趋化因子研究进展2

三、趋化因子的基本功能
（一）趋化作用； （二）上调整合素的表达, 活化白细胞； （三）促进细胞脱颗粒和生物活性物质释放:
CCL2：Ba释放组织胺；CXCL8： Neu产生活性物质，呼吸爆发；
（四）调节血管生成：
ELRCXC 、CCL2促进血管生成； CXCL10 、CCL21/SLC抑制血管生成。
CTCE-9908(Chemokine therapeutics, vancouver, BC, Canada) is a peptide analog of CXCL12 that acts as a competitive antagonist of CXCR4. in a mouse model, treatment with it did not reduce the frequency of metastasis, but did decrease both the tumor burden of breast cancer in the bone and other organs, and also of the primary breast . Plerixafor (MD3100, Genzyme Corporation, Cambridge, Ma, usa) is a CXCR4 antagonist that promotes hematopoietic stem cells to mobilize from the bone marrow into the bloodstream, and is approved for use in autologous transplantation.
Onishi, T. et al. Nat Rev Clin Oncol. 2010 Aug 31. [Epub ahead of print]
KW-0761, finished phase I study for ATL and PTPL
KW-0761, a defucosylated humanized anti-CCR4 antibody, exerts a strong antibody-dependent cellular cytotoxic effect. ATL: adult T-cell leukemia-lymphoma; PTPL: peripheral T-cell lymphoma .
The EMBO Journal (2008), 1–10
Nonsignaling ‘‘Scavenger’’ Chemokine Receptorlike Molecules Adjust the Chemokine Environment
Richard M. Ransohoff1, Immunity, 2009 (31), 711-721.
Clinical trials of this agent are also underway, mainly for hematologic malignancies. Another potential strategy is to combine CXCR4 antagonists with other drugs, such as bisphosphonates, as these drugs are likely to have a synergistic action because zoledronic acid also inhibits CXCR4 expression on breast cancer cells.
肿瘤组织表达的趋化因子受体
Ann Richmond, et al. Pigment Cell Melanoma Res. 2009, 22; 175–186.
Pivotal role of CXCL12/CXCR4 axis in bone metastasis
Due to genetic alterations, epigenetic regulation and hypoxia in tumors, over 23 different cancer types overexpress CXCR4, therapies that target CXCR4 may be applicable to many cancer types. In prostate cancer, CXCR4 expression relates to increasing tumor grade. CXCR4 is highly expressed in breast cancer tissue, with low expression in normal breast tissue. CXCL12 is highly expressed at sites of breast cancer metastasis. CXCR4 is much more highly expressed in bone metastases than in visceral metastases. CXCR4 has an important role in the homing of tumor stem cells to the bone marrow, which is an area enriched with CXCL12.
Yamamoto K et al. J Clin Oncol. 2010 Mar 20;28(9):1591-8. Ishii T et al. Clin Cancer Res. 2010 Mar 1;16(5):1520-31.
Antitumor activity induced by blocking CXCL12/CXCR4 pathway
Antibody to CXCR4 significantly reduces the number of bone metastasis of prostate cancers in an in vivo murine animal.
Therapeutics and Clinical Risk Management 2008:4(2) 473–485.
Selzentry（Maraviroc ）
辉瑞公司生产； 副作用：肝脏或心脏损伤，出现其他感染或罹患 癌症的风险增加； 适应症：FDA强调该药仅适用于对其他抗艾药已 产生耐药性的患者，而不适用于刚确诊的患者。 它是自2003年以来研发成功的首个抗艾新药；也是首个 趋化因子相关药物。
趋化因子及其受体在免疫系统的表达和功能
Ye H. Oo et al, Journal of Autoimmunity 34 (2010) 45–54.
(四) CKR的信号传导途径
Domanska UM et al, Rev Oncol Hematol. 2010 Aug 13. [Epub ahead of print] .
趋化因子受体在不同亚类T细胞中的表达谱
Nature Immunology, 2008 , 9(9), 970-980
（2）CKR在DC迁移和功能成熟中具有不同的表达模式:
非成熟DC：CCR1，2，5， CXCR4， 易于向炎症部位聚集，摄取抗原； 成熟DC：CCR4，7，CXCR4，负载抗原,向淋巴组织迁移。
（二） 趋化因子与其它疾病
1、哮喘： CCL3，5，7，11，22等在靶细胞的迁 移、聚集、活化中发挥关键作用; 2、肿瘤：CXCR4与CXCL12、CCR7与CCL21在肿瘤细胞向 骨、淋巴结等器官的转移中起重要作用；
3、自身免疫病：MS和RA等；
4、动脉粥样硬化：CX3CR1基因缺陷人群对该病不易感； 5、移植排斥。
(2) directing the homing of tumor cells to specific metastatic sites (the CXCL12–CXCR4 axis);
(3) regulating angiogenic processes (mainly the ELR+–CXC and non-ELR–CXC chemokines); (4) acting directly on the tumor cells to control their malignancyrelated functions.
Multifaceted roles of chemokines in malignancy
(1) inducing leukocyte infiltration to tumors and regulating immune functions, with emphasis on tumor-associated macrophages (CCL2, CCL5), T cells (CXCL9, CXCL10), dendritic cells (CCL19, CCL20, CCL21) and NK cells (CX3CL1);
Targets a host protein, CCR5, rather than a viral target; Binding of maraviroc to CCR5 results in blocking HIV-1 attachment to the coreceptor and prevents the virus from entering CD4+ cells.
CCR5、CXCR4是HIV感染人体细胞的共受体
HIV感染人体细胞的过程
Chem Biol Drug Des 2008; 72: 97–110
CCR5、CXCR4和HIV感染
It is currently believed that 90% HIV strains use CCR5 (macrophage tropic) for initial infections, and the infected viruses undergo mutations that allow them to use CXCR4 (T cell tropic) as the infection progresses to AIDS. Entry of HIV into host cells requires the formation of an entry complex including the viral envelop glycoprotein gp120, CD4 and either CCR5 or CXCR4 receptors。
Richard Horuk, Nature reviews, drug discovery, 2009, Jan, 8, 23-33
（一）CKs与AIDS
AIDS:获得性免疫缺陷综合症 （Acquired Immunodeficiency Syndrome, AIDS） CD4分子和CCR5、CXCR4等CKR是HIV-1感染人体细胞 所必须的受体； 针对CCR5的小分子抑制物Maraviroc已获FDA批准并于 2007年8月上市。
Tian Jin et al, Cytokine 44 (2008) 1–8.
CCR5缺失突变对嗜MØ HIV病毒感染有抵抗性
Maraviroc, the first US Food and Drug Administration–approved drug from a new class of antiretroviral agents
趋化因子的基本功能
趋化因子引起的细胞形态改变
CXCL8/IL-8的作用
（五）调控免疫细胞分化、发育、成熟、归巢、 相互作用等。
趋化因子参与T细胞发育
趋化因子及其受体在免疫应答中的作用
趋化因子参与免疫细胞在周围免疫器官的定位
四、 趋化因子与因子受体在免疫细胞中的表达