Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
基本信息
- 批准号:8208131
- 负责人:
- 金额:$ 29.55万
- 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:2008-03-01 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adoptive TransferAffectAllogeneic Bone Marrow TransplantationAllogenicAllograftingAnimalsAntigen-Presenting CellsAntigensBiologyBloodBlood donorCancer VaccinesCell CommunicationChimera organismChimerismClinicDataDendritic CellsDendritic cell activationDevelopmentDonor Lymphocyte InfusionEmigrationsExhibitsGoalsGraft-Versus-Tumor InductionHematopoieticImiquimodImmunityLangerhans cellLeadLigandsMediatingModelingMolecularOligonucleotidesOutcomePatientsPeripheralPlayRelapseRelative (related person)ResearchResidual stateRisk FactorsRoleSkinSourceStem cellsT-LymphocyteTherapeuticToll-like receptorsTranslatingTransplantationTumor ImmunityVaccinationVaccinesWorkabstractingbasegraft vs host diseasehuman TLR7 proteinimprovedin vivoleukemialymph nodesnovel strategiesnovel therapeuticsreceptor-mediated signalingreconstitutionresponsetumorvaccine-induced immunity
项目摘要
Abstract:
The broader, long-term objectives of this proposal are to dissect the mechanisms governing
alloimmune responses of adoptively transferred donor T cells after their administration to established
allogeneic chimeras and to use this data to develop clinically translatable strategies to augment anti-
tumor immunity. Our preliminary studies suggest that after MHC-matched allografting, host-derived
dendritic cells (DCs) persist in the skin, despite the apparent full donor DC chimerism in the blood and
ongoing graft-versus-leukemia (GVL) responses. Furthermore, we found that adoptive transfer of donor
T cells to allogeneic MHC-matched chimeras, in which all blood DCs are of donor origin, can lead to
graft-versus-host (GVH) reactivity toward residual host skin DCs. Interestingly, DLI administration to
chimeras that have been topically treated with the Toll-like receptor (TLR)7 ligand, imiquimod, not only
augmented the DLI-mediated GVH reactivity, but also the GVL response. These responses, if
combined with tumor vaccination, resulted in the ability of treated animals to exhibit an anamnestic
response to tumor re-challenge. Accordingly, the central hypothesis of this proposal is that donor T
cell?host skin DC interactions play a principal role in the induction of an alloimmune response
in complete donor chimeras post-transplant; and, moreover, that the outcome of these
responses can be manipulated in vivo with defined molecular ligands and tumor vaccines to
result in long-lasting anti-tumor immunity.
To investigate this hypothesis, the following specific aims are proposed: 1) To characterize the
cellular and molecular mechanisms governing T cell?DC interactions post MHC-matched
allografting. These studies will determine the roles of host and donor DCs on the DLI-mediated GVH
and GVL reactivities and characterize the role of TLR-mediated signaling; and 2) To determine the
role of T cell?DC interactions on the vaccine-induced responses after allografting. These
studies will examine the functional significance of residual host skin DCs and donor blood DCs on the
induction of antigen-specific T cells and vaccine-induced immunity. The immediate goal of the studies
described in this proposal is to develop novel therapeutic strategies that may lead to improved anti-
tumor immunity; the long-term goal is to translate these findings to the clinic. Scope of the work:
The central hypothesis behind this proposal is that interactions between donor T cells and residual
host skin DCs play a principal role in the induction of alloimmune responses in complete donor
chimeras post-transplant and that outcome of these responses can be manipulated in vivo with defined
molecular ligands and tumor vaccine resulting in long-lasting anti-tumor immunity. Thus, the goal of the
proposed study is to dissect the mechanisms governing alloimmune responses in established MHC-
matched allogeneic chimeras and to use this data to develop clinically translatable strategies to
augment anti-tumor immunity.
摘要:
这项建议的更广泛的长期目标是剖析管理
过继转移的供体T细胞在给予建立的免疫系统后的同种免疫应答
同种异体嵌合体,并使用这些数据来开发临床上可翻译的策略,以增加抗-
肿瘤免疫我们的初步研究表明,在MHC匹配的同种异体移植后,
树突状细胞(DC)持续存在于皮肤中,尽管血液中存在明显的完全供体DC嵌合体,
持续的移植物抗白血病(GVL)反应。此外,我们发现供体的过继转移
T细胞与同种异体MHC匹配的嵌合体,其中所有的血液DC都是供体来源的,可以导致
移植物抗宿主(GVH)反应性对残留的宿主皮肤DC。有趣的是,DLI管理
已经用Toll样受体(TLR)7配体咪喹莫特局部治疗的嵌合体,不仅
增强了DLI介导的GVH反应性,但也增强了GVL反应。这些反应,如果
与肿瘤疫苗接种相结合,导致治疗动物表现出记忆恢复的能力。
对肿瘤再激发的反应。因此,该提议的中心假设是,供体T
手机?宿主皮肤DC相互作用在同种免疫应答的诱导中起主要作用
在移植后的完全供体嵌合体中;而且,这些结果
可以用确定的分子配体和肿瘤疫苗在体内操纵应答,
产生持久的抗肿瘤免疫力。
为了研究这一假设,提出了以下具体目标:1)表征
控制T细胞的细胞和分子机制?MHC匹配后的DC相互作用
同种异体移植这些研究将确定宿主和供体DC在DLI介导的GVH中的作用
和GVL反应性并表征TLR介导的信号传导的作用;和2)为了确定TLR介导的信号传导的作用,
T细胞的作用?同种异体移植后疫苗诱导反应的DC相互作用。这些
研究将检查残留的宿主皮肤DC和供体血液DC对移植物的功能意义。
抗原特异性T细胞的诱导和疫苗诱导的免疫力。研究的直接目标是
在这项建议中描述的是开发新的治疗策略,可能会导致改善抗-
肿瘤免疫;长期目标是将这些发现转化为临床。工作范围:
这一提议背后的核心假设是,供体T细胞和残余T细胞之间的相互作用可能是一种免疫反应。
宿主皮肤DC在诱导完全供体的同种免疫应答中起主要作用
移植后嵌合体,这些反应的结果可以在体内用定义的
分子配体和肿瘤疫苗,产生持久的抗肿瘤免疫。因此,
拟议的研究是剖析在已建立的MHC中控制同种免疫反应的机制,
匹配的同种异体嵌合体,并使用这些数据来开发临床可翻译的策略,
增强抗肿瘤免疫力。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Induction of Major Histocompatibility Complex-mismatched Mouse Lung Allograft Acceptance With Combined Donor Bone Marrow: Lung Transplant Using a 12-Hour Nonmyeloablative Conditioning Regimen.
- DOI:10.1097/tp.0000000000001480
- 发表时间:2016-12
- 期刊:
- 影响因子:6.2
- 作者:Dodd-O JM;Ganguly S;Vulic A;Panoskaltsis-Mortari A;McDyer JF;Luznik L
- 通讯作者:Luznik L
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Leo Luznik其他文献
Leo Luznik的其他文献
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{{ truncateString('Leo Luznik', 18)}}的其他基金
MECHANISMS OF GVHD PREVENTION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
移植后环磷酰胺预防 GVHD 的机制
- 批准号:
8392233 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
MECHANISMS OF GVHD PREVENTION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
移植后环磷酰胺预防 GVHD 的机制
- 批准号:
8766561 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
MECHANISMS OF GVHD PREVENTION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
移植后环磷酰胺预防 GVHD 的机制
- 批准号:
8582562 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
MECHANISMS OF GVHD PREVENTION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
移植后环磷酰胺预防 GVHD 的机制
- 批准号:
8269451 - 财政年份:2011
- 资助金额:
$ 29.55万 - 项目类别:
Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
- 批准号:
7466112 - 财政年份:2008
- 资助金额:
$ 29.55万 - 项目类别:
Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
- 批准号:
8010394 - 财政年份:2008
- 资助金额:
$ 29.55万 - 项目类别:
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