Resistance of Beta 2 Microglobulin Null Mice to Sepsis

描述（由申请人提供）：在当前的资助期间，我们在确定CXC趋化因子受体3（CXCR 3）在感染性休克发病机制中的作用方面取得了重大进展。我们的研究结果表明，CXCR 3是一个重要的调节自然杀伤细胞的运输在脓毒性休克引起的盲肠结扎穿孔（CLP）。此外，CXCR 3缺陷或阻断导致脓毒症诱导的生理功能障碍、全身性细胞因子产生和存活的显著减弱。CXCR 3配体CXCL 10的缺乏或阻断也赋予了对CLP诱导的脓毒性休克的保护。当在CLP后6小时与液体和抗生素一起施用抗CXCR 3 IgG或抗CXCL 10 IgG时，可实现存活益处。因此，CXCR 3阻断在脓毒症发作后开始时是有效的，并且可能代表了治疗脓毒性休克的多模式方法的可行补充。然而，关于CXCR 3阻断在脓毒症的临床相关模型中的功效以及脓毒症期间CXCR 3轴被激活的机制仍存在一些问题。本研究项目的目标有两个方面：1）评价CXCR 3阻断的临床相关方法，目的是使这种方法更接近临床应用; 2）确定CXCR 3激活促进脓毒性休克发病机制的机制，并确定脓毒症期间CXCR 3轴激活的细胞和分子机制。具体目的1：确定CXCR 3阻断在脓毒症临床相关模型中的功效。在这个目标中，我们将评估CXCR 3阻断剂在严重脓毒症发作后开始的疗效，如低灌注和器官损伤的发展所示。将使用CLP模型以及我们开发的铜绿假单胞菌和金黄色葡萄球菌烧伤创面脓毒症模型。除了基于免疫球蛋白的策略外，还将确定小分子量CXCR 3抑制剂AMG 487的疗效。具体目标2：确定CXCR 3轴在宿主对感染的反应中的作用。最近的一些研究表明，CXCL 10在促进不太严重的全身性感染模型中的有效细菌清除机制中发挥作用。为此目的提出的研究将确定CXCR 3轴阻断是否会损害宿主对局部感染的反应，以及在严重脓毒症急性期阻断CXCR 3轴是否会使宿主易于继发感染。具体目标3：确定感染性休克期间CXCR 3轴被激活的机制，并确定负责CXCR 3介导的病理生物学的细胞群。这些研究将确定调节体内CXCL 10产生的机制。重点将放在评估干扰素信号通路的重要性。进一步的研究建议，以确定严重脓毒症期间CXCR 3介导的淋巴细胞运输的功能的重要性，以及CXCR 3是否作为非迁移性淋巴细胞群的活化因子。

DESCRIPTION (provided by applicant): During the current funding period, we made significant progress defining the role of CXC chemokine receptor 3 (CXCR3) in the pathogenesis of septic shock. Our results show that CXCR3 is an important regulator of natural killer cell trafficking during septic shock caused by cecal ligation and puncture (CLP). Furthermore, CXCR3 deficiency or blockade causes significant attenuation of sepsis-induced physiologic dysfunction, systemic cytokine production and survival. Deficiency or blockade of the CXCR3 ligand CXCL10 also conferred protection from CLP-induced septic shock. Survival benefit was achievable when anti-CXCR3 IgG or anti- CXCL10 IgG was administered with fluids and antibiotics at 6 hours after CLP. Therefore, CXCR3 blockade was effective when initiated after the onset of sepsis and may represent a viable addition to a multi-modal approach for the treatment of septic shock. Yet, several questions remain regarding the efficacy of CXCR3 blockade in clinically relevant models of sepsis and the mechanisms by which the CXCR3 axis is activated during sepsis. The goals of this research project are two-fold: 1) To evaluate clinically relevant approaches for CXCR3 blockade with the goal of bringing this approach closer to application in the clinical setting and 2) To define the mechanisms by which CXCR3 activation facilitates the pathogenesis of septic shock and determine the cellular and molecular mechanisms by which the CXCR3 axis is activated during sepsis. Specific Aim 1: To define the efficacy of CXCR3 blockade in clinically relevant models of sepsis. In this aim, we will evaluate the efficacy of CXCR3 blockade when initiated after the onset of severe sepsis as indicated by the development of hypoperfusion and organ injury. The CLP model will be utilized as well as our well-developed models of Pseudomonas aeruginosa and Staphylococcus aureus burn wound sepsis. The efficacy of the small molecular weight CXCR3 inhibitor AMG487 will be determined in addition to immunoglobulin-based strategies. Specific Aim 2: To determine the role of the CXCR3 axis in the host response to infection. Some recent studies indicate that CXCL10 plays a role in facilitating effective bacterial clearance mechanisms in less severe models of systemic infection. Studies proposed in this aim will determine whether CXCR3 axis blockade will impair the host response to local infection and whether blockade of the CXCR3 axis during the acute phase of severe sepsis will predispose the host to secondary infections. Specific Aim 3: To define the mechanisms by which the CXCR3 axis is activated during septic shock and define the cell populations responsible for CXCR3- mediated pathobiology. These studies will define the mechanisms that regulate CXCL10 production in vivo. Emphasis will be placed on evaluating the importance of interferon signaling pathways. Further studies are proposed to determine the functional importance of CXCR3-mediated lymphocyte trafficking during severe sepsis and whether CXCR3 serves as an activating factor for non-migratory lymphocyte populations.