Prolonged blockade of CD40-CD40 ligand interactions by gene transfer of CD40Ig results in long-term heart allograft survival and donor-specific hyporesponsiveness, but does not prevent chronic rejection
Prolonged blockade of CD40-CD40 ligand interactions by gene transfer of CD40Ig results in long-term heart allograft survival and donor-specific hyporesponsiveness, but does not prevent chronic rejection
复制标题
DOI：
10.4049/jimmunol.168.4.1600
复制
发表时间：
2002-02-15
影响因子：
4.4
通讯作者：
Anegon, I
中科院分区：
文献类型：
--
作者：
Guillot, C;Guillonneau, C;Anegon, I
先前使用抗CD 40配体mAb阻断小鼠和灵长类动物中CD 40-CD 40配体相互作用的工作已导致同种异体移植物存活时间适度延长，而不会出现真正的同种异体移植物耐受性。在这项研究中，我们在大鼠中发现，腺病毒介导的CD 40 Ig序列基因转移到移植物中导致CD 40 Ig表达延长（>200天）和长期（>300天）存活。表达CD 40 Ig的受体在移植后早期（第5天和第17天）和晚期时间点（>100天）显示出强烈（>90%）抑制混合白细胞反应和同种抗体产生，但在早期时间点（第5天）通过免疫组织学评估显示出对白细胞浸润和细胞因子产生的有限抑制。长期存活心脏的受体表现出供体特异性低反应性，因为接受第二次心脏移植是供体特异性的。然而，长期同种异体移植（>100天）显示慢性排斥血管病变的迹象。闭塞血管显示白细胞浸润，主要由CD 4（+）和CD 8（+）细胞、巨噬细胞和肥大细胞组成。这些受者也表现出抗供体CTL活性。表达CD 40 Ig的受体没有表现出非特异性免疫抑制，因为它们能够产生在早期时间点部分抑制的抗同源免疫应答，此后恢复正常。我们的结论是，基因转移介导的表达的CD 40免疫球蛋白导致了一个非常有效的抑制大鼠心脏移植急性排斥反应。这种治疗诱导供体特异性抑制某些同种异体反应机制在短期内，但不是长期的，这导致长期生存的同种异体移植伴随着慢性排斥反应的发展。
Previous work on blockade of CD40-CD40 ligand interaction in mice and primates with anti-CD40 ligand mAbs has resulted in a moderate prolongation of allograft survival without the development of true allograft tolerance. In this study, we show in rats that adenovirus-mediated gene transfer of CD40Ig sequences into the graft resulted in prolonged (>200 days) expression of CD40Ig and in long-term (>300 days) survival. Recipients expressing CD40Ig displayed strongly (>90%) inhibited mixed leukocyte reactions and alloantibody production at early (days 5 and 17) and late time points (>100 day) after transplantation, but showed limited inhibition of leukocyte infiltration and cytokine production as evaluated by immunohistology at early time points (day 5). Recipients of long-surviving hearts showed donor-specific hyporesponsiveness since acceptance of second cardiac allografts was donor specific. Nevertheless, long-term allografts (>100 days) displayed signs of chronic rejection vasculopathy. Occluded vessels showed leukocyte infiltration, mainly composed of CD4(+) and CD8(+) cells, macrophages, and mast cells. These recipients also showed antidonor CTL activity. Recipients expressing CD40Ig did not show nonspecific immunosuppression, as they were able to mount anticognate immune responses that were partially inhibited at early time points and were normal thereafter. We conclude that gene transfer-mediated expression of CD40Ig resulted in a highly efficient inhibition of acute heart allograft rejection in rats. This treatment induced donor-specific inhibition of certain alloreactive mechanisms in the short-, but not the long-term, which resulted in long-term survival of allografts concomitant with the development of chronic rejection.