Fló J, Tisminetzky S, Baralle F
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Cell Immunol. 2001 May 1;209(2):120-31. doi: 10.1006/cimm.2001.1784.
The costimulatory pathway that includes CD80, CD86, CD28, and CTLA-4 plays a key role in regulating T cell activation and tolerance and is a promising therapeutic target. We have studied the possibility of down-regulating the immune response to DNA vaccine by codelivery of a plasmid coding for the extracellular domains of CD86 (pDelta86). We found that DeltaCD86 was able to inhibit the engagement of FcCTLA-4 but not of FcCD28 to CD80 and CD86 expressed on COS cells. Coadministration of plasmid pDelta86 encoding for the extracellular domains of CD86 along with a plasmid encoding for the glycoprotein D (pgD) of herpes simplex virus-2 (a membrane-bound protein) by the im route in mice resulted in a strong inhibition of the cell-mediated immune response in the spleen and in draining lymph nodes. In addition, when pDelta86 was coadministered together with a plasmid encoding for the ovalbumin (pOVA) (a soluble protein), a strong inhibition of the cell-mediated immune response was observed in draining lymph nodes and only a partial inhibition was found in the spleen. Furthermore, only a partial down-regulation of the humoral immune response was observed. The mechanism involved could be a preferential engagement of DeltaCD86 to CTLA-4 leading to the transmission of a negative signal to T lymphocytes.
包括CD80、CD86、CD28和CTLA-4的共刺激途径在调节T细胞活化和耐受中起关键作用，是一个有前景的治疗靶点。我们研究了通过共递送编码CD86胞外域的质粒（pDelta86）来下调对DNA疫苗免疫反应的可能性。我们发现DeltaCD86能够抑制FcCTLA-4与COS细胞上表达的CD80和CD86的结合，但不能抑制FcCD28与它们的结合。在小鼠中通过肌内途径将编码CD86胞外域的质粒pDelta86与编码单纯疱疹病毒2糖蛋白D（pgD，一种膜结合蛋白）的质粒共同给药，导致脾脏和引流淋巴结中的细胞介导免疫反应受到强烈抑制。此外，当pDelta86与编码卵清蛋白（pOVA，一种可溶性蛋白）的质粒共同给药时，在引流淋巴结中观察到细胞介导免疫反应受到强烈抑制，而在脾脏中仅发现部分抑制。此外，仅观察到体液免疫反应的部分下调。其中涉及的机制可能是DeltaCD86与CTLA-4的优先结合导致向T淋巴细胞传递负信号。
