ig, anti-CD80 and anti-CD86 monoclonal antibodies were used in vitro. The results showed that both antibodies could apparently stimulate NK cytotoxicity function, and the level of the increased cytotoxicity was similar to that of CTLA4Ig. It indicated that CTLA4Ig enhanced NK cell-mediated cytotoxicity via ligation with CD80/CD86 molecules expressed on NK cell surface.
2) CTLA4Ig could up-regulate NKG2D and NKp44 expression on NK cell surface: As previous reports, NK cell function is controlled by NK cell activated receptors and inhibitory receptors. We thus examined the NK cell activated receptors, such as NKG2D, NKp44 by means of FACS. After stimulation of NK cells by CTLA4Ig, the expressions of NKG2D and NKp44 on NK cell membrane were increased in the percentage of positive cells and the level was comparable to that after stimulation by IL-2. However, hIgG1 showed no effect in receptors expression. These data indicated a possibility that NKG2D and NKp44 might be critically involved in the CTLA4Ig-mediated NK cytotoxicity enhancement.
Conclusion:
Our findings have demonstrated that CTLA4Ig could enhance NK cell function by up-regulation of activated receptors (NKG2D and NKp44) via ligation of CD80/CD86 molecules. Systemic administration of CTLA4Ig (Abatacept) could not only enhance NK cell function in scald mice but also strengthen host defense against Pseudomonas aeruginosa and tumors. This is extremely important in the understanding of CTLA4Ig in regulation of immune responses, the expansion of the indications of CTLA4Ig and in the management of massive burn injuries, some types of tumors, viral and bacteria infections.
NK细胞作为天然免疫系统最重要的细胞在机体杀伤肿瘤细胞和抵抗病原体(病毒、细菌等)感染中发挥着重要作用。NK细胞的活化与否受控于NK细胞表面表达的抑制性受体(如NKG2A)和激活性受体(如NKG2D)的状态。然而,在大面积烧伤后,患者NK细胞毒性功能显著下降(26, 27),是机体容易发生感染的重要原因之一。研究发现,院内获得性绿脓杆菌感染是烧伤感染和败血症发生的重要原因(3)。绿脓杆菌分泌的外毒素可抑制NK细胞毒性和IFN-γ的分泌(4),且对现在临床使用的大部分抗生素均耐药(5)。激活性受体NKG2D在NK细胞清除肺绿脓杆菌感染中起了关键作用(6, 7),那么NK细胞功能的增强是否会降低机体播散性感染发生的几率呢?
在免疫耐受诱导的研究中,20年前发现的CTLA4以及在此基础上制备的重组融合蛋白CTLA4Ig最令人瞩目。由于CTLA4Ig能高亲和力地结合抗原递呈细胞上的CD80/CD86,阻断了共刺激信号,使T细胞不能接受第二信号,从而导致T细胞不应答,所以CTLA4Ig是T细胞活化中重要的负调节分子(8)。目前,CTLA4Ig的衍生物-Abatacept和Belatacept分别被用于治疗自身免疫性疾病和控制器官移植免疫排斥反应(9-12)。我们的前期研究结果(13)和文献报道(14)也证实注射CTLA4Ig或创面局部应用CTLA4Ig重组腺病毒均可延长异体皮移植存活期,因此,CTLA4Ig如果可以应用于烧伤患者将会抑制移植物排斥反应,延长移植物的存活时间。那么,在烧伤情况下使用CTLA4Ig会加重烧伤后的病情和增加并发症及死亡率吗?
Abatacept是被美国FDA批准用于临床治疗类风湿关节炎的药物,由人CTLA4分子胞外区和突变的IgG1 Fc段融合而成。奇怪的是,这一T细胞强有力的抑制剂应用于人体后,其肿瘤形成、病毒及细菌感染等副作用的发生率却比预期大大降低(15-17)。亦有研究证实,小鼠全身应用两倍剂量于人的药物浓度时,并不影响其抵抗肺结核感染的能力,但这一有悖于常理的现象的机制和意义还是未知数(18)。Ursula Grohmann发现,CTLA4Ig与DCs表面B7分子结合后,向DCs胞内传递激活信号(19)。该研究说明,CTLA4Ig对表达CD80/CD86分子的细胞有调节作用。另有报道,天然免疫系统中最重要的细胞-NK细胞表面也表达CD86分子,且在某些条件下可表达CD80分子(20, 21)。Beissert S发现,长期暴露于紫外线中的CTLA4Ig转基因小鼠,其皮肤肿瘤结节数量明显少于野生型小鼠(22),事实上,NK细胞在皮肤癌细胞杀伤中发挥中重要作用(23)。综上所述,CTLA4Ig可通过阻断T细胞激活的共刺激信号通路抑制皮肤移植免疫排斥反应.其全身应用并不会显著增加机体感染和肿瘤形成的风险.同时,CTLA4Ig可能对表面表达CD80/CD86分子且在控制感染和肿瘤形成的其重要作用的细胞(如NK细胞)有调节作用(23).因此,我们提出如下科学问题:CTLA4Ig是否因为与NK细胞表面B7分子结合增强NK细胞毒性而造成机体清除皮肤癌细胞(或其他肿瘤细胞)能力的增强?其机制如何?这些作用可否解释CTLA4Ig在活体内使用后并不显著降低整体抵抗力的现象?
本实验通过体内、体外试验验证CTLA4Ig对NK细胞功能是否具有调节功能,通过小鼠感染、烫伤和肿瘤模型验证上述调节作用,并初步探讨其分子机制。从而深化对CTLA4Ig免疫调节作用的认识,并为CTLA4Ig应用于大面积烧伤治疗提供理论基础。我们将本研究获得的主要结果和结论归纳如下:
一、CTLA4Ig及其衍生物Abatacept是NK细胞强有力的激活剂:
1、CTLA4Ig在体外可明显增强人PBMC和NK细胞功能:
为了研究CTLA4Ig体外对人PBMC和NK细胞功能有无调节作用,我们利用流式细胞技术检测加入不同浓度的CTLA4Ig后的人PBMC和NK细胞毒性。在本实验系统中,我们发现:1)浓度大于1μg/ml的CTLA4Ig作用于人PBMC和NK细胞后,其杀伤K562细胞的能力(即NK细胞毒性)明显增强;2)加入CTLA4Ig与加入IL-2后对人PBMC和NK细胞毒性调节无明显差异;3)在本实验浓度范围内,人PBMC和NK细胞毒性并没有随CTLA4Ig浓度增加而发生明显变化。上述结果说明CTLA4Ig在体外可明显增强人PBMC和NK细胞毒性,CTLA4Ig与IL-2激活NK细胞毒性的能力相当,且在我们的实验体系中CTLA4Ig对NK细胞毒性调节作用与其浓度无关。
2、CTLA4Ig(Abatacept)在体内可显著增强小鼠NK细胞毒性:
为了研究Abatacept在抑制T细胞活化的同时却并未显著增加肿瘤或感染发生的几率的现象是否与Abatacept对NK细胞功能调节有关,我们将高于临床治疗类风湿关节炎剂量的Abatacept经小鼠尾静脉注射入小鼠体内,比较其脾脏NK细胞毒性与未注射小鼠是否有差异。结果显示注射Abatacept 24h和48h后小鼠脾脏NK细胞毒性较未注射小鼠脾脏NK细胞毒性明显上升。这一结果说明,Abatacept注射小鼠体内后,CTLA4分子可显著增强小鼠NK细胞的毒性。这可能是Abatacept应用并未显著增加肿瘤或感染发生的几率的重要原因。
3、CTLA4Ig增强人NK细胞毒性的作用是CTLA4分子依赖的:
为了明确CTLA4Ig对NK细胞毒性增强的效应是否全部由ADCC引起,我们进行如下实验:首先在体外实验系统中引入可溶性hIgG1或模拟膜表达的hIgG1作为对照,通过比较加入CTLA4Ig与引入FcR信号后的NK细胞毒性,明确ADCC作用在CTLA4Ig对NK细胞调节中的作用。结果显示加入CTLA4Ig后NK细胞毒性增加的比率远高于引入FcR。因此,CTLA4Ig对NK细胞毒性的增强效应主要是由CTLA4分子介导的;为了进一步说明上述问题,我们选用表面仅表达少量低亲和力FcR-CD16,且无CD32和CD64的表达(25)的NK92细胞株作为效应细胞。在NK92细胞和K562共培养体系中加入CTLA4Ig后,NK92细胞的毒性仍然明显增强,证实CTLA4分子在增强NK细胞毒性作用中起绝对的主导作用。因此我们认为体外实验中CTLA4Ig增强人NK细胞毒性的作用是CTLA4分子依赖的。
二、CTLA4Ig(Abatacept)可增强机体抗肿瘤的能力:
NK细胞在机体抗肿瘤形成中起着至关重要的作用,因此本实验探讨CTLA4Ig对NK细胞毒性增强作用是否有利于机体控制肿瘤形成。我们的实验发现注射超过临床剂量的Abatacept不仅没有因为抑制T细胞激活促进肿瘤形成和生长,相反地,极大地减少了B16细胞肺转移。不仅如此,荷瘤小鼠的生存时间亦明显延长。提示Abatacept可增强机体抗肿瘤(B16)的能力。
三、我们对CTLA4Ig(Abatacept)在大面积烧伤治疗中的新认识:
我们的前期研究结果(13)和文献报道(14)都证实注射CTLA4Ig或创面局部应用CTLA4Ig重组腺病毒均可延长异体皮移植存活期,这就意味着CTLA4Ig如果可以应用于烧伤患者将会抑制移植物排斥反应,延长移植物的存活时间。因此,我们利用绿脓杆菌感染模型和烫伤模型评价CTLA4Ig用于烧伤患者治疗皮肤移植排斥反应的安全性,我们的研究首次发现使用Abatacept不仅可以显著提高Balb/c小鼠清除绿脓杆菌的能力而且还能增强烫伤小鼠脾脏细胞的毒性,与体外的实验结果一致。这一研究发现提示CTLA4Ig未来可用于大面积严重烧伤患者以诱导对皮肤移植物的免疫耐受,增强机体天然免疫力。这将是严重烧伤疾病治疗的重大突破。
四、CTLA4Ig通过与NK细胞表面CD80/CD86分子结合上调激活性受体NKG2D和NKp44表达,增强NK细胞毒性功能:
1,CTLA4Ig通过与NK细胞表面CD80/CD86分子的结合促进NK细胞的毒性功能:本实验研究抗CD80抗体和抗CD86抗体对NK细胞有无调节作用。结果发现:抗CD80抗体和抗CD86抗体在体外可明显增强人PBMC对K562细胞的毒性,且与CTLA4Ig组NK细胞毒性无明显差异。结合上述实验结果我们认为,CTLA4Ig通过与NK细胞表面CD80/CD86分子的结合促进NK细胞的毒性功能。
2,CTLA4Ig可上调NK细胞表面激活性受体NKG2D、NKp44的表达:我们采用流式细胞技术探讨CTLA4Ig对NK细胞表面NKG2D和NKp44表达的调节作用。结果发现体外加入CTLA4Ig后,人NK细胞表面激活性受体NKG2D、NKp44表达明显上调,且程度与IL-2相似。FcR受体与NK细胞结合不会导致NKG2D、NKp44表达上调。这一结果说明NK细胞表面激活性受体NKG2D、NKp44的在CTLA4Ig增强NK细胞毒性功能的调节作用中可能发挥了重要作用。
总结:
一、CTLA4在体内、体外均可增强NK细胞毒性;
二、CTLA4Ig通过与NK细胞表面CD80/CD86分子结合上调NK细胞表面NKG2D和NKp44的表达,增强NK细胞功能;
三、CTLA4Ig及其衍生物(如Abatacept)在全身应用,可增强小鼠抗肿瘤和抗感染的能力,不增加患者罹患肿瘤及感染的几率,扩大了其临床应用的适应症;
四、CTLA4Ig全身应用不仅可治疗皮肤移植物排斥反应,且可增加烫伤小鼠NK细胞毒性,减少播散性感染的发生,为CTLA4Ig应用于治疗烧伤患者提供了新思路;
五、我们发现CTLA4对于获得性免疫系统(T细胞)和天然免疫系统(NK细胞)截然不同的作用,这对我们深入了解免疫系统的调节和内环境的稳定具有重大意义,将为临床肿瘤生物治疗和大面积烧伤救治提供全新的理论基础和研究方向。
Patients who suffer from massive burn injury are hyporesponsive and susceptible to infection (1, 2), while the rejection towards skin graft is severe. Therefore, maintenance of long-term skin graft survival without increasing incidence of disseminated infection is the key problem to be solved in treatment of massive burn patients.
NK cells, as the most important cells in innate immune system, play a considerable role in tumor surveillance and anti-infection. Whether NK cells are activated or not is mostly dependent on the balance between the inhibitory (i.e.NKG2A) and activated (i.e.NKG2D) receptors expressed on the cell surface. However, NK cell function is proved to be severely suppressed after massive burn, which leads to susceptibility to infection. It is believed that nosocomially-acquired resistant Pseudomonas aeruginosa infection is the major cause of infection and sepsis after burn injury(3). Pseudomonas aeruginosa exotoxin A is found to be able to inhibit NK cell-mediated cytotoxicity and IFN-gamma synthesis (4). Furthermore, it has been 10 years since Pseudomonas aeruginosa was identified, while unfortunately, it became multidrug resistance (5). However, it is demonstrated that NKG2D is critical for NK cell activation in host defense against Pseudomonas aeruginosa respiratory infection (6, 7). Accordingly, we are very interested in the question that whether the enhancement of NK cell-mediated cytotoxicity can decrease the incidence of disseminated infection.
Recombinant protein CTLA4Ig has been shown to be able to induce immune tolerance. The necessary co-stimulatory signal for T cell full stimulation is provided by ligation of CD28 with either B7-1 or B7-2 molecules expressed on antigen-presenting cells and can be blocked by a soluble form of CTLA4Ig which binds with high affinity to both B7-1 and B7-2(8). Recently, selective immunomodulatory agents such as Belatacept and Abatacept have shown great promise in treatment of rheumatoid arthritis and promoting allograft survival (9-12). Additionally, not only our previous research (13), but also other work(14) have proved that systemic or local administration of recombinant adenovirus CTLA4Ig can promote skin allograft survival. Nonetheless, CTLA4Ig utilization in promoting skin allograft survival in massive burn patients is rarely because of the consideration of the side-effects, especially disseminated infection.
Abatacept is a fusion protein composed of a mutant immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. It is licensed by FDA for the treatment of rheumatoid arthritis. One interesting aspect of CTLA4Ig is that patients treated with this fusion protein experience much lower incidence of tumors and infectious episodes than the prediction (15-17). Meanwhile, Abatacept does not impair the ability of mice to control a chronic M tuberculosis infection(18). However, the corresponding mechanism of these phenomenons has not yet been determined. Grohmann et al. found that CTLA4Ig could influence on the antigen presenting cell function via the interaction with B7 molecules on APC (19), which means CTLA4Ig is possibly able to regulate all the cells that expressed CD80/CD86 molecules. Moreover, recent studies demonstrated that resting NK cells can express CD86, and activated NK cells express both CD80 and CD86 receptors(20, 21), which prompted us to study the possibility role of CTLA4Ig in NK cell function. Beissert S et al. found that Chronic UV exposure of CTLA4Ig transgenic mice resulted in significantly reduced numbers of skin tumors, when compared to control mice (22). Taken together, previous data showed that CTLA4Ig could inhibit immune rejection of skin grafts without increasing the infection morbidity via blocking co-stimulatory pathway, meanwhile,CTLA4Ig might regulate the functions of CD80/CD86 positive cells such as NK cells that play an important role in control of infections and in tumor cell clearance (23). Thus it prompts us to determine the questions as to: 1,whether the ligation of CTLA4Ig and B7 molecules expressed on NK cell surface leads to the enhancement of NK cell-mediated cytotoxicity and clearance of tumor cells and bacteria.2, what the underlying mechanisms are. 3, whether the regulation of CTLA4Ig on NK cell-mediated cytotoxicity can explain CTLA4Ig systemic administration does not increase the morbidity of infections and tumorogenesis.
In the present study, we detected the possible roles of CTLA4Ig in the regulation of NK cell function both in vitro and in vivo, and in the models of Pseudomonas aruginosa infection, scald injury and B16 melanoma metastasis. The corresponding molecular mechanisms were also been examined. Our main findings and conclusions of this study are summarized as follows:
1. CTLA4Ig and Abatacept are strong activator of NK cells:
1) CTLA4Ig could enhance PBMC or purified human NK cell function in vitro:
In order to determine that whether CTLA4Ig can regulate PBMC or purified human NK cell function in vitro, we used FACS to detect the cytotoxicity after administration of different concentrations of CTLA4Ig. In our study, we found that:Ⅰ.CTLA4Ig significantly enhanced PBMC or purified human NK cell cytotoxicity to NK cell-sensitive target cells (K562 cell line) in vitro when its concentration was more than 1μg/ml.Ⅱ.The enhanced cytotoxicity was comparable to IL-2 that has long been identified as the T cell and NK cell stimulator.Ⅲ.PBMC or purified human NK cell cytotoxicity did not change significantly with the increase of CTLA4Ig concentration in our experiment. These data indicated that CTLA4Ig can enhance NK cell-mediated cytotoxicity in vitro, which is comparable to IL-2 and the enhancement did not change significantly with the increase of CTLA4Ig concentration in our experiment.
2) CTLA4Ig (Abatacept) could augment NK cell-mediated cytotoxicity of mice in vivo
To determine that whether the augmentation of Abatacept on NK cell-mediated cytotoxicity was related to the phenomenon that systemic administration of Abatacept did not significantly increase the incidence of tumor and infection, we injected Abatacept into mice via tail vein at a dose higher than clinical utilization and then detected the splenetic NK cell-mediated cytotoxicity. It was demonstrated that administration of Abatacept via mouse tail vein could significantly increase NK cell cytotoxicity as compared with PBS at 24 and 48 hours after injection. These data indicated that CTLA4 molecule could significantly enhance NK cell-mediated cytotoxicity in vivo. It might be the major reason that administration of Abatacept did not significantly increase the incidence of tumor and infection.
3) The augmentation of CTLA4Ig on NK cell-mediated cytotoxicity is mainly CTLA4 dependent:
NK cell cytotoxicity could be activated via FcR signaling as referred as antibody-dependent cellular cytotoxicity (ADCC)(24). To test whether the enhanced cytotoxicity of NK cells is ADCC-dependent in the presence of the Fc portion of CTLA4Ig, IgG1 containing the same Fc portion was added into the co-culture system in the form of either soluble human IgG1 or plate-bound human IgG1. Either soluble human IgG1 or plate-bound human IgG1 could significantly affect NK cell cytotoxicity, which, however, was much lower than that in the presence of CTLA4Ig. These data suggested that the CTLA4 portion rather than the Fc portion was the main part of CTLA4Ig that was responsible for enhancement of NK cell cytotoxicity. To further determine whether CTLA4Ig mediated NK cell cytotoxicity was mainly CTLA4 dependent, we chose human NK cell-line (NK92) as the effective cells that only express minimal low-affinity FcR CD16 and are lack of CD32/CD64(25). We found that CTLA4Ig could also significantly increased NK92 cell cytotoxicity. These data strongly argued that CTLA4Ig-mediated NK cell activation is mainly CTLA4 dependent.
2. CTLA4Ig(Abatacept)could strengthen host defense against tumors:
As is known that NK cells are very important in tumor surveillance in the body, we then tested whether this enhanced NK cell cytotoxicity could favor the control of tumor formation. In the B16 melanoma bearing-mice, injection of Abatacept significantly decreased the melanoma formation in the number of tumor nodules on the lung surface and finally prolonged the survival of B16 melanoma bearing-mice as compared with PBS control. Experiment in vivo model of B16 melanoma showed that Abatacept could significantly retard B16 melanoma metastasis. These date indicated that Abatacept could strengthen host defense against tumors (B16 melanoma).
3. CTLA4Ig(Abatacept)application in massive burn:
It was reported that systemic or local administration of CTLA4Ig both in our(13) and other work(14) could promote allogenic skin graft survival. Take account of disseminated infection, we valued the safety of CTLA4Ig utilization in massive burn patients via Pseudomonas aeruginosa infectious model and scald mice model. We for the first time found that systemic administration of Abatacept could not only strengthen host defense against Pseudomonas aeruginosa but also enhance splenetic NK cell-mediated cytotoxicity of scald mice in vivo, which was coincidence with in vitro experiments. These data prompted that CLTA4Ig might be safety when utilized in massive burn patients in order to induce immune tolerance and promote skin graft survival.
4. CTLA4Ig enhanced NK cell-mediated cytotoxicity by up-regulation of activated receptors (NKG2D and NKp44) via ligation of CD80/CD86 molecules:
1) CTLA4Ig enhanced NK cell-mediated cytotoxicity via ligation with CD80/CD86 molecules expressed on NK cell surface: To test whether CD80/CD86 contributed to the activation of NK cell cytotoxicity induced by CTLA4Ig, anti-CD80 and anti-CD86 monoclonal antibodies were used in vitro. The results showed that both antibodies could apparently stimulate NK cytotoxicity function, and the level of the increased cytotoxicity was similar to that of CTLA4Ig. It indicated that CTLA4Ig enhanced NK cell-mediated cytotoxicity via ligation with CD80/CD86 molecules expressed on NK cell surface.
2) CTLA4Ig could up-regulate NKG2D and NKp44 expression on NK cell surface: As previous reports, NK cell function is controlled by NK cell activated receptors and inhibitory receptors. We thus examined the NK cell activated receptors, such as NKG2D, NKp44 by means of FACS. After stimulation of NK cells by CTLA4Ig, the expressions of NKG2D and NKp44 on NK cell membrane were increased in the percentage of positive cells and the level was comparable to that after stimulation by IL-2. However, hIgG1 showed no effect in receptors expression. These data indicated a possibility that NKG2D and NKp44 might be critically involved in the CTLA4Ig-mediated NK cytotoxicity enhancement.
Conclusion:
Our findings have demonstrated that CTLA4Ig could enhance NK cell function by up-regulation of activated receptors (NKG2D and NKp44) via ligation of CD80/CD86 molecules. Systemic administration of CTLA4Ig (Abatacept) could not only enhance NK cell function in scald mice but also strengthen host defense against Pseudomonas aeruginosa and tumors. This is extremely important in the understanding of CTLA4Ig in regulation of immune responses, the expansion of the indications of CTLA4Ig and in the management of massive burn injuries, some types of tumors, viral and bacteria infections.
引文
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