A research team led by Professor Shin Kaneko and Junior Associate Professor Akitsu Hotta at the Center for iPS Cell Research and Application (CiRA), Kyoto University, has succeeded in generating iPS cells (iPSCs) with less risk of immune rejection by genome editing.<\/p>\n\n\n\n
\u00a0The\u00a0significance of this research<\/em><\/strong> The risk of immune rejection in regenerative medicine<\/strong> Current methods to reduce immune rejection<\/strong> 2) B2M gene knockout iPSCs<\/strong> Results of this study<\/strong> First, they generated HLA pseudo-homozygous iPSCs by removing only one side of each of paired HLA-A, -B, and -C gene alleles. Pseudo-homozygous iPSCs were differentiated into blood cells and they were co-cultured with T cells. The differentiated blood cells could escape from the aggressive activity of T cells while non-edited cells were attacked by T cells. For HLA matching of this strategy, 73 iPSC lines are needed to cover >95% of the Japanese population. <\/p>\n\n\n\n Second, they generated HLA-C-retained iPSCs by disrupting both sides of HLA-A and -B genes, and one side of HLA-C gene. The activity of NK cells is suppressed by HLA-C. Although B2M knockout cells are attacked by NK cells, HLA-C-retained iPSCs would escape from the immune response of NK cells. HLA-C-retained iPSCs were differentiated into blood cells and they were co-cultured with both T cells and NK cells. The differentiated blood cells could escape from the immune response while non-genome-edited cells and B2M knockout cells were attacked by these immune cells. Furthermore, the differentiated blood cells and T cells were transplanted into immunodeficient mice to assess the graft survival of the HLA-edited iPSCs in vivo. HLA-C-retained cells survived >1 week after transplantation, in contrast to the non-edited cells. Even when NK cells were injected, HLA-C-retained cells showed significantly better survival in vivo than B2M knockout cells. For this strategy, they estimated that only 7 iPSC lines are required to cover >95% of the Japanese population, and only 12 lines are sufficient to cover >90% of the world population.<\/p>\n\n\n\n These results will greatly reduce the number of donors required to generate iPSCs for regenerative medicine, which could contribute to the spread of regenerative medicine using iPSCs.<\/p>\n\n\n\n Title: Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility. A research team led by Professor Shin Kaneko and Junior Associate Professor Akitsu Hotta at the Center for iPS Cell Research and Application (CiRA), Kyoto University, has succeeded in generating iPS cells (iPSCs) with less risk of immune rejection by genome editing. \u00a0The\u00a0significance of this researchBy editing HLA genes in iPSCs, they have succeeded in […]<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[131],"tags":[169,167,36,168],"class_list":["post-1214","post","type-post","status-publish","format-standard","hentry","category-cancer","tag-immune-rejection","tag-ips-cell","tag-ipsc","tag-stem-cell-cancer-treatment"],"yoast_head":"\n
By editing HLA genes in iPSCs, they have succeeded in creating iPSC-derived T cells with less immune rejection. This will allow us to create T cells that can exist more stably in vivo and attack cancer.<\/p>\n\n\n\n
iPSCs have strong potential in regenerative medicine applications. However, immune rejection is a concern when transplanted cells are from a person other than the patient. The immune system uses human leukocyte antigens (HLAs), which are proteins expressed on the surface of most cells, to\u00a0distinguish between self and foreign cells<\/em> and attacks foreign\u00a0cells<\/em>. To avoid immune rejection, it is necessary to match HLA type of the patient and donor as closely as possible. The HLA type is determined by a combination of genes such as HLA-A, -B, and -C, and there are tens of thousands of HLA combinations.<\/p>\n\n\n\n
1) HLA homozygous iPSCs<\/strong>
The risk of rejection can be reduced by making iPSCs from the blood of donors who are HLA homozygous<\/em>. HLA homozygous<\/em>\u00a0is a genetic condition where an individual has inherited the same DNA sequence for a particular HLA gene from both their biological mother and father.\u00a0Transplanting HLA homozygous cells into HLA heterozygous people, who have inherited different DNA sequences for HLA genes from their parents, is less likely to cause rejection. However, most people are heterozygous. To cover 90% of the Japanese population, 140 HLA homozygous iPSC lines are needed and >150,000 donors must be screened to establish them.<\/p>\n\n\n\n
B2M gene knockout by genome editing can also address the issue of immune rejection. Suppression of the B2M gene induces removal of HLA proteins from the cell surface. It would prevent an immune response from T cells, which are immune cells that destroy foreign cells including virus-infected cells and cancer cells. However, the lack of these HLA proteins would activate a response by natural killer (NK) cells, which are other immune cells and attack cells that do not express HLA. In addition, the lack of them would risk the proliferation of transplanted cells that are infected by pathogens or are oncogenic because T cells do not attack them.<\/p>\n\n\n\n
The research team has developed two methods to generate iPSCs with less risk of rejection by genome editing (CRISPR-Cas9).<\/p>\n\n\n\n
Journal: Cell Stem Cell 24, 566\u2013578<\/p>\n","protected":false},"excerpt":{"rendered":"