Kumar V, Bennett M, Eckner R J
J Exp Med. 1974 May 1;139(5):1093-109. doi: 10.1084/jem.139.5.1093.
Resistance to malignant erythropoiesis induced by Friend spleen focus-forming virus and resistance to marrow stem cell allografts are under genetic control. Strains of mice, e.g., C57BL/6 and B10.D2, which are homozygous for resistance at the Fv-2 locus, are also good rejectors of most bone marrow allografts. (89)Sr, a bone-seeking isotope, irradiates marrow but not other lymphoid organs and abrogates resistance to marrow allografts without suppressing T- or B-cell functions. Thus, marrow-dependent effector cells (M cells) seem to resist allogeneic stem cells. To test if the genetic resistance to Friend virus (FV) is also mediated by M cells, B6 mice were treated with (89)Sr using a dosage schedule known to abrogate resistance to allogeneic marrow cells. 9 days after FV infection of such mice, the spleens showed malignant erythroblastosis which could not be suppressed by prior hypertransfusion, a procedure which suppresses physiologic erythropoiesis. Such (89)Sr-treated B6 mice also supported extensive virus replication, while control mice did not. FV markedly suppressed the ability of (89)Sr-treated B6 mice to produce antisheep red blood cell (SRBC) antibodies, a feature seen normally only in genetically susceptible mice. Thus, (89)Sr-treated B6 mice behaved in these respects as if they were susceptible to FV. When increasing doses of (89)Sr were administered to B6 mice, a dose-related loss of resistance to FV was seen. Therefore, it appears that (89)Sr-sensitive M cells mediate the genetic resistance to FV. The results of experiments with (89)Sr indicated that genetically resistant mice would be expected to possess target cells which are susceptible to transformation by FV. To verify this corollary, bone marrow cells from B10.D2 (Fv-2(rr)) mice were transplanted into previously infected and lethally irradiated DBA/2 (Fv-2(ss)) recipients which share the same H-2(d) alleles. 5-15 days later, the spleens of DBA/2 primary recipients yielded transformed cells which were capable of producing splenic tumor colonies upon transplantation into adult, unirradiated B10.D2 secondary recipients. Various control experiments clearly indicated that the tumor colonies so induced were of B10.D2 marrow origin. This indicated that B10.D2 stem cells could be transformed when allowed to interact with FV in the spleens of susceptible DBA/2 mice. However, 30 days after transplantation of B10.D2 bone marrow cells into DBA/2 recipients, no transformed cells were detected. Apparently, in the 30-day interval precursors in the B10.D2 marrow gave rise to mature M cells which resisted the leukemic process. Since M cells recognize hybrid or hemopoietic histocompatability antigens expressed on primitive normal and transformed hematopoietic cells, we suggest that M cells may exert surveillance by rejecting leukemic cells. Thus, marrow transplantation from genetically resistant donors may provide a new mode of treatment for leukemia, by providing precursors of M cells and other immunocompetent cell types.
对弗氏脾脏集落形成病毒诱导的恶性红细胞生成的抗性以及对骨髓干细胞同种异体移植的抗性受基因控制。例如，在Fv - 2位点纯合抗性的小鼠品系，如C57BL/6和B10.D2，也是大多数骨髓同种异体移植的良好排斥者。（89）锶是一种亲骨性同位素，可照射骨髓但不影响其他淋巴器官，并且在不抑制T细胞或B细胞功能的情况下消除对骨髓同种异体移植的抗性。因此，骨髓依赖性效应细胞（M细胞）似乎能抵抗同种异体干细胞。为了测试对弗氏病毒（FV）的遗传抗性是否也由M细胞介导，使用已知能消除对同种异体骨髓细胞抗性的剂量方案，用（89）锶处理B6小鼠。在这些小鼠感染FV 9天后，脾脏出现恶性成红细胞增多症，且不能被预先的大量输血所抑制，大量输血是一种抑制生理性红细胞生成的操作。经（89）锶处理的B6小鼠也支持广泛的病毒复制，而对照小鼠则不然。FV显著抑制经（89）锶处理的B6小鼠产生抗绵羊红细胞（SRBC）抗体的能力，这一特征通常仅在遗传易感小鼠中出现。因此，经（89）锶处理的B6小鼠在这些方面的表现就好像它们对FV易感。当给B6小鼠施用递增剂量的（89）锶时，观察到对FV的抗性呈剂量相关的丧失。因此，似乎（89）锶敏感的M细胞介导对FV的遗传抗性。用（89）锶进行的实验结果表明，预计遗传抗性小鼠会拥有易被FV转化的靶细胞。为了验证这一推论，将来自B10.D2（Fv - 2（rr））小鼠的骨髓细胞移植到先前感染并经致死剂量照射的DBA/2（Fv - 2（ss））受体中，这些受体具有相同的H - 2（d）等位基因。5 - 15天后，DBA/2初级受体的脾脏产生了转化细胞，将其移植到成年未照射的B10.D2次级受体中时能够产生脾脏肿瘤集落。各种对照实验清楚地表明，如此诱导的肿瘤集落起源于B10.D2骨髓。这表明当B10.D2干细胞在易感的DBA/2小鼠脾脏中与FV相互作用时能够被转化。然而，将B10.D2骨髓细胞移植到DBA/2受体30天后，未检测到转化细胞。显然，在30天的间隔期内，B10.D2骨髓中的前体细胞产生了抵抗白血病过程的成熟M细胞。由于M细胞识别原始正常和转化造血细胞上表达的杂种或造血组织相容性抗原，我们认为M细胞可能通过排斥白血病细胞来发挥监测作用。因此，来自遗传抗性供体的骨髓移植可能通过提供M细胞和其他免疫活性细胞类型的前体，为白血病提供一种新的治疗模式。
