来氟米特在大鼠仓鼠心脏异种移植过程中对非T细胞依赖性IgM异种抗体形成的抑制作用。
Suppression of T-independent IgM xenoantibody formation by leflunomide during xenografting of hamster hearts in rats.
作者信息
Lin Y, Vandeputte M, Waer M
机构信息
Laboratory for Experimental Transplantation, Rega Institute, Leuven, Belgium.
出版信息
Transplantation. 1998 Feb 15;65(3):332-9. doi: 10.1097/00007890-199802150-00007.
BACKGROUND
It was recently shown that leflunomide (LF) delayed xenoantibody (XAb) formation and xenograft (Xg) rejection in a hamster-to-rat heart transplantation model. Our aim in this study was further investigation of the mechanism of LF-mediated suppression of XAb formation.
METHODS
Hamster hearts were heterotopically transplanted to euthymic or nude rats receiving LF and/or cyclosporine (CsA). Second hamster hearts were transplanted at the time of first Xg rejection. Serum from rejecting rats was transferred to naive rats receiving a hamster heart Xg. The isotype of XAbs was examined by fluorescence-activated cell sorting. Tissue deposition of XAbs and complement was determined by immunofluorescence. XAb formation and its response to LF were also investigated in severe combined immunodeficient mice reconstituted with purified CD5+ or CD5- rat B cells.
RESULTS
After xenografting, untreated PVG rats developed high titers of anti-hamster IgM XAbs that appeared T-independent (T-I) as they could not be suppressed by CsA and also occurred in athymic nude rats. A second Xg transplanted in control or CsA-treated rats rejecting a first Xg was subject to hyperacute rejection. Hyperacute rejection also occurred in naive rats after adoptive transfer of serum from rejecting rats. Monotherapy with LF resulted in a suppression of early IgM XAb formation and in a delay of Xg rejection, which was associated with predominantly IgG anti-hamster XAbs. These XAbs were T-dependent, as they did not occur in nude rats and were suppressed by CsA. CD5+ B lymphocytes appeared to contribute to T-I IgM XAb formation, as LF reduced the percentage of peripheral blood CD5+ B lymphocytes and severe combined immunodeficient mice reconstituted with purified CD5+ B cells, but not with CD5- B cells, produced anti-hamster IgM which were suppressed by LF but not CsA.
CONCLUSIONS
In rats, T-I XAb formation is a first step leading to hamster Xg rejection and is suppressed by LF leading to prolonged Xg survival.
背景
最近的研究表明，在仓鼠到大鼠的心脏移植模型中，来氟米特（LF）可延迟异种抗体（XAb）的形成和异种移植物（Xg）的排斥反应。本研究的目的是进一步探究LF介导抑制XAb形成的机制。
方法
将仓鼠心脏异位移植到接受LF和/或环孢素（CsA）的正常胸腺或裸鼠体内。在首次Xg排斥反应时移植第二颗仓鼠心脏。将排斥大鼠的血清转移到接受仓鼠心脏Xg的未接触过抗原的大鼠体内。通过荧光激活细胞分选检测XAbs的亚型。通过免疫荧光法测定XAbs和补体在组织中的沉积。在用纯化的CD5 +或CD5-大鼠B细胞重建的严重联合免疫缺陷小鼠中，也研究了XAb的形成及其对LF的反应。
结果
异种移植后，未经治疗的PVG大鼠产生高滴度的抗仓鼠IgM XAbs，这些抗体似乎是不依赖T细胞的（T-I），因为它们不能被CsA抑制，并且在无胸腺裸鼠中也会出现。在排斥第一颗Xg的对照或CsA处理的大鼠中移植的第二颗Xg会发生超急性排斥反应。在接受来自排斥大鼠的血清的过继转移后，未接触过抗原的大鼠中也发生了超急性排斥反应。LF单药治疗可抑制早期IgM XAb的形成，并延迟Xg排斥反应，这主要与IgG抗仓鼠XAbs有关。这些XAbs是依赖T细胞的，因为它们在裸鼠中不出现，并且被CsA抑制。CD5 + B淋巴细胞似乎有助于T-I IgM XAb的形成，因为LF降低了外周血CD5 + B淋巴细胞的百分比，并且用纯化的CD5 + B细胞而不是CD5- B细胞重建的严重联合免疫缺陷小鼠产生了抗仓鼠IgM，这些抗体被LF抑制但不被CsA抑制。
结论
在大鼠中，T-I XAb的形成是导致仓鼠Xg排斥反应的第一步，并且被LF抑制，从而延长了Xg的存活时间。
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