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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>

我们寻求开发一种临床适用的策略来诱导“真正的”移植耐受治疗

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.