rBPI21 & Endotoxin-directed Innate Immunity in Stem Cell Transplantation
重组BPI21
基本信息
- 批准号:7465106
- 负责人:
- 金额:$ 26.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Graft Versus Host DiseaseAddressAlloantigenAllogenicAnimal ModelBenignBindingBiologicalBlood CirculationCD14 AntigenClinicalClinical TrialsCohort StudiesCytoplasmic GranulesDataDiseaseDoseDrug KineticsElementsEnd PointEndotoxemiaEndotoxinsEventFunctional disorderGoalsHematopoietic Stem Cell TransplantationHumanImmuneImmune responseImmunosuppressive AgentsIn VitroIndividualInflammationInflammatory ResponseInfusion proceduresIntestinesIntravenousLaboratoriesLipopolysaccharidesMalignant - descriptorMarrowMediatingModelingMolecularMorbidity - disease rateN-terminalNatural ImmunityPatientsPeripheralPhasePilot ProjectsPlasmaPopulationProductionProtein DeficiencyProtein FragmentProteinsPublic HealthReactionRecombinantsRiskRoleSafetyScheduleSpecificitySpiral Computed TomographyStem cell transplantT-LymphocyteTLR4 geneTNF geneTimeTissuesToxic effectTransplantationTreatment Protocolsbactericidal permeability increasing proteincohortconditioningcytokinedesignendotoxin receptorhuman studyin vivointravenous administrationmonocytemortalityneutrophilnovelnovel therapeuticsrBPI21research studyresponsesuccess
项目摘要
DESCRIPTION (provided by applicant): The impact of hematopoietic stem cell transplantation (HSCT), a potentially curative therapy for both malignant and benign lymphohematopoietic diseases, is limited by acute graft-versus-host disease (aGVHD). Both animal models and human studies indicate that an important trigger of aGVHD is lipopolysaccharide (LPS, or endotoxin) that is believed to enter the peripheral circulation as a consequence of intestinal damage due to myeloablative conditioning regimens. Our preliminary data demonstrate that myeloablative HSCT is associated with severely diminished plasma levels of bactericidal/permeability-increasing protein (BPI), a neutrophil- derived molecule with potent and specific LPS-neutralizing activity. Thus, patients undergoing myeloablative HSCT are endotoxemic at a time when an endogenous anti-endotoxin defense, BPI, is severely deficient. We hypothesize that BPI deficiency compromises the ability of individuals undergoing HSCT to neutralize LPS, increasing risk for LPS-induced TNF-1 production and other downstream events that result in an increased risk for aGVHD and regimen-related toxicity. The premise of the proposed clinical trial is that early infusion of a bioactive recombinant N-terminal BPI fragment (rBPI21, Opebacan; XOMA U.S. LLC) with potent endotoxin- neutralizing activity and demonstrated safety in human clinical trials, will replace the deficient BPI thereby rapidly shielding patients from endotoxin-induced inflammatory responses. In Specific Aim 1, we will determine the tolerability and pharmacokinetics of rBPI21 in BPI-deficient HSCT recipients in order to establish an understanding of the dose and schedule that will effectively block LPS mediated toxicity. The effects of rBPI21 infusion on the endotoxin-modulating activity of plasma will be investigated in Specific Aim 2. Specific Aim 3 will focus on determining the effect of rBPI21 infusion on the functional expression of the endotoxin receptor composed of MD-2, TLR4, and mCD14. This clinical experiment and its biological endpoints will establish whether rBPI21 modulates endotoxin mediated pathophysiology in HSCT patients. Moreover, the data derived from the proposed experiments will provide the necessary clinical and scientific information to design pivotal studies that will examine the potential of this novel and uniquely non-immunosuppressive approach to ameliorate one of the major causes of HSCT morbidity and mortality. PUBLIC HEALTH RELEVANCE: The success of hematopoietic stem cell transplantation, a potentially curative therapy for many diseases, is limited by acute graft-versus-host disease (aGVHD). Our preliminary data demonstrate that myeloablative transplant is associated with severely diminished plasma levels of the endotoxin-neutralizing protein (BPI), thereby increasing risk for endotoxin-induced events that result in aGVHD and other toxicities. Here, we will conduct a clinical trial and laboratory experiments to determine whether administering BPI will bind endotoxin and shield patients from endotoxin-induced inflammatory responses that trigger transplant toxicity including aGVHD.
描述(由申请人提供):造血干细胞移植(HSCT)是一种治疗恶性和良性淋巴造血疾病的潜在治疗方法,其影响受到急性移植物抗宿主病(aGVHD)的限制。动物模型和人体研究都表明,aGVHD的一个重要触发因素是脂多糖(LPS,或内毒素),据认为,由于清髓调节方案引起的肠道损伤,脂多糖或内毒素会进入外周循环。我们的初步数据表明,清髓性造血干细胞移植与血浆中杀菌/通透性增加蛋白(BPI)水平严重降低有关,BPI是一种中性粒细胞衍生的分子,具有强效和特异性的lps中和活性。因此,在内源性抗内毒素防御系统(BPI)严重缺乏的时候,接受清髓性造血干细胞移植的患者是内毒素中毒的。我们假设BPI缺乏损害了接受HSCT的个体中和LPS的能力,增加了LPS诱导的TNF-1产生的风险和其他下游事件,导致aGVHD和方案相关毒性风险增加。提出的临床试验的前提是,早期输注具有生物活性的重组n端BPI片段(rBPI21, Opebacan; XOMA U.S. LLC),具有有效的内毒素中和活性,并在人体临床试验中证明了安全性,将取代缺乏的BPI,从而迅速保护患者免受内毒素诱导的炎症反应。在Specific Aim 1中,我们将确定rBPI21在缺乏bpi的HSCT受者中的耐受性和药代动力学,以便了解有效阻断LPS介导的毒性的剂量和时间表。rBPI21输注对血浆内毒素调节活性的影响将在Specific Aim 2中进行研究。特异性Aim 3将侧重于确定rBPI21输注对MD-2、TLR4和mCD14组成的内毒素受体功能表达的影响。本临床实验及其生物学终点将确定rBPI21是否调节HSCT患者内毒素介导的病理生理。此外,从实验中获得的数据将为设计关键研究提供必要的临床和科学信息,这些研究将检验这种新颖且独特的非免疫抑制方法的潜力,以改善HSCT发病率和死亡率的主要原因之一。公共卫生相关性:造血干细胞移植作为一种治疗许多疾病的潜在疗法,其成功受到急性移植物抗宿主病(aGVHD)的限制。我们的初步数据表明,清髓移植与血浆内毒素中和蛋白(BPI)水平严重降低相关,从而增加内毒素诱导事件导致aGVHD和其他毒性的风险。在这里,我们将进行一项临床试验和实验室实验,以确定给予BPI是否会结合内毒素并保护患者免受内毒素诱导的炎症反应,这些炎症反应会引发包括aGVHD在内的移植毒性。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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EVA C GUINAN其他文献
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{{ truncateString('EVA C GUINAN', 18)}}的其他基金
26th Annual Fanconi Anemia Research Fund Scientific Symposium
第26届范可尼贫血研究基金年度科学研讨会
- 批准号:
8786035 - 财政年份:2014
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$ 26.63万 - 项目类别:
In vivo irradiations with patients undergoing radiation therapy: dana farber canc
接受放射治疗的患者的体内照射:达纳法伯癌症
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8013161 - 财政年份:2010
- 资助金额:
$ 26.63万 - 项目类别:
Ex Vivo Alloanergization to Improve Immunity After Haploidentical Transplant
离体同种异能提高单倍体移植后的免疫力
- 批准号:
7772239 - 财政年份:2009
- 资助金额:
$ 26.63万 - 项目类别:
Ex Vivo Alloanergization to Improve Immunity After Haploidentical Transplant
离体同种异能提高单倍体移植后的免疫力
- 批准号:
7656464 - 财政年份:2009
- 资助金额:
$ 26.63万 - 项目类别:
rBPI21 & Endotoxin-directed Innate Immunity in Stem Cell Transplantation
重组BPI21
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7597147 - 财政年份:2008
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$ 26.63万 - 项目类别:
CELLULAR CORRECTION OF CONGENITAL HEMATOPOIETIC DISORDERS
先天性造血障碍的细胞纠正
- 批准号:
6660971 - 财政年份:2002
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$ 26.63万 - 项目类别:
CELLULAR CORRECTION OF CONGENITAL HEMATOPOIETIC DISORDERS
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