Lin Y, Ji P, Xia G, Vandeputte M, Waer M
Laboratory for Experimental Transplantation, University of Leuven, Belgium.
Transplantation. 1998 Feb 15;65(3):340-5. doi: 10.1097/00007890-199802150-00008.
We have shown previously that a 2-week course of leflunomide (LF) together with a maintenance therapy of cyclosporine (CsA) rendered hamster-to-rat heart xenografts (Xg) resistant against anti-hamster IgM xenoantibody (XAb)-mediated rejection, a state compatible with the notion of accommodation. Our aim in this study was to investigate the mechanism underlying this Xg accommodation.
"Accommodated" Xgs were retransplanted to CsA-treated naive rats in the presence or absence of additional LF treatment or anti-hamster IgM serum injection. Immunohistopathology and fluorescence-activated cell sorting was performed to detect IgM and complement (C) deposition in Xgs, and endothelial cell (EC) expression of P- and E-selectin, ICAM-1, and VCAM-1 in vivo and in vitro.
Retransplanted accommodated Xgs were rejected in CsA-treated naive rats and elicited IgM XAbs. Passive transfer of IgM XAbs provoked hyperacute rejection of both control and retransplanted Xgs. Addition of a 5-day course of LF prevented the rejection of only accommodated Xgs. Adoptively transferred IgM XAbs were deposited in rejected control and accommodated Xgs, but not in accommodated Xgs accepted by LF-treated rats. LF blocked the EC induction of P- and E-selectins in both control fresh and accommodated Xgs. Hence, after retransplantation accommodated Xgs express mainly induced xenoantigens (XAgs), such as P- and E-selectins, that can entirely be suppressed by LF. In contrast, control hamster Xgs express additional XAgs and remain susceptible to XAb-mediated rejection. These findings are in agreement with in vitro studies showing that LF totally suppressed induced EC antigens (e.g., P-selectin and E-selectin), but not constitutively expressed antigens (e.g., ICAM-1).
Accommodated Xgs show a down-regulation of constitutive XAgs, but may be rejected after retransplantation by a mechanism involving EC expression of inducible XAgs. LF is able to block this latter XAg induction.
我们之前已经表明，为期2周的来氟米特（LF）疗程与环孢素（CsA）维持疗法可使仓鼠到大鼠的心脏异种移植（Xg）对抗仓鼠IgM异种抗体（XAb）介导的排斥产生抗性，这种状态与适应性的概念相符。我们在本研究中的目的是探究这种Xg适应性的潜在机制。
在有或没有额外的LF治疗或抗仓鼠IgM血清注射的情况下，将“适应性”Xg重新移植到经CsA治疗的未致敏大鼠体内。进行免疫组织病理学和荧光激活细胞分选以检测Xg中IgM和补体（C）的沉积，以及体内和体外内皮细胞（EC）上P-选择素、E-选择素、细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）的表达。
重新移植的适应性Xg在经CsA治疗的未致敏大鼠中被排斥，并引发IgM XAb。IgM XAb的被动转移引发了对照和重新移植的Xg的超急性排斥。添加为期5天的LF疗程仅能防止适应性Xg被排斥。过继转移的IgM XAb沉积在被排斥的对照和适应性Xg中，但未沉积在经LF治疗的大鼠所接受的适应性Xg中。LF可阻断对照新鲜Xg和适应性Xg中EC对P-选择素和E-选择素的诱导。因此，重新移植后，适应性Xg主要表达诱导性异种抗原（XAg），如P-选择素和E-选择素，而LF可完全抑制这些抗原。相比之下，对照仓鼠Xg表达额外的XAg，并且仍然易受XAb介导的排斥。这些发现与体外研究结果一致，即LF完全抑制诱导性EC抗原（如P-选择素和E-选择素），但不抑制组成性表达的抗原（如ICAM-1）。
适应性Xg显示组成性XAg下调，但在重新移植后可能通过涉及诱导性XAg的EC表达的机制被排斥。LF能够阻断后一种XAg的诱导。
