Mohiuddin M M, Qin Y, Qian X, Meng Y, DiSesa V J
Department of Cardiovascular-Thoracic Surgery, Rush Presbyterian St. Lukes Medical Center, Chicago, Illinois 60612, USA.
Ann Thorac Surg. 2001 Sep;72(3):740-5; discussion 745-6. doi: 10.1016/s0003-4975(01)02811-9.
The shortage of human hearts remains a major barrier to the efficacy of heart transplantation for the treatment of end-stage heart disease. One potential solution to the supply problem would be the use of hearts from nonhuman donors (xenografts). We have established a model of mouse to rat xenogeneic bone marrow chimerism, and in this study we have hypothesized that such chimeric rats will accept both donor and recipient specific heart grafts while rejecting third-party mouse and rat grafts. We also investigated humoral responses in naive and chimeric rats with and without donor murine cardiac grafts.
Recipient Lewis rats (n = 22) were given 1100 cGy lethal total body irradiation and the same day received 300 x 10(6) donor B10.BR mouse bone marrow cells intravenously. Peripheral blood of surviving rats (n = 18) was typed at 4 weeks and then monthly thereafter. Donor and recipient specific and third-party heterotopic heart transplantations were performed at 6 to 8 weeks after reconstitution with bone marrow.
Multilineage bone marrow chimerism was produced in all experimental animals with complete replacement of recipient marrow by donor cells. Murine donor and rat recipient strain hearts transplanted in chimeric rats survived indefinitely. Third-party rat and mouse hearts were rejected, though at a slower rate than bone marrow matched naive controls. High levels of antimouse antibodies were detected in rats with rejected hearts. These antibodies were absent in chimeric animals with long-term surviving heart grafts.
Long-term multilineage bone marrow chimerism can be produced in a mouse --> rat bone marrow transplant model. Long-term survival of donor specific and recipient specific vascularized cardiac grafts can be produced in these chimeric animals. These animals are clinically normal but show signs of subclinical immunosuppression regimen as they reject third-party hearts later than naive animals. Our results suggest that antibodies also play a significant role in concordant xenograft rejection, and induction of bone marrow chimerism can overcome this barrier.
人类心脏的短缺仍然是心脏移植治疗终末期心脏病疗效的主要障碍。解决供应问题的一个潜在办法是使用非人类供体的心脏（异种移植物）。我们建立了小鼠到大鼠异种骨髓嵌合模型，在本研究中我们假设，这种嵌合大鼠将接受供体和受体特异性心脏移植物，同时排斥第三方小鼠和大鼠移植物。我们还研究了有无供体鼠心脏移植物的未处理大鼠和嵌合大鼠的体液反应。
给受体Lewis大鼠（n = 22）进行1100 cGy的致死性全身照射，并在同一天静脉注射300×10⁶个供体B10.BR小鼠骨髓细胞。存活大鼠（n = 18）的外周血在4周时进行分型，此后每月进行一次。在骨髓重建后6至8周进行供体和受体特异性以及第三方异位心脏移植。
所有实验动物均产生了多谱系骨髓嵌合，供体细胞完全替代了受体骨髓。移植到嵌合大鼠体内的鼠供体和大鼠受体品系心脏无限期存活。第三方大鼠和小鼠心脏被排斥，尽管排斥速度比骨髓匹配的未处理对照慢。在心脏被排斥的大鼠中检测到高水平的抗小鼠抗体。在心脏移植物长期存活的嵌合动物中不存在这些抗体。
在小鼠→大鼠骨髓移植模型中可产生长期多谱系骨髓嵌合。在这些嵌合动物中可实现供体特异性和受体特异性血管化心脏移植物的长期存活。这些动物临床正常，但由于它们排斥第三方心脏的时间比未处理动物晚，显示出亚临床免疫抑制方案的迹象。我们的结果表明，抗体在协调性异种移植排斥中也起重要作用，诱导骨髓嵌合可克服这一障碍。
