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IMMUNE REGULATION OF MURINE GRAFT-VERSUS-HOST DISEASE

小鼠移植物抗宿主病的免疫调节

基本信息

批准号：
3182285
负责人：
LOREN D. FAST
金额：
$ 9.4万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-05-01 至 1991-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3182285
关键词：
T lymphocyte bone marrow transplantation disease /disorder model genetic mapping graft versus host disease immunogenetics immunoregulation immunosuppression laboratory mouse major histocompatibility complex neoplasm /cancer immunology radiation sensitivity suppressor T lymphocyte tissue donors

项目摘要

Graft-versus-host disease (GVHD) is a common occurrence following bone marrow transplantation. Despite the use of major histocompatibility complex (MHC)-matched bone marrow donors and immunosuppression regimens following transplant, large numbers of patients still develop GVHD. These findings indicate that non-MHC loci play an important role in the regulation and induction of GVHD. The goal of these studies is to characterize non-MHC loci which are important for the regulation and induction of murine GVHD. These studies will use a murine model of GVHD in which chronic GVHD is induced by intravenous injection of DBA/2 spleen cells into unirradiated (C57BL/6 x DBA/2)F1 mice while injection of spleen cells from the other parental strain, C57BL/6, results in acute GVHD. The presence of in vivo cytolytic T lymphocytes and suppressor cells in the acute form but the chronic form of GVHD are some of the distinguishing characteristics of the two forms of GVHD. These differences have been shown to be regulated by non-MHC loci. Preliminary experiments using BXD recombinant inbred strains have identified a putative locus or loci mapping approximately 10 map units distal to Hbb on chromosome 7 that regulates in vivo CTL production. Backcross experiments will attempt to quantitate the number of loci that regulate each GVHD trait and to more precisely map the locus or loci on chromosome 7. Additional experiments will determine the strain distribution of the B6 and DBA/2 alleles regulating in vivo CTL production and will test if the locus or loci regulating CTL were transferred as passenger loci during the production of H-1 or Hbb congenic strains. Further experiments will attempt to define the characteristics of the recipient and donor cells which contribute to the inability of the DBA/2 spleen cells to generate in vivo CTL when injected into B6D2F1 recipients. CTL precursor frequency analysis will be done to verify the finding that DBA/2 CTL precursors are being eliminated and not suppressed. Because spleen cells from 30-40 week old DBA/2 mice respond differently in vivo than cells from 6-8 week old mice, these differences will be studied to determine the donor cells' role in the in vivo response.

移植物抗宿主病（GVHD）是一种常见的疾病，骨髓移植后。尽管使用了主要组织相容性复合体（MHC）匹配的骨髓供体和移植后的免疫抑制方案，大许多患者仍然出现GVHD。这些发现表明非MHC基因座在调节中起重要作用，诱导GVHD。这些研究的目的是描述非MHC基因座，这是重要的调控，诱导鼠GVHD。这些研究将使用小鼠模型其中慢性GVHD是由静脉内将DBA/2脾细胞注射到未照射的（C57 BL/6x DBA/2）F1小鼠，同时注射另一只小鼠的脾细胞亲本株C57 BL/6导致急性GVHD。的存在体内溶细胞性T淋巴细胞和抑制细胞在急性形式，但慢性形式的GVHD是一些区别两种GVHD的特点。这些差异已被证明受非MHC基因座的调控。初步使用BXD重组近交系的实验已经鉴定出一个或多个推测的基因座，其在距离与7号染色体上的Hbb结合，其调节体内CTL产生。回交实验将试图定量基因座，调节每个GVHD性状，并更精确地映射 7号染色体上的一个或多个位点。其他实验将确定B6和DBA/2等位基因的菌株分布调节体内CTL产生，并将测试一个或多个基因座是否调节性CTL作为乘客基因座转移，产生H-1或Hbb同源菌株。进一步的实验将尝试定义接收者的特征，供体细胞导致DBA/2脾不能当注射到B6 D2 F1中时，受惠人士将进行CTL前体频率分析，验证DBA/2 CTL前体被消灭而不是压制。因为30-40岁的脾细胞一周大的DBA/2小鼠在体内的反应不同于来自 6-8这些差异将被研究以确定供体细胞在体内反应中的作用。