Immunosuppression-free islet transplantation via localized immunomodulatory exosome tethering
通过局部免疫调节外泌体束缚进行无免疫抑制的胰岛移植
基本信息
- 批准号:10610867
- 负责人:
- 金额:$ 22.33万
- 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:2022-04-19 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAllogenicAmericanAntigen PresentationAntigen Presentation PathwayAntigen-Presenting CellsAntigensBindingBiologicalBlood GlucoseCell TherapyCell TransplantationCellsChronicClinicalDevelopmentDevicesDiffusionDiseaseDoseEncapsulatedEngineeringEnvironmentFlow CytometryGeneral PopulationGraft SurvivalHistologyHumanHydrogelsImmuneImmune ToleranceImmune mediated destructionImmune responseImmune systemImmunosuppressionIn VitroInflammatoryInsulinInsulin-Dependent Diabetes MellitusIslets of Langerhans TransplantationLabelLifeMalignant NeoplasmsMaternal-Fetal ExchangeMediatingMethodsMissionMorbidity - disease rateOrgan TransplantationOutcomePhysiologic tolerancePlacentaProceduresProtein ArrayProtocols documentationPublic HealthReactionRegimenReplacement TherapyResearchRiskSchemeSignal TransductionSiteSolidSurfaceTissue TransplantationTissuesTitrationsTransplant RecipientsTransplantationUnited States National Institutes of HealthWorkblood glucose regulationdiabetes riskdiabetic patientexosomeexperimental studyfetalfluorescence imagingimmune clearanceimmune modulating agentsimmunoregulationimproved outcomein vivoin vivo imaginginfection riskinsulin signalinginterestisletmethod developmentpreventresponseside effectsuccesssynergismtooltrophoblasttype I diabetic
项目摘要
PROJECT SUMMARY/ABSTRACT
Clinical islet transplantation is a promising treatment for insulin-dependent diabetic patients, with the
potential to eliminate long-term secondary complications by restoring native insulin signaling. While clinical
successes have demonstrated the feasibility of achieving insulin independence through islet replacement
therapy, the necessity of a long-term immunosuppressive regimen limits the widespread applicability of this
procedure, as the substantial risk associated with chronic immunosuppression outweighs the risk of diabetes
associated morbidities. As a result, there is great interest in the development of macroencapsulation devices to
isolate transplanted cells from the recipient immune system, with the intent to eliminate immune recognition via
the direct antigen presentation pathway. While this strategy can reduce immune response to the graft,
encapsulation cannot prevent the diffusion of shed antigens, which activate immune cells via the indirect antigen
presentation pathway to ultimately target and destroy the transplanted cells. As such, a synergistic approach to
macroencapsulation is required to fully ameliorate the immune response to islet grafts.
The placental microenvironment is a unique biological example of localized, normal physiological
tolerance, maintained by trophoblasts at the fetal-maternal interface via two mechanisms: (1) creating a barrier
to prevent contact between allogeneic tissue and host, and (2) localized presentation and secretion of
immunomodulatory factors to induce tolerogenic innate and adaptive immune cells. One potent method by which
trophoblasts deliver immunomodulatory payloads is via secreted exosomes. We aim to mimic these two
mechanisms of trophoblast-mediated tolerance through encapsulating islets in an immunoisolating hydrogel
device and tethering immunomodulatory trophoblast-derived exosomes to the device surface.
We hypothesize that localized presentation of immunomodulatory trophoblast-derived exosomes at the
surface of a synthetic hydrogel macroencapsulation device will synergize with immunoisolation to produce
localized immune tolerance to the graft. We anticipate that localized exosome presentation will result in local
tolerance to the graft by inducing tolerogenic innate and adaptive immune cells at the site of transplantation.
Encapsulation within the hydrogel device will prevent direct antigen presentation, and surface-bound exosomes
will induce tolerogenic antigen presenting cells, preventing immune destruction via indirect antigen recognition.
These hypotheses will be addressed in the experiments of the following Specific Aims: (1) Engineer an
immunomodulating exosome-presenting synthetic hydrogel-based macroencapsulation device; and (2) Evaluate
immunomodulatory macroencapsulation device impact on the localized graft immune environment. We
anticipate that this study will demonstrate the immunosuppressive capacity of tolerogenic trophoblast exosomes,
and their potential for synergy with islet encapsulation.
项目总结/文摘
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Engineering of Trophoblast Extracellular Vesicle-Delivering Hydrogels for Localized Tolerance Induction in Cell Transplantation.
用于细胞移植中局部耐受诱导的滋养层细胞外囊泡递送水凝胶的工程。
- DOI:10.1007/s12195-023-00778-8
- 发表时间:2023
- 期刊:
- 影响因子:2.8
- 作者:Hiremath,ShivaniC;Weaver,JessicaD
- 通讯作者:Weaver,JessicaD
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{{ truncateString('Jessica Diane Weaver', 18)}}的其他基金
Immunosuppression-free islet transplantation via localized immunomodulatory exosome tethering
通过局部免疫调节外泌体束缚进行无免疫抑制的胰岛移植
- 批准号:
10348870 - 财政年份:2022
- 资助金额:
$ 22.33万 - 项目类别:
Immunosuppression-free transplantation through placental mimicry
通过胎盘拟态进行无免疫抑制移植
- 批准号:
10244763 - 财政年份:2021
- 资助金额:
$ 22.33万 - 项目类别:
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