Gandy K L, Weissman I L
Department of Pathology, Stanford University School of Medicine, California 94305, USA.
Transplantation. 1998 Feb 15;65(3):295-304. doi: 10.1097/00007890-199802150-00001.
Animals reconstituted with allogeneic whole bone marrow (WBM) are often tolerant of donor-specific solid organ grafts. Clinical application of bone marrow transplantation in solid organ transplantation has been limited, however, principally by graft-versus-host disease. We previously demonstrated that hematopoietic stem cells (HSCs) reconstitute lethally irradiated allogeneic mice without producing graft-versus-host disease. The purpose of this study was to determine whether tolerance to solid organ grafts could be induced in mice reconstituted with HSCs.
BALB/c mice were lethally irradiated and reconstituted with allogeneic C57BL/Ka, Thy-1.1 WBM or HSCs. An isolated group was given a limited number of HSCs (250 cells) and a subpopulation of allogeneic cells known to facilitate HSC engraftment (facilitators). C57BL/Ka, Thy-1.1 neonatal heart grafts were placed in reconstituted animals either at the time of hematopoietic transplant or 35 days later. Third-party C3H grafts were placed over 2 months after hematopoietic reconstitution. Tolerance was defined as the persistence of cardiac contraction for the duration of evaluation (125-270 days).
All surviving mice that were reconstituted with C57BL/Ka, Thy-1.1 HSCs, WBM, or HSCs and facilitators were tolerant of C57BL/Ka grafts long-term. Third-party C3H grafts placed in reconstituted animals were rejected by day 12, whereas those placed in unmanipulated mice were rejected by day 9.
These data indicate that tolerance to concurrently or subsequently placed solid organ grafts can be reliably achieved with limited numbers of purified HSCs in a model where immunocompetence to third-party major histocompatibility complex antigens is delayed but intact.
用同种异体全骨髓（WBM）重建的动物通常对供体特异性实体器官移植耐受。然而，骨髓移植在实体器官移植中的临床应用主要受限于移植物抗宿主病。我们之前证明，造血干细胞（HSCs）可重建经致死性照射的同种异体小鼠，且不产生移植物抗宿主病。本研究的目的是确定在用HSCs重建的小鼠中是否能诱导对实体器官移植的耐受。
对BALB/c小鼠进行致死性照射，并用同种异体C57BL/Ka、Thy-1.1 WBM或HSCs进行重建。一个单独的组给予有限数量的HSCs（250个细胞）和已知可促进HSC植入的同种异体细胞亚群（促进细胞）。在造血移植时或35天后，将C57BL/Ka、Thy-1.1新生心脏移植物植入重建的动物体内。在造血重建后2个月以上植入第三方C3H移植物。耐受定义为在评估期间（125 - 270天）心脏持续收缩。
所有用C57BL/Ka、Thy-1.1 HSCs、WBM或HSCs与促进细胞重建的存活小鼠长期耐受C57BL/Ka移植物。植入重建动物体内的第三方C3H移植物在第12天被排斥，而植入未处理小鼠体内的移植物在第9天被排斥。
这些数据表明，在对第三方主要组织相容性复合体抗原的免疫能力延迟但完整的模型中，用有限数量的纯化HSCs可可靠地实现对同时或随后植入的实体器官移植物的耐受。
