The novel role of beta3 integrin in regulating alloimmunity
β3整合素在调节同种免疫中的新作用
基本信息
- 批准号:10573306
- 负责人:
- 金额:$ 76.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-14 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdhesionsAllograftingAntigen PresentationBiologyBlood PlateletsBlood VesselsCD8-Positive T-LymphocytesCell CommunicationCell Surface ReceptorsCellsCellular ImmunityChronicDataDrug Delivery SystemsEncapsulatedEndothelial CellsEngraftmentExtracellular MatrixFamilyGoalsGraft RejectionHeart DiseasesHeart TransplantationITGB3 geneImmuneImmune ToleranceImmunosuppressive AgentsImpairmentInflammationInflammatory ResponseIntegrinsInterdisciplinary StudyKnockout MiceLesionMediatingMembrane ProteinsMethodsMusNanodeliveryNatural ImmunityOrganOrgan TransplantationOrgan failureOutcomePathogenesisPatientsPerfusionPeriodicityPlayRGD (sequence)Reperfusion InjuryRoleSignal TransductionSiteT cell infiltrationT-Cell ActivationT-LymphocyteTestingTherapeuticTimeTransplant RecipientsTransplantationWild Type Mouseadaptive immunityallograft rejectionantagonistcell motilitycell typeconditional knockoutcytokineheart allograftimprovedinflammatory milieuinflammatory modulationinnovationinsightisoimmunitymigrationmouse modelnanoparticlenew therapeutic targetnovelnovel strategiesnovel therapeutic interventionoptimal treatmentspreventrecruitresponseside effecttargeted deliverytrafficking
项目摘要
Abstract
Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, a
several challenges remain to improve allograft and recipient survival. Immunosuppressive agents used to
prevent rejection have improved, but they still cannot consistently eliminate acute and chronic rejection, and they
are implicated in the pathogenesis of organ failure. New insights into how innate and adaptive immunity
contribute to rejection, identification of new therapeutic targets, and novel approaches to promote immune
tolerance are major unmet needs in transplantation. Early innate inflammatory responses in the organs (e.g.,
due to ischemia-reperfusion injuries) enhance acute and chronic heart allograft rejection. Integrins are
heterodimeric cell surface receptors involved in immune cell trafficking and signaling; therefore, they are
attractive targets to inhibit inflammation, including transplant rejection. The main goal of this project is to elucidate
the novel role of β3 integrin in regulating alloimmune responses via control of platelet- and T cell- mediated
immunity. Our ultimate objective is to develop new anti-β3 integrin-based strategies to promote engraftment. Our
data indicate that β3 integrin-/- mice (β3-/-) show significantly prolonged heart allograft survival in comparison to
wild-type (WT) mice, a finding that is associated with reduced CD8+ T cell infiltration into the grafts. We also
show that β3 is expressed by activated CD8+ T cells, and that the trafficking of T cells from β3-/- mice is impaired.
Notably, targeting β3 integrin also substantially reduces lesions typical of chronic rejection. The β3 subunit is
shared by the two integrin molecules, αVβ3 and αIIbβ3, which are expressed by T cells and platelets,
respectively. Based on extensive preliminary data, our specific hypothesis is that β3 on both cell types
contributes to rejection. In this proposal, we aim to define the relative roles of β3 integrins expressed on platelets
(in early promotion of inflammatory responses) and T cells (in enhancement of alloimmunity) in mediating
allograft rejection. Furthermore, our targeted delivery method of therapeutics usingnanoparticles (NPs) has
emerged as a promising method that increases efficacy and reduces side effects. Here, we have developed first-
in-class NPs for targeted delivery of cyclic RGD tripeptides (cRGD) to suppress β3 integrin- mediated recruitment
of platelets and T cells for early reduction of chronic rejection, using a murine model of heart transplantation. In
this proposal, we present three main aims to determine the roles of αIIbβ3 on platelets (Aim 1) and T cell-
expressed β3 (Aim 2) in regulating alloimmunity. In Aim 3, we will perfuse organs prior to transplantation with
NPs carrying cRGD to promote graft acceptance.
摘要
项目成果
期刊论文数量(0)
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Reza Abdi其他文献
Reza Abdi的其他文献
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{{ truncateString('Reza Abdi', 18)}}的其他基金
Targeted immune therapies in heart transplantation
心脏移植中的靶向免疫治疗
- 批准号:
10573846 - 财政年份:2023
- 资助金额:
$ 76.13万 - 项目类别:
The novel role of beta3 integrin in regulating alloimmunity
β3整合素在调节同种免疫中的新作用
- 批准号:
10467425 - 财政年份:2022
- 资助金额:
$ 76.13万 - 项目类别:
New way in delivering immunomodulatory drugs in T1D
在 T1D 中提供免疫调节药物的新方法
- 批准号:
10576373 - 财政年份:2022
- 资助金额:
$ 76.13万 - 项目类别:
New way in delivering immunomodulatory drugs in T1D
在 T1D 中提供免疫调节药物的新方法
- 批准号:
10457732 - 财政年份:2022
- 资助金额:
$ 76.13万 - 项目类别:
Lymph nodes at the crossroads of allo immunity and regulation
淋巴结处于同种异体免疫和调节的十字路口
- 批准号:
10662304 - 财政年份:2020
- 资助金额:
$ 76.13万 - 项目类别:
HVEM pathway regulating FRC function and transplant tolerance
HVEM 通路调节 FRC 功能和移植耐受
- 批准号:
10662313 - 财政年份:2020
- 资助金额:
$ 76.13万 - 项目类别:
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