TRANSPLANT IMMUNOMODULATION BY ALLOCHIMERIC MOLECULES

通过异种嵌合分子进行移植免疫调节

基本信息

批准号：
7156937
负责人：
Rafik MARK GHOBRIAL
金额：
$ 25.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7156937
关键词：
Abbreviations Address Allograft Tolerance Allografting Alloimmunization Antigens Autoradiography CD4 Positive T Lymphocytes Cells Chronic Class Coupled Cyclosporine Cyclosporins Data Dendritic Cells Detection Development Engineering Epitopes Event Exhibits Foundations Generations Genes Growth Factor Hepatic Histocompatibility Antigens Class I IgG1 Immune Immune response In Vitro Isoantibodies Label Localized Major Histocompatibility Complex Maps Mediating Modeling Mononuclear Organ Pathway interactions Peptide Mapping Physiologic pulse Polymerase Chain Reaction Population Process Proteins Pulse taking Rattus Recombinants Research Personnel Sequence Analysis Site Specificity Spliced Genes T-Cell Receptor T-Lymphocyte Testing Transplant Recipients Transplantation Transplantation Tolerance Ursidae Family Venous base cell type heart allograft immunogenic immunoregulation in vivo innovation insight novel programs response

项目摘要

We seek to develop a clinically applicable strategy to induce "true" transplantation tolerance treated with allochimeric Class I MHC molecules. Our novel findings in a rat cardiac allograft model provide the foundation of this proposal. We hypothesize: (i) allochimeric-induced tolerance is applicable to genetically diverse allograft recipients; (ii) allochimeric molecules modulate the immune response b y indirect presentation; (iii) a Ilochimeric molecules generate unique regulatory T cells with distinctive functional and TcR allospecificities. We propose: 1. To Define the Requirements of Different AIIochimeric Molecules to Induce Tolerance. Multiple allochimeric molecules, in different strain combinations, will be constructed to define critical immunogenic epitopes in the polymorphic regions of class I MHC. AIIochimeric molecules that display donor-dominant epitopes on recipient- class I antigens will be tested for their ability to induce "true" chronic rejection-free tolerance. 2. To Analyze AIIoimmune Modulation by Indirect Presentation of Allochimeric [_lh___U]-RT1.aA Class I MHC Molecules. Fine mapping of immunogenic/cryptic self-epitopes that are critical for allograft tolerance will be _erformed. Indirect allochimeric deviation of T cell responses will be addressed by employing host or donor-type dendritic cells that have been pulsed in vitro with donor wild-type or [Ohh_U]-RT1.Aa molecules. AIIochimeric protein labeling and detection will localize the site and cell-type involved in allochimeric processing and presentation. Requirement of 'immature vs mature' hepatic DC for allochimeric tolerance induction will be investigated in vivo by functional stimulation of DC matudty and allostimulatory capacity using FIt3L, a heamatopoietic growth factor, to potentially abrogate indirectly induced tolerance following intra-portal allochimeric delivery. 3. To Characterize the Unique Population of Requlatory T Cells Induced by Indirect Allorecognition. We will perform in vivo and ex vivo phenotypic and functional characterization of regulatory T cells. Allochimeric generation of regulatory T cells, a possible key tolerogenic mechanism in this model, will be probed in vitro by studying immature hepatic dendritic cells that indirectly present allochimeric molecules to CD4+ T cells. Third, in vivo analysis of chronic rejection coupled with CDR3 spectrotyping, immunoscope and sequence analysis of allochimedc-induced clonally-restricted regulatory T cells will define unique T cell functional specificities and the influence of allochimeric sequence on the allospecific TcR repertoire>

我们试图制定一种临床上适用的策略，以诱导使用的“真实”移植耐受性同种元素I类MHC分子。我们在大鼠心脏同种异体模型中的新颖发现为这个建议。我们假设：（i）同种型耐受性适用于遗传多样的同种异体移植接收者；（ii）同种分子通过间接表现调节免疫反应；（iii）一个叶胆大子分子产生具有独特功能和TCR分类性的独特调节T细胞。我们建议： 1。定义不同的Aiiochimeric分子诱导公差的要求。多个同种聚合物分子以不同的应变组合的形式构建，以定义关键的免疫原性表位 I类MHC的多态区域。在接受者上显示供体主导的表位的Aiiochimeric分子 - I级抗原将通过诱导“真实”慢性拒绝耐受性的能力进行测试。 2。通过间接呈现同粒子[_lh ___ u] -rt1.aa类I MHC分析AIIOMMUNE的调制分子。对同种异体移植耐受至关重要的免疫原性/隐性自我映射的精细映射将是 _erformed。 T细胞反应的间接异源偏差将通过使用宿主或供体类型来解决用供体野生型或[OHH_U] -RT1.AA分子在体外脉冲的树突状细胞。 Aiiochimeric蛋白标记和检测将定位参与异偶会加工和表现的细胞类型。将在体内研究“未成熟与成熟”肝直流对异源耐受性诱导的要求使用Heamatopoietic生长因子FIT3L对DC的Matudty和Allostimulativation的功能刺激潜在地废除了体内异聚体递送后间接诱导的公差。 3。表征通过间接同种异体识别引起的重新定义T细胞的独特种群。我们将在体内和体内表型和调节性T细胞的功能表征。异源产生调节性T细胞是该模型中可能的关键耐受性机制，将在体外探测未成熟的肝树突状细胞间接地呈现给CD4+ T细胞的同种分子。第三，体内慢性排斥与CDR3光谱，免疫镜和序列分析的分析异菌C诱导的克隆限制调节性T细胞将定义独特的T细胞功能特异性，并同种序列对同种TCR库的影响>

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Donor MHC class I peptides in conjunction with self-epitopes induce donor-specific tolerance in a dose-dependent manner but unable to abrogate chronic rejection.

供体 MHC I 类肽与自身表位结合以剂量依赖性方式诱导供体特异性耐受，但无法消除慢性排斥。

DOI：
10.1016/j.transproceed.2005.02.114
发表时间：
2005
期刊：
Transplantation proceedings.
影响因子：
0
作者：
Semiletova,NV;Shen,X-D;Feldman,DM;Busuttil,RW;Kupiec-Weglinski,JW;Ghobrial,RM
通讯作者：
Ghobrial,RM

Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model.

移植物内基因表达谱与大鼠心脏移植模型中异源嵌合 MHC I 诱导耐受相关。

DOI：
10.1002/dvg.20574
发表时间：
2010
期刊：
Genesis (New York, N.Y. : 2000)
影响因子：
0
作者：
Lisik,Wojciech;Gong,Yongquan;Tejpal,Neelam;Skelton,ThomasS;Bremer,EricG;Kloc,Malgorzata;Ghobrial,RafikM
通讯作者：
Ghobrial,RafikM

Downregulation of RhoA and changes in T cell cytoskeleton correlate with the abrogation of allograft rejection.

DOI：
10.1016/j.trim.2010.06.009
发表时间：
2010-08
期刊：
Transplant immunology
影响因子：
1.5
作者：
Skelton TS;Tejpal N;Gong Y;Kloc M;Ghobrial RM
通讯作者：
Ghobrial RM

Allochimeric molecules and mechanisms in abrogation of cardiac allograft rejection.

同种异体嵌合分子和消除心脏同种异体移植排斥反应的机制。

DOI：
10.1016/j.healun.2011.01.715
发表时间：
2012
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
0
作者：
Skelton,TSpencer;Tejpal,Neelam;Gong,Yongquan;Kubiak,JacekZ;Kloc,Malgorzata;Ghobrial,RafikM
通讯作者：
Ghobrial,RafikM

Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I.