Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance
项目 2:用于心脏同种异体移植耐受的下一代混合嵌合诱导
基本信息
- 批准号:10270361
- 负责人:
- 金额:$ 66.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAllograft ToleranceAllograftingAntibodiesAntibody-drug conjugatesBone Marrow Stem CellCellsChestChimerismChronicClinicClinicalDataDefectDevelopmentEngraftmentGoalsHalf-LifeHeart DiseasesHeart TransplantationHematopoieticHematopoietic Stem Cell subsetsHomeostasisHumanImmune ToleranceImmunityImmunosuppressionKidneyLifeLungLymphoproliferative DisordersMarrowMethodsMorbidity - disease rateMusMutationOrganPTPRC genePatient riskPatientsProto-Oncogene Protein c-kitProtocols documentationRegimenRegulatory T-LymphocyteRiskRosaniline DyesSafetySirolimusStem cell transplantTNFSF4 geneTestingTherapeuticToxic effectTranslatingTranslationsTransplant RecipientsTransplantation Toleranceallograft rejectionbasecancer riskclinical translationclinically translatableconditioningdesigngenotoxicitygraft vs host diseaseheart allograftheart-lung allografthigh riskimmunomodulatory strategyimmunoregulationimprovedinnovationirradiationlung allograftmTOR inhibitionmortalitynext generationnonhuman primatenovelnovel strategiespost-transplantpreservationpreventstem cellssuccess
项目摘要
PROJECT SUMMARY / ABSTRACT
Heart transplantation represents the best therapeutic option for patients with end-stage cardiac disease.
However, while one-year success rates are reasonable, heart transplant recipients encounter high rates of
morbidity and mortality, both from allograft rejection and from immunosuppression-associated toxicities. Given
these issues, the ultimate goal is immune tolerance induction, which promises life-long graft acceptance without
chronic immunosuppression. While tolerance to kidneys has been achieved in non-human primates (NHPs) and
in humans with transient mixed chimerism, the same protocols have failed to induce tolerance to heart (and lung)
allografts. Importantly, although lung allografts will not be studied in this Project, our recent findings in lung
recipients provide proof of principle that durable mixed chimerism can be achieved in NHP thoracic allograft
recipients which results in long term tolerance. This represents a major advance. However, this first success
employed agents that are not currently clinically available, and conferred ongoing risks of graft-versus-host
disease (GVHD) and of post-transplant lymphoproliferative disorder. These data, along with murine studies,
suggest that durable mixed chimerism represents a robust platform for thoracic organ tolerance induction, but
that improved strategies are needed, with a focus on preventing GVHD, preserving protective immunity, and
rapid clinical translation. In this Project, we will address three major hurdles in translating durable chimerism-
based strategies for heart transplant tolerance to the clinic: (A) Controlling graft versus host disease (GVHD)
during chimerism-induction; (B) Developing novel methods of recipient conditioning that are non-genotoxic; and
(C) Inducing chimerism using the safest and most efficiently engrafting subset of hematopoietic stem cells. We
will do so by completing the following Specific Aims: Specific Aim 1: To induce durable mixed chimerism, optimize
Treg homeostasis and preserve protective immunity with OX40L blockade and mTOR inhibition. Specific Aim
2: To develop toxicity-free induction by using antibody-drug conjugate (ADC)-based non-genotoxic conditioning
to induce durable mixed-chimerism and transplant tolerance. Specific Aim 3: To induce durable chimerism with
a highly purified subset of stem cells capable of rapid multilineage engraftment. If successful, this project will
optimize durable chimerism induction strategies for heart allograft tolerance, amenable to immediate clinical
translation.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Leslie S Kean其他文献
Leslie S Kean的其他文献
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{{ truncateString('Leslie S Kean', 18)}}的其他基金
Project 2: The New Era of Cellular Therapies For Lung Transplant Tolerance
项目 2:肺移植耐受细胞疗法的新时代
- 批准号:
10622128 - 财政年份:2023
- 资助金额:
$ 66.32万 - 项目类别:
Defining the T Cell Mediators of Clinical Response in Chronic GVHD
定义慢性 GVHD 临床反应的 T 细胞介质
- 批准号:
10698167 - 财政年份:2022
- 资助金额:
$ 66.32万 - 项目类别:
Defining the T Cell Mediators of Clinical Response in Chronic GVHD
定义慢性 GVHD 临床反应的 T 细胞介质
- 批准号:
10493799 - 财政年份:2022
- 资助金额:
$ 66.32万 - 项目类别:
Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance
项目 2:用于心脏同种异体移植耐受的下一代混合嵌合诱导
- 批准号:
10457401 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance
项目 2:用于心脏同种异体移植耐受的下一代混合嵌合诱导
- 批准号:
10673079 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency
低剂量与中剂量白消安治疗严重联合免疫缺陷移植的随机研究
- 批准号:
10474806 - 财政年份:2017
- 资助金额:
$ 66.32万 - 项目类别:
Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency
低剂量与中剂量白消安治疗严重联合免疫缺陷移植的随机研究
- 批准号:
10683141 - 财政年份:2017
- 资助金额:
$ 66.32万 - 项目类别:
Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency
低剂量与中剂量白消安治疗严重联合免疫缺陷移植的随机研究
- 批准号:
10474994 - 财政年份:2017
- 资助金额:
$ 66.32万 - 项目类别:
Integrated Molecular and Cellular Immunology Core
综合分子和细胞免疫学核心
- 批准号:
8705988 - 财政年份:2014
- 资助金额:
$ 66.32万 - 项目类别:
相似海外基金
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针对先天免疫诱导强大的肾同种异体移植耐受
- 批准号:
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- 资助金额:
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- 批准号:
10622127 - 财政年份:2023
- 资助金额:
$ 66.32万 - 项目类别:
Bcl-2 and Mcl-1 inhibition for induction of hematopoietic chimerism and renal allograft tolerance without myelosuppression in nonhuman primates
在非人灵长类动物中抑制 Bcl-2 和 Mcl-1 可诱导造血嵌合和肾同种异体移植耐受,而无需骨髓抑制
- 批准号:
10634698 - 财政年份:2022
- 资助金额:
$ 66.32万 - 项目类别:
Project 3: Enhanced Costimulation Blockade to Achieve Clinically Relevant Heart Allograft Tolerance
项目 3:增强共刺激阻断以实现临床相关的同种异体移植心脏耐受性
- 批准号:
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- 资助金额:
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New Approaches to Inducing Cardiac Allograft Tolerance
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- 批准号:
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- 资助金额:
$ 66.32万 - 项目类别:
New Approaches to Inducing Cardiac Allograft Tolerance
诱导心脏同种异体移植耐受的新方法
- 批准号:
10457397 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
New Approaches to Inducing Cardiac Allograft Tolerance
诱导心脏同种异体移植耐受的新方法
- 批准号:
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$ 66.32万 - 项目类别:
Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance
项目 2:用于心脏同种异体移植耐受的下一代混合嵌合诱导
- 批准号:
10457401 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Project 3: Enhanced Costimulation Blockade to Achieve Clinically Relevant Heart Allograft Tolerance
项目 3:增强共刺激阻断以实现临床相关的同种异体移植心脏耐受性
- 批准号:
10270362 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别: