IL-22 in epithelial regeneration after allogeneic transplant
IL-22在同种异体移植后上皮再生中的作用
基本信息
- 批准号:8354485
- 负责人:
- 金额:$ 13.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Graft Versus Host DiseaseAdvisory CommitteesAgeAgingAllogenicAutoimmunityAwardBenignBiological ModelsBiologyCD4 Positive T LymphocytesCeliac DiseaseCell physiologyCellsClinicalClinical OncologyCombined Modality TherapyDataDevelopmentDiseaseEngineeringEnsureEnvironmentEpithelialEpitheliumExperimental ModelsFunctional disorderFundingGenerationsGeneric DrugsGeneticGoalsGrantHealedHelper-Inducer T-LymphocyteHematological DiseaseHematologyHematopoieticHomologous TransplantationImmuneImmune responseImmune systemImmunityImmunobiologyImmunologyImmunosuppressionIndividualInfectionInflammatoryInflammatory Bowel DiseasesIntestinal Graft Versus Host DiseaseIntestinesLaboratoriesLeadLymphoid CellLymphomaMaintenanceMalignant - descriptorMedical OncologyMedicineMemorial Sloan-Kettering Cancer CenterMentorsMentorshipMorbidity - disease rateMusNatural regenerationNon-MalignantOrganPathologyPathway interactionsPatientsPhysiciansPlayPre-Clinical ModelPrevention strategyQuality of lifeRadiationRadioRecombinant InterleukinsResearchResearch PersonnelResistanceRoleScientistShockSpecificityStem cellsT-LymphocyteTarsTechniquesTestingTherapeuticThromboplastinThymeThymus GlandTissuesToxic effectTrainingTranslatingTranslationsTransplant RecipientsTransplantationTransplanted tissuecareercareer developmentchemotherapyconditioningcytokineexpression vectorgastrointestinalgraft vs host diseasegraft vs leukemia effecthealingimmune functionimprovedin vivoinsightinterleukin-21interleukin-22intestinal epitheliumleukemialeukemia/lymphomamortalitynanoparticleneutralizing antibodynovelnovel strategiesnovel therapeuticspreclinical studypreventprogramsreceptor expressionreconstitutionresponsestemsuccesstranslational study
项目摘要
DESCRIPTION (provided by applicant): Allogeneic hematopoietic transplantation is a curative therapy for numerous malignant and non-malignant he- matopoietic diseases that are otherwise incurable. Despite decades of intensive research, several major complications remain, including prolonged post-transplant immune deficiency and graft vs. host disease (GVHD). Gastrointestinal GVHD in particular is the predominant contributor to acute GVHD-related mortality, and dam- age to other target organs such as the thymus contributes significantly towards post-transplant immune deficiency. While much progress has been made toward understanding the immune response of the donor graft against the transplant recipient, there is little understanding of how transplant recipients respond to GVHD and its concomitant damage. Furthermore, virtually all strategies available to reduce clinical GVHD do so by limiting the donor immune system at the expense of therapeutic graft vs. leukemia/lymphoma (GVL) responses. IL-22 is a recently characterized cytokine that has been shown to protect intestinal epithelium during experimental inflammatory bowel disease. IL-22 receptor expression is restricted to non-hematopoietic cells, thus providing specificity to recipient epithelium in the transplant setting. Manipulation of this cytokine could there- fore protect epithelial tissues in transplant recipients without altering donor immunity or reducing GVL. Our preliminary data demonstrate that IL-22 is produced post-transplant by radio resistant host-derived innate lymphoid cells. These cells were eliminated during GVHD and deficiency if host-derived IL-22 led to increased GVHD morbidity, mortality, and pathology. Our data also indicate that the intestinal stem cells (ISC) necessary for nor- mal epithelial maintenance are targets of GVHD, and that IL-22 may be critical for the protection of these ISC during GVHD. Finally, our data indicate that IL-22 is critical for protecting the function of thyme epithelium post-transplant, an that IL-22 administration can eliminate thyme damage due to GVHD. We propose to test the hypothesis that IL-22 promotes survival and healing of damaged epithelium during allow- generic transplant. This project aims to: study the effects of IL-22 deficiency on GVHD and conditioning-related epithelial damage in experimental models, and study administration of IL-22 for reduction of post-transplant morbidity and mortality. Our ultimate goal is to develop a novel therapeutic strategy for prevention and treatment of GVHD. Potential therapeutic strategies will be tested in leukemia-bearing mice to ensure that GVL activity is preserved. We anticipate that these translational studies will not only lead to better understanding of immunobiology, intestinal
stem cell physiology, epithelial regeneration, and GVHD pathophysiology, but will also lead to the development novel strategies to reduce epithelial damage post-transplant and improve the lives of transplant patients with both malignant and non-malignant hematopoietic disease. The specific aims are: 1: To study the effects of IL-22 deficiency on GVHD, conditioning-related damage, and post-transplant immune function. We will utilize a combination of IL-22 KO mice and IL-22 neutralizing antibody to assess the role of IL- 22 in target tissues and cells. 2: To study administration of IL-22 for reduction of post-transplant tissue damage and augmentation of post- transplant immunity. We will treat transplants recipients with systemic short-acting recombinant IL-22, induce constitutive IL-22 with an engineered expression vector, and administer IL-22 with intermediate-duration IL-22- loaded nanoparticles to test therapeutic administration strategies. The applicant, Dr. Alan Hanash, a medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) has outlined a five-year career plan that will build upon his background in immunology and clinical oncology/malignant hematology. Under the mentorship of Dr. Marcel van den Brink, a recognized leader in transplant immunology, GVHD, and immune reconstitution post-transplant, Dr. Hanash will utilize translational in vivo pre-clinical models with a combination of genetic deficiencies and cytokine administration approaches to study the role of IL-22 in reducing tissue damage and augmenting immune function after allogeneic transplant. Dr. Hanash will be mentored by an Advisory Committee of internationally recognized experts in the field. Finally, this plan is ideally carried out in the Department of Medicine and Program in Immunology at MSKCC, given its distinguished record for training physician-scientists in a rich and collaborative environment. With the support provided by the K08 award, Dr. Hanash's project will lead to the development of novel biologic insights into the relationship between lymphoid cells and stromal maintenance, as well as clinically effective strategies for promoting this maintenance during inflammatory tissue damage. In addition, the career development goal of this project is to help Dr. Hanash transition into an independent investigator with his own laboratory and R01 funding.
PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic transplantation is a potentially curative treatment for benign and malignant hematologic diseases, however the success of transplantation is limited by complications of graft vs. host-disease and complications of the immunosuppression meant to prevent it. Our preliminary data indicates that IL-22 is a protective factor for the tissues of transplant recipients, and administration of IL-22 may prevent the tissue
damage associated with graft vs. host disease without limiting the critical functions of the donor immune sys- tem. This grant aims to study the mechanisms by which IL-22 may reduce tissue damage in transplant recipients and translate these findings into therapeutic strategies that will improve the survival and quality of life for patients undergoing allogeneic transplantation.
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(1)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alan M Hanash其他文献
Alan M Hanash的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alan M Hanash', 18)}}的其他基金
T cell invasion of the stem cell compartment during immune-mediated GI damage
免疫介导的胃肠道损伤过程中 T 细胞入侵干细胞区室
- 批准号:
10322754 - 财政年份:2021
- 资助金额:
$ 13.68万 - 项目类别:
T cell invasion of the stem cell compartment during immune-mediated GI damage
免疫介导的胃肠道损伤过程中 T 细胞入侵干细胞区室
- 批准号:
10542401 - 财政年份:2021
- 资助金额:
$ 13.68万 - 项目类别:
Alloreactive and autoreactive immune-mediated mechanisms of impaired epithelial regeneration in the GI tract
胃肠道上皮再生受损的同种反应性和自身反应性免疫介导机制
- 批准号:
9770648 - 财政年份:2018
- 资助金额:
$ 13.68万 - 项目类别:
Alloreactive and autoreactive immune-mediated mechanisms of impaired epithelial regeneration in the GI tract
胃肠道上皮再生受损的同种反应性和自身反应性免疫介导机制
- 批准号:
10178081 - 财政年份:2018
- 资助金额:
$ 13.68万 - 项目类别:
Regulation of the intestinal stem cell compartment after hematopoietic transplantation
造血移植后肠道干细胞区室的调节
- 批准号:
9076641 - 财政年份:2015
- 资助金额:
$ 13.68万 - 项目类别:
Regulation of the intestinal stem cell compartment after hematopoietic transplantation
造血移植后肠道干细胞区室的调节
- 批准号:
8911079 - 财政年份:2015
- 资助金额:
$ 13.68万 - 项目类别:
IL-22 in epithelial regeneration after allogeneic transplant
IL-22在同种异体移植后上皮再生中的作用
- 批准号:
8882539 - 财政年份:2012
- 资助金额:
$ 13.68万 - 项目类别:
IL-22 in epithelial regeneration after allogeneic transplant
IL-22在同种异体移植后上皮再生中的作用
- 批准号:
8536359 - 财政年份:2012
- 资助金额:
$ 13.68万 - 项目类别:
IL-22 in epithelial regeneration after allogeneic transplant
IL-22在同种异体移植后上皮再生中的作用
- 批准号:
9107906 - 财政年份:2012
- 资助金额:
$ 13.68万 - 项目类别:
IL-22 in epithelial regeneration after allogeneic transplant
IL-22在同种异体移植后上皮再生中的作用
- 批准号:
8680364 - 财政年份:2012
- 资助金额:
$ 13.68万 - 项目类别:
相似海外基金
A Novel Small Molecule Therapeutic for Acute Graft Versus Host Disease
一种治疗急性移植物抗宿主病的新型小分子疗法
- 批准号:
10759657 - 财政年份:2023
- 资助金额:
$ 13.68万 - 项目类别:
Investigation of the association between acute graft-versus-host disease and renal impairment.
急性移植物抗宿主病与肾功能损害之间关系的调查。
- 批准号:
23K19558 - 财政年份:2023
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Impact of gut mycobiome on acute graft-versus-host disease
肠道真菌组对急性移植物抗宿主病的影响
- 批准号:
20K08748 - 财政年份:2020
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Harnessing the single-cell biology and biomarker involving in the therapeutic response of patients with severe acute graft-versus-host disease undergoing mesenchymal stem cell transfusion
利用单细胞生物学和生物标志物参与接受间充质干细胞输注的严重急性移植物抗宿主病患者的治疗反应
- 批准号:
19K16605 - 财政年份:2019
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effectiveness of dimethyl fumarate for acute graft-versus-host disease
富马酸二甲酯治疗急性移植物抗宿主病的有效性
- 批准号:
19K24001 - 财政年份:2019
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Role of T cells and the Intestinal Microbiota in the Pathogenesis of Acute Graft- versus- Host Disease
T 细胞和肠道微生物群在急性移植物抗宿主病发病机制中的作用
- 批准号:
9754362 - 财政年份:2019
- 资助金额:
$ 13.68万 - 项目类别:
Frequency analysis of graft-versus-host reactive T cell clones in human acute graft-versus-host disease tissues
人急性移植物抗宿主病组织中移植物抗宿主反应性T细胞克隆的频率分析
- 批准号:
18K08321 - 财政年份:2018
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Prevention of acute Graft-versus-Host disease after allogeneic stem cell transplantation by molecular targeting of anti-apoptotic proteins in activated donor T-cells (A08*)
通过分子靶向活化供体 T 细胞中的抗凋亡蛋白来预防同种异体干细胞移植后的急性移植物抗宿主病 (A08*)
- 批准号:
278130007 - 财政年份:2015
- 资助金额:
$ 13.68万 - 项目类别:
Collaborative Research Centres
Pathological analysis of acute graft-versus-host disease and development of molecular targeted therapy for acute GVHD
急性移植物抗宿主病的病理分析及急性GVHD分子靶向治疗的进展
- 批准号:
15K09657 - 财政年份:2015
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Altered Exosomal miRNA expression of late onset acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation.
异基因造血干细胞移植中迟发型急性移植物抗宿主病外泌体 miRNA 表达的改变。
- 批准号:
26860373 - 财政年份:2014
- 资助金额:
$ 13.68万 - 项目类别:
Grant-in-Aid for Young Scientists (B)