Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection
Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection
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DOI：
10.1073/pnas.93.24.13967
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发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Turka, LA
中科院分区：
文献类型：
--
作者：
Hancock, WW;Sayegh, MH;Turka, LA
最近的数据表明CD40-CD40配体(CD40L)通路在移植物排斥反应中起作用，一个潜在的机制是通过CD40L直接共刺激T细胞。或者，CD40刺激诱导抗原提呈细胞(APC)上CD80(B7-1)和CD86(B7-2)表达的能力导致了CD40-CD-40L相互作用在移植排斥反应中的作用可能是间接的假设，即，为了促进APC的共刺激能力，在这里，我们使用小鼠血管化的同种异体心脏移植模型来验证这一假设，用供者的脾细胞和单剂抗CD40L单抗治疗受者可以诱导移植物的长期存活(>；在所有动物中，这与移植物内Th1细胞因子[干扰素-γ和白介素2]和IL-12的表达显著抑制以及Th2细胞因子(IL-4和IL-10)的相互上调有关。在未经处理的同种异体移植受体中，CD86在24小时内在移植物的内皮细胞和浸润性单个核细胞上有较强的表达，而CD80在移植物植入后72小时才见表达。抗CD40L单抗对CD86的上调无明显影响，但几乎完全消除了CD80的诱导。然而，用抗CD80单抗或突变形式的CTLA4Ig(不与CD86结合)处理的动物排斥了移植物，表明单用CD80阻断不能介导抗CD40L单抗的延缓移植物生长的作用。这些数据支持CD40-CD40L在移植排斥反应中的作用不仅仅是促进CD80或CD86的表达，而是这一途径可以直接和独立地共刺激T细胞。这些数据还表明，移植肾的长期存活可以在不阻断T细胞受体介导的信号或CD28-CD86参与的情况下实现。
Recent data implicates a role for the CD40-CD40 ligand (CD40L) pathway in graft rejection, One potential mechanism is direct costimulation of T cells through CD40L. Alternatively, the ability of CD40 stimulation to induce CD80 (B7-1) and CD86 (B7-2) expression on antigen-presenting cells (APCs) has led to the hypothesis that the role of CD40-CD-40L interactions in transplant rejection might be indirect, i.e., to promote the costimulatory capacity of APCs, Here, we have used a murine vascularized cardiac allograft model to test this hypothesis, Treatment of the recipients with donor splenocytes and a single dose of anti-CD40L mAb induces long-term graft survival (>100 days) in all animals, This is associated with marked inhibition of intragraft Th1 cytokine [interferon gamma and interleukin (IL) 2] and IL-12 expression with reciprocal up-regulation of Th2 cytokines (IL-4 and IL-10). In untreated allograft recipients, CD86 is strongly expressed on endothelial cells and infiltrating mononuclear cells of the graft within 24 hr, In contrast, CD80 expression is not seen until 72 hr after engraftment Anti-CD40L mAb has no detectable effect on CD86 up-regulation, but almost completely abolishes induction of CD80, However, animals treated with anti-CD80 mAb or with a mutated form of CTLA4Ig (which does not bind to CD86) rejected their cardiac allografts, indicating that blockade of CD80 alone does not mediate the graft-prolonging effects of anti-CD40L mAb. These data support the notion that the role of CD40-CD40L in transplant rejection is not solely to promote CD80 or CD86 expression, but rather that this pathway can directly and independently costimulate T cells, These data also suggest that long-term graft survival can be achieved without blockade of either T cell receptor-mediated signals or CD28-CD86 engagement.