基于打破树突状细胞耐受的抗肿瘤免疫治疗

树突状细胞(DC)是专职抗原呈递细胞,具有强大的免疫监视功能.由于在诱导免疫反应中的重要作用,DC已被广泛地应用于抗肿瘤免疫治疗.但是由于肿瘤细胞对荷瘤宿主免疫系统,尤其是对DC功能的抑制,使以DC为基础的抗肿瘤免疫治疗疗效受到了很大的限制.所以,通过调节DC功能,可打破肿瘤对DC的免疫抑制,引导有效的抗肿瘤反应,提高以DC为基础的抗肿瘤免疫效果,这在抗肿瘤免疫治疗中具有重要意义.     

Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial

BACKGROUND: Immunotherapy with Hymenoptera venoms is highly effective but causes allergic side-effects frequently, especially when honeybee venom is used. Therefore, our objective was to investigate the effect of pretreatment with the antihistamine fexofenadine on the incidence of allergic side-effects during ultrarush immunotherapy with bee venom. METHODS: In a double-blind, placebo-controlled trial, 57 patients with a history of systemic allergic reactions to honeybee stings and positive diagnostic tests (skin tests, serum specific IgE to honeybee venom) were investigated. Bee venom immunotherapy was started with an ultrarush protocol and patients were randomized to pretreatment with either fexofenadine 180 mg or placebo on days 1, 8, 22, and 50 of the protocol. Local and systemic allergic side-effects were registered. RESULTS: Fifty-four patients completed the study, 28 on fexofenadine and 26 on placebo pretreatment. On day 1, large local reactions were significantly reduced in both extension and duration by fexofenadine pretreatment (P<0.025). Systemic allergic side-effects on the whole were not reduced. However, the symptoms pruritus, urticaria, and angioedema occurred less frequently with fexofenadine (P<0.05). CONCLUSIONS: Pretreatment with fexofenadine during venom immunotherapy reduces local allergic reactions and generalized symptoms of the urticaria and angioedema type.     

Tumour cell killing using chemically engineered antibody constructs specific for tumour cells and the complement inhibitor CD59

Immunotherapy using MoAbs is inefficient due to limited activation of human effectors by mouse antibodies and multiple protective mechanisms available to host cells against autologous complement. We have used chemically engineered antibody constructs and human complement in vitro to specifically target and kill neoplastic B lymphoid cells (Raji). Fab′γFcγ² chimaeric antibody (specific for human CD37) was used to activate the classical pathway of human complement on Raji cells, whilst CD59 was neutralized using one of two different bispecific F(ab′γ)² antibody constructs which contained both cell-targeting (anti-CD19 or anti-CD38) and CD59-neutralizing moieties. When either bispecific construct was used to neutralize CD59, 15–25% of cells were lysed. If CD55 was also neutralized using specific antibody, Raji cells were efficiently killed (70% lysis). When added to a mixture of target (Raji) and bystander (K562) cells, one bispecific antibody (anti-CD38 × anti-CD59) could be specifically delivered to Raji, avoiding significant uptake on CD59-expressing bystander cells (K562). The second bispecific antibody (anti-CD19 × anti-CD59) bound equally well to either cell type. Cell-specific targeting was dependent upon combination of a low-affinity anti-CD59 Fab′γ with a high-affinity anti-tumour cell Fab′γ. When Raji and K562 cells were mixed and incubated with a combination of the engineered constructs and anti-CD55 antibodies, Raji cell lysis (30–40%) was observed in the absence of K562 killing. We propose that combinations of these constructs may be of use for treatments such as ex vivo purging of autologous bone marrow or in vivo targeting of tumour cells.     

CD3AK细胞过继免疫治疗的实验研究

目的: 分析抗CD3分子的单克隆抗体 (mAb)yCD3的免疫学特性和生物学活性, 观察其激活的免疫活性细胞CD3AK体外及动物体内的抑瘤作用。方法: 用流式细胞术(FCM)测定yCD3的特异性, 以及CD3AK细胞的免疫表型和产生细胞因子的情况。用 3H -TdR法测定yCD3对淋巴细胞转化的作用; 乳酸脱氢酶法 (LDH)测定CD3AK细胞的体外细胞毒活性。建立荷瘤小鼠模型, 观察静脉注射CD3AK细胞后肿瘤生长的情况、转移灶数量和小鼠存活天数。结果: yCD3与T细胞呈特异性反应, 5μgyCD3可竞争抑制 70%的标准抗CD3抗体与细胞表面CD3分子的结合。yCD3刺激外周血淋巴细胞增殖的有效浓度为 8μg/L, 并与IL- 2、抗CD28抗体有协同作用。活化的CD3AK细胞中CD3 、CD8 和CD25 细胞增多; 产生IL- 2和IFN γ的CD3 细胞均有不同程度的增加, 在抗CD28抗体协同刺激下分别增加 3. 29和 2. 47倍。当效靶细胞比为 80∶1时, CD3AK细胞对体外肿瘤细胞杀伤的百分率为 57. 54%。分组观察荷瘤动物, CD3AK细胞治疗组的抑瘤率为 33. 17%, 对小鼠肿瘤肺转移的抑制率为39. 70%, 与LAK细胞联合治疗的疗效更显著。结论: yCD3可活化T细胞, 诱导的CD3AK细胞在体外及动物体内显示抑制肿瘤的作用, 在临床抗肿瘤过继性免疫治疗中具有重要意义。     

参杞合剂对小鼠腹水型肝癌细胞株H22细胞周期及凋亡的影响

目的：观察参杞合剂(SQ)在体内、外对小鼠腹水型肝癌细胞株(HcaF16A3)细胞周期及凋亡的影响。方法：用SQ对荷瘤小鼠连续胃饲治疗10d，观察其NK细胞／Mφ的杀伤活性及细胞周期的改变。用流式细胞仪检测SQ对HcaF16A3细胞增殖的抑制作用与诱导凋亡的作用。结果：SQ的抑瘤率为65．68％。流式细胞仪检测发现，SQ可使肿瘤细胞的细胞周期阻滞到S期，并在体外诱导其凋亡。结论：SQ在体内、外均有抑瘤作用，其机制与细胞周期阻滞继而诱发凋亡有关。     

Exploiting T cell receptor genes for cancer immunotherapy

Adoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for 'unconventional' antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8(+) and CD4(+) lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.     

A Double-Blind, Multicenter Immunotherapy Trial in Children, Using a Purified and Standardized Cladosporium herbarum Preparation II. In Vitro Results

This double-blind immunotherapy trial in children, using a purified and standardized Cladosporium herbarum allergen preparation, has shown that children with mould asthma and/or rhinoconjunctivitis, responded to immunotherapy with a decrease in specific IgE and a significant increase in specific IgG. There was a marked increase in the ratio specific IgG/specific IgE as a result of active treatment. IgE-CRIE radiostaining patterns showed no pronounced changes after 10 months' active treatment and no "new sensitivities" could be detected in the studied patients. IgG-CRIE radiostaining, primarily directed towards the important allergens, was significantly increased in the active group and particularly towards Ag-12 (partially identical to a previously described major allergen in Cladosporium herbarum, Ag-54). Children treated with histamine placebo showed no change in antibody patterns during 10 months of treatment.     

84例变应性鼻炎患儿过敏原皮内试验结果分析

目的 了解新疆地区变应性鼻炎患儿气传过敏原的分布状况,探讨气传变应原分布的地区差异及产生原因,为本地区儿童变应性鼻炎的防治方案提供客观依据.方法 采用阿罗格(NHD)点刺液进行皮肤点刺试验84例变应性鼻炎患儿进行气传变应原测试.结果 84例变应性鼻炎患儿吸入变应原测试总阳性率96.4%(81例),以藜属花粉最高70.2%(59例),蒿属植物次之42.9%(36例),其后依次为杨树27.4%(23例),榆树25.0%(21例),槭树17.8%(15例),柳树11.9%(10例),豚草(巨大豚草、普通豚草)11.9%(10例),粉螨10.7%(9例),尘螨9.5%(8例),交链孢霉8.3%(7例),特异青霉7.1%(6例),白色念珠菌4.8%(4例)等.81例对不同变应原过敏,其中42例(51.9%)患儿对2种或2种以上变应原过敏.点刺试验皮肤反应强度蒿属最明显,强阳性占蒿属过敏病人的50.0%,藜属次之,强阳性占藜属过敏病人的40.7%.结论 藜属和蒿属为新疆地区变应性鼻炎患儿最主要的变应原,在治疗过程中对这类变应性鼻炎患儿可采取有效的避、忌、替、移等措施,明确变应原后对特异性免疫治疗具有重要的指导意义.     

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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