MHC CLASS II INDUCTION IN ALLOGRAFT REJECTION

同种异体移植排斥中的 MHC II 类诱导

• 批准号: 3454464
• 负责人: DILIP S KITTUR
• 金额: $ 11.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3454464
• 关键词: MHC class II antigen; biopsy; gene expression; heart transplantation; histochemistry /cytochemistry; histocompatibility; histocompatibility gene; homologous transplantation; immunopharmacology; interferons; laboratory mouse; membrane activity; nucleic acid probes; radiation immunosuppression; tissue donors; tumor necrosis factor alpha

MHC class II Antigen (Ag) induction is seen in allografts undergoing rejection and is considered to be an important event in the cascade of allograft rejection. But presently, it is not clear if this induction is causal or an epiphenomenon in rejection. Cell surface expression of MHC Ag in allograft rejection is well studied, but the expression of these genes and the mechanism responsible for their induction has not been studied. Our goal is to determine the relevance and mechanism of MHC class II gene expression in allograft rejection. We will critically test the hypothesis that strength of rejection is influenced by quantitative variations in donor MHC class II expression. For this, we will test the following predictions resulting from this hypothesis in cardiac allografts between congenic strains of mice: (1) Magnitude and/or kinetics of class II induction in allografts enjoying prolonged survival are different than those in rapidly rejected grafts, (2) In an allograft enjoying prolonged survival, induction of rejection is preceded by an increase in basal expression of class II in that graft, and (3) Increased expression of class II in donor organs accelerates rejection in "slow rejector" strain combination and conversely, decreased expression of class II delays rejection. Discrimination of donor specific class II expression necessary for these experiments is possible with our allele I- A specific oligonucleotide probes. Quantitative analysis of mRNA content in allografts will be done to provide objective parameters necessary to verify the predictions. Allele specific I-E oligo probes will be developed to test if differential expression of I-A versus I-E occurs in allografts and is more relevant to allorecognition. Immunoperoxidase staining will be performed to identify the donor cell type on which class II induction occurs and also to ascertain that mRNA expression correlates with cell surface expression. Mechanism of class II induction in allografts will be studied by sequential analysis of IFN and TNF gene expression in the allograft to determine temporal relation of expression of these genes to induction of class II genes. This study will not only provide data regarding the relevance of class II expression in allorecognition, but will also provide insight in the mechanism of this important gene expression. This knowledge may be applied in the future to reduce immunogenicity of an allograft to circumvent rejection.

同种异体移植物中MHC-II类抗原(Ag)的诱导 被拒绝，被认为是 同种异体排斥反应。但目前还不清楚这种诱导是否 排斥中的因果现象或附带现象MHC在细胞表面的表达 AG在同种异体移植排斥反应中的作用已有很好的研究，但这些表达 基因及其诱导机制目前尚不清楚 学习。我们的目标是确定MHC的相关性和机制 同种异体移植排斥反应中II类基因的表达。我们将严格测试 拒绝强度受数量因素影响的假说 供体MHC-II类基因表达的变异。为此，我们将测试 根据这一假说对心脏疾病的预测 同源品系小鼠之间的同种异体移植：(1)大小和/或 延长存活期同种异体移植物II类诱导的动力学 与快速排斥移植物不同，(2)在同种异体移植物中 由于存活时间较长，诱导排斥反应之前会出现一种 移植物中II类基础表达增加，以及(3)增加 供体器官中II类分子的表达加速了“慢”的排斥反应 Rejector“菌株组合，反之，表达减少 第二类延迟拒绝。对特定捐赠者第II类的歧视 这些实验所必需的表达是可能的，我们的等位基因I- 一种特定的寡核苷酸探针。信使核糖核酸含量的定量分析 将在同种异体移植中提供必要的客观参数 证实这些预测。等位基因特异的I-E寡核苷酸探针将 用于测试I-A和I-E的差异表达是否发生在 同种异体移植，与同种异体识别更相关。免疫过氧化物酶 将进行染色以确定哪个类别的供体细胞类型 Ii诱导发生，也是为了确定mRNA表达与 与细胞表面表达有关。Ⅱ类诱导机制的研究进展 同种异体移植将通过对干扰素和肿瘤坏死因子基因的序列分析进行研究 在同种异体移植物中的表达以确定表达的时间关系 这些基因对II类基因的诱导作用。这项研究不仅将 提供有关第II类表达的相关性数据 异体识别，但也将提供对这一机制的洞察 重要的基因表达。这些知识可能会在未来得到应用。 降低同种异体移植物的免疫原性以避免排斥反应。

项目成果

Graft-specific MHC class II gene expression in response to allogeneic stimulus in heterotopic murine cardiac allografts.

异位小鼠心脏同种异体移植物中移植物特异性 MHC II 类基因响应同种异体刺激的表达。

• 发表时间: 1992
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Xu,R;Burdick,JF;Scott,A;Beschorner,WE;Adler,W;Kittur,DS
• 通讯作者: Kittur,DS

Role of naturally occurring xenoantibodies in hyperacute rejection strengthened by their avid binding to ex vivo pig to human liver xenografts and to isolated pig liver preparations.

天然存在的异种抗体在超急性排斥反应中的作用通过其与离体猪、人肝异种移植物和分离的猪肝制剂的强烈结合而得到加强。

• 发表时间: 1994
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Nair,J;Fair,JH;Burdick,JF;Stephenson,GR;Klein,AS;Olson,JL;Maley,WR;Kittur,DS
• 通讯作者: Kittur,DS

Allele specific oligonucleotide probes for mouse I-A region and gene: I-A beta.

针对小鼠 I-A 区域和基因：I-A beta 的等位基因特异性寡核苷酸探针。

• DOI: 10.3109/08820139009041838
• 发表时间: 1990
• 期刊: Immunological investigations
• 影响因子: 2.8
• 作者: Xu,R;Scott,AF;Adler,WH;Kittur,DS
• 通讯作者: Kittur,DS

Does high MHC class II gene expression in normal lungs account for the strong immunogenicity of lung allografts?

正常肺中 MHC II 类基因的高表达是否可以解释同种异体肺移植物的强免疫原性？

• DOI: 10.1007/bf00335663
• 发表时间: 1994
• 期刊: Transplant international : official journal of the European Society for Organ Transplantation
• 作者: Alwayn,IP;Xu,R;Adler,WH;Kittur,DS
• 通讯作者: Kittur,DS