de Haan A, van der Gun I, van Dijk E, Hepkema B G, Prop J, de Leij L F
Department of Cardiopulmonary Surgery, University Hospital Groningen, The Netherlands.
Transplantation. 2000 Apr 27;69(8):1637-44. doi: 10.1097/00007890-200004270-00020.
After solid organ transplantation most alloantigens are presented to the recipient's immune system by normal tissue cells, which can be considered to act as nonprofessional antigen-presenting cells (APC). It is well accepted that such nonprofessional APC fail to activate recipient resting T cells due to their inability to deliver costimulatory activity. In our study, we tested a hypothesis that such costimulatory activity may be provided by "bystander" recipient professional APC.
We set up mixed lymphocyte cultures (MLC) of purified T cell responders and T cell stimulator cells, the latter as nonprofessional APC carrying allogeneic MHC class I and II, and tested if responder-type autologous APC could facilitate responder T cell proliferation. In this assay also the effects of anti-CD28 antibody and interleukin- (IL) 1beta, IL-6, or IL-12 mediated costimulation on responder T cell proliferation and IL-2 production were investigated.
Autologous APC, i.e., monocytes, were found to facilitate the proliferative response of resting T cells stimulated by allogeneic nonprofessional APC. IL-12 was identified as the most important costimulatory factor for induction of proliferation. IL-1beta enhanced IL-2 production and proliferation of allostimulated resting T cells but its presence was not essential. Although CD28 triggering alone was ineffective, this costimulatory pathway enhanced IL-2 production and proliferation when combined with IL-12 or IL-1beta.
We conclude that costimulatory activity for activation of resting human T cells by nonprofessional donor APC can be delivered through activity of bystander recipient-type autologous APC. This mechanism of allostimulation may contribute to the induction and perpetuation of alloreactivity "in vivo" in a time frame when intragraft professional donor-type APC have been replaced with professional recipient-type APC.
实体器官移植后，大多数同种异体抗原由正常组织细胞呈递给受体的免疫系统，这些正常组织细胞可被视为非专职抗原呈递细胞（APC）。人们普遍认为，此类非专职APC由于无法传递共刺激活性，因而无法激活受体静息T细胞。在我们的研究中，我们检验了一个假设，即这种共刺激活性可能由“旁观者”受体专职APC提供。
我们建立了纯化的T细胞应答者与T细胞刺激细胞的混合淋巴细胞培养（MLC），后者作为携带同种异体MHC I类和II类分子的非专职APC，并检测应答者型自体APC是否能促进应答者T细胞增殖。在该试验中，还研究了抗CD28抗体和白细胞介素（IL）-1β、IL-6或IL-12介导的共刺激对应答者T细胞增殖和IL-2产生的影响。
发现自体APC，即单核细胞，可促进同种异体非专职APC刺激的静息T细胞的增殖反应。IL-12被确定为诱导增殖的最重要共刺激因子。IL-1β可增强同种异体刺激的静息T细胞的IL-2产生和增殖，但它的存在并非必需。尽管单独触发CD28无效，但当与IL-12或IL-1β联合时，该共刺激途径可增强IL-2产生和增殖。
我们得出结论，非专职供体APC激活静息人T细胞的共刺激活性可通过旁观者受体型自体APC的活性来传递。这种同种异体刺激机制可能在移植体内专职供体型APC已被专职受体型APC取代的时间段内，促进“体内”同种异体反应性的诱导和持续存在。
