Inflammatory B cells defined by TIM-4 in the Alloimmune response
同种免疫反应中 TIM-4 定义的炎症 B 细胞
基本信息
- 批准号:10455071
- 负责人:
- 金额:$ 41.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAllograft ToleranceAllograftingAnti-Inflammatory AgentsAntigen PresentationAttenuatedAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityB-LymphocytesBiologyBone MarrowCell CommunicationCell ShapeCell physiologyCellsChronicClinicalCytoplasmic TailDataDevelopmentDiseaseExhibitsExperimental Autoimmune EncephalomyelitisGenerationsGenetic TranscriptionGoalsHeart TransplantationHumanHumoral ImmunitiesImmune ToleranceImmune responseIndividualInfectionInflammation MediatorsInflammatoryIntegrinsInterferon Type IIInterleukin-10Interleukin-17Interleukin-2Interleukin-6IsoantibodiesKnockout MiceLeftLigationMonoclonal AntibodiesMusPatientsPatternPeptidesPhenotypePlasma CellsPlayProductionRegulationRegulator GenesRegulatory ElementRodentRoleSignal PathwaySignal TransductionT-LymphocyteTNF geneTherapeuticTimeTransplant RecipientsTransplantationVascular DiseasesWorkallograft rejectionanti-CD20antimicrobialcytokinedesignimmunoregulationimprovedinsightislet allograftkidney allograftnano-stringnovelprogramsproteoglycan induced arthritisresponsetranscription factortranscriptometranscriptome sequencingtumor
项目摘要
Summary: It is clear that B cells play important Ab-independent roles either promoting or inhibiting immune
responses through the opposing activity of regulatory B cells (Bregs) and proinflammatory effector B cells
(Beff). This is likely to explain observations that B cell depletion with anti-CD20 can rapidly improve auto-
immune diseases, such as RA and MS, without depleting auto-Ab. Yet in other patients, disease is worsened.
Moreover, peri-transplant depletion of B cells can markedly increase acute rejection in renal allograft recipients
and chronic vasculopathy in heart transplantation. These contradictory results are likely due to the presence of
both Bregs and Beff, and not knowing which predominates at a given time, in a given clinical setting, or in a
given patient. A similar dichotomy is present in mice, where B cell depletion/deficiency can either inhibit or
promote autoimmunity and allograft rejection. We contend that targeting B cells in autoimmune and transplant
patients would have far better results if Beff were selectively targeted and Bregs were left intact. Unfortunately,
little is known about Bregs, and even less is known about Beff cells. In mice, B cells expressing pro-
inflammatory cytokines such as IL-6 and IFNγ play a key role promoting autoimmune responses in EAE and
proteoglycan-induced arthritis. Moreover, in response to various infections, B cells exhibit rapid and transient
innate-like protective responses through expression of TNFα, IFNγ, IL-2, and IL-17. However, it is unknown
whether, or how, any of these responses relate to one another, because no phenotype for such Beff has been
established and individual cytokines were examined in isolation. Thus, major aspects of Beff biology, including
what regulates their differentiation and cytokine expression, are completely unknown. We have now discovered
that TIM-4 identifies Beff that express inflammatory cytokines including IFNγ and IL-17, and accelerate allograft
rejection. Eliminating expression of these cytokines by B cells, reverses this proinflammatory role, but can also
markedly inhibit the alloimmune response and promote tolerance. Moreover, some cytokines affect the
expression of others. Notably, IL-17 is not only a potent effector cytokine, but is essential for Beff to develop an
inflammatory rather than regulatory program. Finally, TIM-4 ligation inhibits expression of proinflammatory
cytokines. Understanding the role of TIM-4+ Beff in priming the immune response and identifying how this
response can be regulated to promote tolerance, are key and unique aspects of this proposal. These results
are likely to provide a unifying framework for understanding Beff cells, and will have major impact on the field.
In Aim 1 we will determine whether TIM-4+ Beff express a “proinflammatory module” comprised of additional
effector molecules and transcriptional regulatory elements, and determine key aspects of its regulation. In Aim
2 we will define key mechanisms by which TIM-4+ Beff promote allograft rejection. In Aim 3 we will determine
how TIM-4 signaling regulates expression of the Beff pro-inflammatory module. This work will greatly enhance
our understanding of Beff biology and provide therapeutic insights highly relevant to immune tolerance.
结论:B细胞在促进或抑制免疫应答中发挥重要的非Ab依赖性作用,
通过调节性B细胞(Bcl-2)和促炎效应B细胞的相反活性产生的反应
(Beff).这可能解释了用抗CD 20去除B细胞可以迅速改善自体免疫的观察结果。
免疫性疾病,如RA和MS,不会耗尽自身抗体。然而,在其他患者中,疾病恶化。
此外,肾移植术前后B细胞的耗竭可显著增加肾移植受者的急性排斥反应
和慢性血管病变。这些相互矛盾的结果可能是由于
在给定的时间,在给定的临床环境中,或在给定的临床环境中,
给病人。在小鼠中也存在类似的二分法,其中B细胞耗竭/缺乏可以抑制或
促进自身免疫和同种异体移植排斥。我们认为,在自身免疫和移植中靶向B细胞
如果选择性地靶向Beff,而Beff保持完整,患者将获得更好的结果。不幸的是,
对Besides知之甚少,对Beff细胞的了解更少。在小鼠中,表达前-
炎性细胞因子如IL-6和IFNγ在EAE中促进自身免疫应答起关键作用,
蛋白多糖引起的关节炎此外,响应于各种感染,B细胞表现出快速和短暂的
通过表达TNFα、IFNγ、IL-2和IL-17的先天性样保护性应答。但不清楚
这些反应中的任何一个是否或如何相互关联,因为还没有这种Beff的表型被发现。
单独检测已建立的和单个的细胞因子。因此,贝夫生物学的主要方面,包括
是什么调节了它们的分化和细胞因子的表达是完全未知的。我们现在发现
TIM-4鉴定了表达炎性细胞因子包括IFNγ和IL-17并加速同种异体移植Beff,
排斥反应消除B细胞表达的这些细胞因子,逆转了这种促炎作用,但也可以
显著抑制同种免疫反应并促进耐受性。此外,一些细胞因子影响细胞因子的表达。
他人的表达。值得注意的是,IL-17不仅是一种有效的效应细胞因子,而且是Beff发展免疫系统所必需的。
而非监管计划。最后,TIM-4连接抑制促炎性细胞因子的表达。
细胞因子了解TIM-4+ Beff在引发免疫应答中的作用,并确定这是如何发生的。
可以调节反应,以促进宽容,是这一建议的关键和独特的方面。这些结果
很可能为理解Beff细胞提供一个统一的框架,并将对该领域产生重大影响。
在目标1中,我们将确定TIM-4+ Beff是否表达由额外的细胞因子组成的“促炎模块”。
效应分子和转录调控元件,并确定其调控的关键方面。在Aim中
我们将明确TIM-4+ Beff促进同种异体移植排斥反应的关键机制。在目标3中,我们将确定
TIM-4信号传导如何调节Beff促炎模块的表达。这项工作将大大提高
我们对Beff生物学的理解,并提供与免疫耐受高度相关的治疗见解。
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)
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 }}
DAVID M ROTHSTEIN其他文献
DAVID M ROTHSTEIN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('DAVID M ROTHSTEIN', 18)}}的其他基金
Role of TIM Molecules in Regulatory and Inflammatory B cells in Allo andAutoimmunity
TIM 分子在同种异体和自身免疫中调节性和炎症性 B 细胞中的作用
- 批准号:
9751742 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Inflammatory B cells defined by TIM-4 in the Alloimmune response
同种免疫反应中 TIM-4 定义的炎症 B 细胞
- 批准号:
10214481 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Immunoregulation by TLR-activated TIM-1+ ProB Cells in Transplantation
TLR 激活的 TIM-1 ProB 细胞在移植中的免疫调节
- 批准号:
10455069 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Role of TIM Molecules in Regulatory and Inflammatory B cells in Allo andAutoimmunity
TIM 分子在同种异体和自身免疫中调节性和炎症性 B 细胞中的作用
- 批准号:
10214475 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Role of TIM Molecules in Regulatory and Inflammatory B cells in Allo andAutoimmunity
TIM 分子在同种异体和自身免疫中调节性和炎症性 B 细胞中的作用
- 批准号:
10455065 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Immunoregulation by TLR-activated TIM-1+ ProB Cells in Transplantation
TLR 激活的 TIM-1 ProB 细胞在移植中的免疫调节
- 批准号:
10214480 - 财政年份:2018
- 资助金额:
$ 41.58万 - 项目类别:
Inflammatory B Cells Defined by TIM-4 in the Alloimmune Response
TIM-4 在同种免疫反应中定义的炎症 B 细胞
- 批准号:
9542016 - 财政年份:2017
- 资助金额:
$ 41.58万 - 项目类别:
In Vivo Detection And Mechanisms Of Regulatory B Cell Function In Transplantation
移植中调节性 B 细胞功能的体内检测和机制
- 批准号:
9197259 - 财政年份:2015
- 资助金额:
$ 41.58万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 41.58万 - 项目类别:
Research Grant