研究人員在11月在線出版的《自然—免疫學(xué)》（Nature Immunology）期刊上報告說,，一種基因能夠讓小鼠更有效地接受人體骨髓細(xì)胞,。這種名為Sirpa的基因限制了移植造血干細(xì)胞在移植過程中的失敗，它是在研究不同免疫缺陷小鼠接受人體骨髓血干細(xì)胞的不同能力時被發(fā)現(xiàn)的,。
對研究人類血細(xì)胞缺損或血細(xì)胞疾病來說,，這是一種很有研究價值的小鼠。遺傳關(guān)系很接近的小鼠品種在接受移植器官上表現(xiàn)了差異性,，研究人員因此能很快縮小基因的搜尋范圍,。小鼠的Sirpa基因是多形態(tài)的，這意味著可以在這些基因中找到穩(wěn)定的遺傳差異性,，并改變其功能,。
Sirpa基因所編碼的蛋白質(zhì)被稱為SIRP-阿爾法，它能與一種在人血細(xì)胞表面表達(dá)的CD47蛋白相互作用,。這種相互作用被認(rèn)為阻止了免疫清道夫噬菌細(xì)胞攻擊和吃掉缺失CD47的細(xì)胞,，或者是擁有CD47分子但不能被Sirpa基因識別的細(xì)胞。第二種可能性也許可以解釋為什么部分小鼠拒絕人體血液的移植而別的小鼠卻不會,。
然而,，這些差異性不僅僅局限于小鼠。人體Sirpa基因中也展示了同樣的多態(tài)性,。作者推測,，這種差異性也許可以解釋為什么有些捐贈者和接受者的組織類型匹配、但骨髓移植仍被拒絕的現(xiàn)象,。如果這種推測正確,，那么Sirpa基因就會成為鑒定捐贈者與接受者是否匹配的名單上的一員，從而讓移植更安全,、更成功,。（科學(xué)時報）
原始出處:
Nature Immunology 8, 1313 - 1323 (2007)
Published online: 4 November 2007 | doi:10.1038/ni1527
Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells
Katsuto Takenaka1,6, Tatiana K Prasolava2,6, Jean C Y Wang1,3, Steven M Mortin-Toth2, Sam Khalouei2, Olga I Gan1, John E Dick1,4 & Jayne S Danska2,5
Abstract
Graft failure in the transplantation of hematopoietic stem cells occurs despite donor-host genetic identity of human leukocyte antigens, suggesting that additional factors modulate engraftment. With the nobese diabetic (NOD)–severe combined immunodeficiency (SCID) xenotransplantation model, we found that the NOD background allowed better hematopoietic engraftment than did other strains with equivalent immunodeficiency-related mutations. We used positional genetics to characterize the molecular basis for this strain specificity and found that the NOD Sirpa allele conferred support for human hematopoiesis. NOD SIRP- showed enhanced binding to the human CD47 ligand, and its expression on mouse macrophages was required for support of human hematopoiesis. Thus, we have identified Sirpa polymorphism as a potent genetic determinant of the engraftment of human hematopoietic stem cells.
Division of Cellular and Molecular Biology, University Health Network, Toronto, Ontario M5G2M9, Canada.
Program in Genetics and Genomic Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada.
Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
Department of Molecular Genetics and Microbiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
Departments of Immunology and Medical Biophysics and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
These authors contributed equally to this work.
Correspondence to: Jayne S Danska2,5 e-mail: [email protected]
