以人源化小鼠模型检测HLA I类分子敲除hES细胞的免疫原性

Human embryonic stem cells (hESCs) have the ability of robust self-renewal and retain the pluripotency to differentiate into all cell types in the body. Therefore, hESCs are considered an important source for cell therapy. One key bottleneck for clinical application of hESCs is rejection of hESC derived cells by patients’ immune system. Human leukocyte antigens (HLAs) on the cell surface are the major cause of graft rejection. β2-microglobulin（B2M）is a component of HLA class I molecules, which are present on all nucleated cells. In the absence of B2M, class I HLAs cannot be properly assembled and are not presented on the cell membrane where they function. By using TALEN technique, we try to disrupt the β2-microglobulin（B2M）gene in hESCs to deplete HLA classⅠmolecules on the cell surface. Immunogenicity of B2M knockout hESCs will be studied. Due to physiological and immune differences between human and mouse, many of the results on human cell immunogenicity gathered from mouse models cannot be completely recapitulated in human clinical trials. Therefore, we also try to establish human immune system in mouse body via combined transplantation of human fetal thymus tissues and isogenic CD34+ fetal liver cells into immunodeficient mouse. The humanized mouse will be used to evaluate the immunogenicity of B2M knockout hESCs. In a word, this program tries to generate hypoimmunogenic hESCs by depleting HLA classⅠmolecules, and study the immunogenicity of the modified cells. These hESCs might become a reliable “universal”source for cell therapy.

人胚胎干细胞（hESC）具有自更新能力和分化多能性，可用作再生医学的种子细胞。但是免疫排斥严重限制了其临床应用。免疫排斥主要因为供受体间HLA的异质性。B2M是HLAⅠ类复合体的重要组分，对HLAⅠ的组装和上膜起关键作用。本项目拟利用TALEN技术在hESC中敲除B2M基因，使hESC表面的HLAⅠ缺失，进而研究HLAⅠ缺失hESC移植后是否能逃避受体的免疫攻击。由于人类和小鼠生理及免疫系统的差异，从小鼠体内获得的人类细胞免疫原性的研究结果可能无法反应人体内的真实情况。因此，本项目也将通过把人类胎儿胸腺和CD34+胎肝细胞移植到免疫缺陷小鼠体内，在小鼠中重建人类免疫系统，并利用由此方法建立的人源化小鼠评估B2M敲除hESC的免疫原性。总之，本项目试图通过敲除HLAⅠ类分子产生低免疫原性hESC，并建立人源化小鼠模型验证其在体的免疫原性，使之有望成为再生医学中可靠的、“普适”的种子细胞来源。

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