Warrens A N, Simon A R, Theodore P R, Sachs D H, Sykes M
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
Transplantation. 1998 Jul 27;66(2):252-9. doi: 10.1097/00007890-199807270-00020.
One way to circumvent the need for chronic immunosuppression in solid organ xenografting may be to induce donor-specific tolerance using bone marrow transplantation. If this approach is to succeed in the pig-to-human species combination, pig marrow must be capable of maturing into relevant tolerance-inducing cells and replenishing itself in host human marrow. One possible barrier is adhesion molecule incompatibility. We have studied the compatibility across the pig-human species barrier of two well-characterized ligands known to be important in hematopoiesis, CD44 and very late antigen (VLA)-4.
In vitro long-term bone marrow cultures were studied in which the effects of blocking antibodies were assessed by measuring cell numbers and colony-forming units.
The blocking of CD44 had a comparable inhibitory effect on the hematopoiesis of human and pig marrow, even if the latter was maintained on a human stromal layer. Both cellular proliferation and colony-forming activity were inhibited by anti-CD44 monoclonal antibody. By contrast, a significant difference was observed in VLA-4 usage by hematopoietic cells of the two species. Blocking VLA-4 markedly inhibited human hematopoietic cellular proliferation but had no effect on pig hematopoiesis, on either porcine or human stroma.
The data suggest that the incompatibility of either CD44 or VLA-4 is unlikely to limit the efficiency of porcine hematopoiesis in a human marrow environment. However, the difference in VLA-4 utilization between these species raises the possibility that other interactions may be important for effective porcine hematopoiesis and that their failure to function between species may contribute to the poor function of porcine hematopoietic cells in primate marrow microenvironments.
在实体器官异种移植中，一种规避长期免疫抑制需求的方法可能是利用骨髓移植诱导供体特异性耐受。如果这种方法要在猪 - 人异种组合中取得成功，猪骨髓必须能够成熟为相关的耐受诱导细胞，并在宿主人类骨髓中自我补充。一个可能的障碍是黏附分子不相容性。我们研究了两种在造血过程中已知重要的、特征明确的配体——CD44和极晚期抗原（VLA）-4在猪 - 人异种屏障间的相容性。
研究了体外长期骨髓培养，通过测量细胞数量和集落形成单位来评估阻断抗体的作用。
阻断CD44对人和猪骨髓的造血具有类似的抑制作用，即使后者维持在人基质层上。细胞增殖和集落形成活性均受到抗CD44单克隆抗体的抑制。相比之下，观察到两种物种造血细胞对VLA - 4的利用存在显著差异。阻断VLA - 4显著抑制人造血细胞增殖，但对猪在猪或人基质上的造血均无影响。
数据表明，CD44或VLA - 4的不相容性不太可能限制猪造血在人类骨髓环境中的效率。然而，这些物种之间VLA - 4利用的差异增加了其他相互作用可能对有效的猪造血很重要的可能性，并且它们在物种间无法发挥作用可能导致猪造血细胞在灵长类骨髓微环境中功能不佳。
