Lin Y, Soares M P, Sato K, Csizmadia E, Robson S C, Smith N, Bach F H
Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Immunol. 2000 May 1;164(9):4883-92. doi: 10.4049/jimmunol.164.9.4883.
We transplanted hamster hearts into rats that had been sensitized to hamster cardiac grafts 5 days earlier as a model for discordant xenotransplantation. Sensitized rats had high serum levels of elicited anti-donor IgM and IgG that caused hyperacute rejection. Transient complement inhibition with cobra venom factor (CVF) plus daily and continuing cyclosporin A (CyA) prevented hyperacute rejection. However, grafts underwent delayed xenograft rejection (DXR). DXR involved IgG and associated Ab-dependent cell-mediated rejection, because depletion of IgG or Ab-dependent cell-mediated rejection-associated effector cells prolonged graft survival and the serum-mediated Ab-dependent cell-mediated cytotoxicity in vitro. Blood exchange in combination with CVF/CyA treatment dramatically decreased the level of preexisting Abs, but DXR still occurred in association with the return of Abs. Splenectomy and cyclophosphamide acted synergistically to delay Ab return, and when combined with blood exchange/CVF/CyA facilitated long-term survival of grafts. These grafts survived in the presence of anti-donor IgM, IgG, and complement that precipitated rejection of naive hearts, indicating that accommodation (survival in the presence of anti-graft Abs and complement) had occurred. We attribute the long-term survival to the removal of preexisting anti-donor Abs and therapy that attenuated the rate of Ab return. Under such conditions, the surviving hearts showed expression in endothelial cells and smooth muscle cells of protective genes and an intragraft Th2 immune response. Th2 responses and protective genes are associated with resistance to IgM- and IgG-mediated, complement-dependent and -independent forms of rejection.
我们将仓鼠心脏移植到5天前已对仓鼠心脏移植物致敏的大鼠体内，以此作为非协调性异种移植的模型。致敏大鼠血清中诱导产生的抗供体IgM和IgG水平较高，会引发超急性排斥反应。用眼镜蛇毒因子（CVF）进行短暂的补体抑制并每日持续给予环孢素A（CyA）可预防超急性排斥反应。然而，移植物仍发生了延迟性异种移植物排斥反应（DXR）。DXR涉及IgG以及相关的抗体依赖性细胞介导的排斥反应，因为去除IgG或抗体依赖性细胞介导的排斥反应相关效应细胞可延长移植物存活时间，并降低体外血清介导的抗体依赖性细胞介导的细胞毒性。血液交换联合CVF/CyA治疗可显著降低预先存在的抗体水平，但随着抗体水平的回升，DXR仍会发生。脾切除术和环磷酰胺协同作用可延迟抗体回升，与血液交换/CVF/CyA联合使用时可促进移植物的长期存活。这些移植物在存在抗供体IgM、IgG和补体的情况下存活下来，而这些物质会导致未致敏心脏发生排斥反应，这表明发生了适应性改变（在存在抗移植物抗体和补体的情况下存活）。我们将长期存活归因于预先存在的抗供体抗体的清除以及减缓抗体回升速度的治疗。在这种情况下，存活的心脏在内皮细胞和平滑肌细胞中表现出保护性基因的表达以及移植物内的Th2免疫反应。Th2反应和保护性基因与对IgM和IgG介导的、补体依赖性和非依赖性排斥反应形式的抗性相关。
