Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.
Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.
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DOI：
10.1371/journal.ppat.1004770
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Kalman D
中科院分区：
文献类型：
--
作者：
Napier RJ;Norris BA;Swimm A;Giver CR;Harris WA;Laval J;Napier BA;Patel G;Crump R;Peng Z;Bornmann W;Pulendran B;Buller RM;Weiss DS;Tirouvanziam R;Waller EK;Kalman D
伊马替尼甲磺酸盐（格列卫）抑制c-kit和相关的蛋白酪氨酸激酶（PTKs），并作为慢性髓细胞性白血病和胃肠道间质瘤的治疗。伊马替尼还具有针对各种病原体的功效，包括致病性分枝杆菌，其中它降低了小鼠中的细菌负荷，尽管剂量低于用于治疗癌症的剂量。我们报告说，伊马替尼在如此低的剂量意外地诱导骨髓造血干细胞和祖细胞的分化，增强骨髓生成，但不是淋巴细胞生成，并增加血液和脾脏中的髓系细胞的数量。而祖细胞分化依赖于伊马替尼对c-Kit的部分抑制，谱系定型依赖于对其他PTK的抑制。因此，伊马替尼模拟“紧急造血”，一种对感染的生理性先天免疫反应。通过过继转移增加中性粒细胞数量足以降低分枝杆菌载量，伊马替尼降低弗朗西斯菌属的细菌载量，其不利用伊马替尼敏感性PTKs进行发病。因此，低剂量伊马替尼增强免疫应答可能有助于清除各种微生物病原体。针对感染性疾病的宿主导向疗法（HDTs）靶向病原体进入、穿过或离开细胞的细胞机制。例如，Abl酪氨酸激酶（TK）抑制剂和癌症治疗剂甲磺酸伊马替尼（Gleevec）通过对病原体进入（多瘤病毒）、细胞内转运（分枝杆菌）和离开（痘病毒和丝状病毒）的作用而具有针对细菌和病毒病原体的活性。其他HDTs通过抑制或激活循环先天性和适应性细胞来靶向宿主免疫系统。在这里，我们报告说，伊马替尼的剂量是有效清除分枝杆菌感染，但比用于癌症的剂量低10倍，模拟了骨髓感染的生理先天反应，称为“紧急反应”，其中造血干细胞和多能祖细胞扩增并分化为迁移到外周部位的成熟髓系细胞。伊马替尼的作用部分通过部分抑制c-Kit发生，表明c-Kit控制造血的最早阶段的机制。模拟生理抗菌反应可能使伊马替尼广泛有用。因此，伊马替尼还具有针对弗朗西斯菌属引起的感染的功效，其不使用伊马替尼敏感的TK用于发病机制。这些观察结果将骨髓生成确定为HDTs的重要靶点，并提供了如何给伊马替尼用于临床的信息。
Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens. Host-directed therapeutics (HDTs) for infectious diseases target cellular mechanisms used by pathogens to move into, through, or out of cells. The Abl tyrosine kinase (TK) inhibitor and cancer therapeutic imatinib mesylate (Gleevec), for example, has activity against bacterial and viral pathogens via effects on pathogen entry (polyomaviruses), intracellular transit (Mycobacteria) and exit (poxviruses and filoviruses). Other HDTs target the host immune system by suppressing or activating circulating innate and adaptive cells. Here we report that imatinib at doses that are effective in clearing Mycobacterial infections but which are 10-fold lower than those used for cancer, mimics a physiological innate response to infection in the bone marrow, called the “emergency response,” in which hematopoietic stem cells and multipotent progenitors expand and differentiate into mature myeloid cells that migrate to peripheral sites. Imatinib effects occur in part via partial inhibition of c-Kit, suggesting a mechanism by which c-Kit controls the earliest stages of hematopoiesis. Mimicking a physiological antimicrobial response may make imatinib broadly useful. Accordingly, imatinib also has efficacy against infections caused by Franciscella spp., which do not use imatinib-sensitive TKs for pathogenesis. These observations identify myelopoiesis as an important target for HDTs, and provide information on how to dose imatinib for clinical use.
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DOI：
10.4049/jimmunol.1201538
发表时间：
2012-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bruns H;Stegelmann F;Fabri M;Döhner K;van Zandbergen G;Wagner M;Skinner M;Modlin RL;Stenger S
通讯作者：
Stenger S
影响因子：
20.3
作者：
Eash, Kyle J.;Means, Jacquelyn M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
15.9
作者：
Dillon, S;Agrawal, S;Pulendran, B
通讯作者：
Pulendran, B
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW