Habiro Katsuyoshi, Kotani Motoko, Omoto Kazuya, Kobayashi Sakiko, Tanabe Kazunari, Shimmura Hiroaki, Suzuki Keiko, Hayashi Tomohito, Toma Hiroshi, Abe Ryo
Division of Immunobiology, Research Institute for Biological Sciences, Tokyo University of Science, Noda City, Japan.
Transplantation. 2003 Sep 15;76(5):854-8. doi: 10.1097/01.TP.0000084868.09385.83.
It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice.
Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+ and CD8+ T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay.
BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+ T cells. In vitro studies indicated that CD8+ T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice.
In the absence of CD28 and CD40 costimulatory signals, CD8+ T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation.
研究表明，同时阻断CD28和CD40介导的共刺激信号可显著延长同种异体移植物的存活时间。尽管这些结果引发了人们对建立器官移植特异性免疫耐受疗法的期望，但很明显，这些治疗很少能使同种异体移植物无限期存活。为了揭示这些共刺激阻断抗性同种异体移植物排斥反应的潜在机制，我们研究了CD28和CD40配体（L）双缺陷（双敲除[dKO]）小鼠的同种异体皮肤移植排斥过程。
将来自BALB/c或BALB.B小鼠的皮肤移植物移植到C57BL/6背景的dKO小鼠体内。通过细胞染色分析确定直接或间接途径呈递的同种异体抗原反应性CD4+和CD8+T细胞的频率。
BALB/c皮肤移植物被dKO小鼠迅速排斥。这种不依赖CD28和CD40L的同种异体移植物排斥反应可通过清除CD8+T细胞来抑制。体外研究表明，来自接受BALB/c皮肤移植的dKO小鼠的CD8+T细胞仅对直接途径呈递的供体抗原产生反应。与主要组织相容性复合体（MHC）不匹配的供体不同，来自MHC匹配供体的同种异体皮肤移植物被dKO小鼠接受。
在缺乏CD28和CD40共刺激信号的情况下，CD8+T细胞通过直接途径识别MHC抗原，导致来自MHC不匹配供体的皮肤移植物被排斥。相比之下，MHC匹配和非MHC不匹配供体的皮肤移植物在dKO小鼠中可无限期存活。这些结果表明，供体-宿主MHC匹配对于器官移植的共刺激阻断治疗可能仍然至关重要。
