Resistance of Beta 2 Microglobulin Null Mice to Sepsis

描述（由申请人提供）：在当前资助期内，我们在确定CXC趋化因子受体3 （CXCR3）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，CXCR3是盲肠结扎和穿刺（CLP）引起的脓毒性休克中自然杀伤细胞运输的重要调节因子。此外，CXCR3缺乏或阻断可显著减弱败血症诱导的生理功能障碍、全身细胞因子的产生和生存。CXCR3配体CXCL10的缺乏或阻断也对clp诱导的感染性休克具有保护作用。在CLP后6小时，通过液体和抗生素给予抗cxcr3 IgG或抗CXCL10 IgG，可获得生存益处。因此，在脓毒症发作后开始CXCR3阻断是有效的，并且可能是治疗脓毒症休克的多模式方法的可行补充。然而，关于CXCR3阻断在临床相关脓毒症模型中的有效性以及CXCR3轴在脓毒症期间被激活的机制，仍存在一些问题。本研究项目的目标有两个方面：1)评估CXCR3阻断的临床相关方法，以使该方法更接近临床应用；2)确定CXCR3激活促进脓毒性休克发病的机制，并确定脓毒症期间CXCR3轴被激活的细胞和分子机制。特异性目的1：明确CXCR3阻断在脓毒症临床相关模型中的疗效。在这个目的中，我们将评估在严重脓毒症发作后启动CXCR3阻断的疗效，这表明了灌注不足和器官损伤的发展。CLP模型以及我们已经建立的铜绿假单胞菌和金黄色葡萄球菌烧伤创面脓毒症模型将被利用。除了基于免疫球蛋白的策略外，还将确定小分子量CXCR3抑制剂AMG487的疗效。特异性目的2：确定CXCR3轴在宿主对感染反应中的作用。最近的一些研究表明，在不太严重的全身性感染模型中，CXCL10在促进有效的细菌清除机制中发挥作用。本目的研究将确定CXCR3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CXCR3轴是否会使宿主易发生继发性感染。特异性目的3：确定脓毒性休克期间CXCR3轴被激活的机制，并确定负责CXCR3介导的病理生物学的细胞群。这些研究将确定体内调节CXCL10产生的机制。重点将放在评估干扰素信号通路的重要性。在严重脓毒症中，CXCR3介导的淋巴细胞运输的功能重要性以及CXCR3是否作为非迁移淋巴细胞群的激活因子有待进一步研究。

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.