肿瘤疫苗的分子设计

诱因
pro-oncogene
Suppressor gene
第一节 肿瘤和宿主免疫系统间的相互作用
The Tumors As A grafted tissue
Immune Surveillance (recognizing abnormal cell)
Immune cells killed a tumor cell
Escape from immuno-surveillance
逃脱免疫监视
缺乏协同刺激分子 肿瘤分泌免疫抑制分子
缺乏新抗原
缺乏MHC I分子 可溶性抗原封闭抗体
1 7
2 3
6
4
5
Tumor escape mechanisms
ICAM-1: intercellular adhesion molecule-1
-
+
-
+
-
+
-
+
-
+
-
可溶性抗原封闭抗体
二、细胞毒细胞是免疫抑制性细胞因子的靶细胞
TGF- , IL-6, IL-10 (-) 下调
a growth inhibitory molecule,
表达FasL,并通过Fas-
FasL相互作用而杀灭浸润
的免疫效应细胞。
Fas ligand expression by a variety of tumor cell lines and primary tumor isolates. Expression of Fas ligand by tumor cells has been suggested as a tumor escape mechanism, how tumor cells kill activated cytotoxic T cells and thus avoid an anti-tumor immune response.
increased expression of class I MHC, possible cytostatic anti-tumor effect,
increased MHC antigens; macrophage, Tc and NK cell activation
T-cell proliferation and activation, NK cells activation
Detection of Fas ligand expression by immunofluorescence in a human lung carcinoma cell line.
三、肿瘤细胞中抗原处理机制的缺陷
*
缺乏协同刺激分子
第二节 肿瘤的免疫学治疗
IL-2
Ab
Figure1. Recurrent melanoma, unresponsive to radiotherapy, prior to immunotherapy with intralesional (病灶内的) injections of human monoclonal antibody to GM2 or GD2. GD3, a prominent ganglioside (神经节糖 苷)on the surface of melanoma cells.
表 -1 免疫抑制性细胞因子对肿瘤浸润性淋巴细胞功能的作用
作用
TGF- IL-10 VEGF
T细胞生长抑制
+
CTL分化抑制
+
细胞因子产生抑制
+
T细胞无反应性诱导
+
细胞毒性作用下调
+
抗原呈递作用抑制
+
Th1-Th2细胞平衡移至Th2细胞 +
粘附/协同刺激分子下调
+
CTL介导裂解的抗性
-
-
+
+
+
+
-
-
macrophage and lymphocyte activation
四ຫໍສະໝຸດ Baidu基因治疗
transfection
Tumor cell
肿瘤基因治疗系指将外源的正常基 因导入人体,达到直接或间接抑制 或杀伤肿瘤细胞的目的。
第三节 肿瘤特异性主动免疫治疗的新策略
几个特点:
1 通过主动免疫能够激发全身性的抗肿瘤效应,特别适用于多 发病灶或有广泛转移的恶性肿瘤;
RCAS1: a growth inhibitory molecule, which react with T cell bearing their corresponding receptors and stop them in their trackes.
一、肿瘤诱发的细胞因子和免疫抑制
肿 瘤 分 泌 免 疫 抑 制 分 子
Figure 2. The same patient 2 years later following complete regression of all disease.
二、细胞免疫治疗
1、CML的细胞免疫治疗 2、骨髓移植后疾病复发的细胞免疫治疗
Treatment o leukemias by autologous (自体) bone marrow rescue.
IFN-gamma IL-2
remission of peritoneal carcinoma of ovary: ineffective systemically
remission in renal carcinoma and melanoma
TNF-alpha can reduce malignant ascites
2 主动免疫治疗通过调动机体自身的力量达到抗肿瘤作用,与 放疗和化疗相比,副作用很小;
三、细胞因子的应用
Table 3. Cytokine therapy of tumors
cytokine tumor type and result antitumor mechanism(s)
IFN-alpha, beta remission of hairy cell leukemia, weak effect on some carcinomas
肿瘤疫苗的分子设计
Somatic mutations are not transmitted to progeny, but germinal mutations may be transmitted to some or all progeny
肿瘤发生的机制
pro-oncogene
Suppressor gene