Codelivery of DNA coding for the soluble form of CD86 results in the down-regulation of the immune response to DNA vaccines

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 e xtracellular domains of CD86 (p Delta 86). We found that Delta CD86 was abl e to inhibit the engagement of FcCTLA-4 but not of FcCD28 to CD80 and CD86 expressed on COS cells.: Coadministration of plasmid p Delta 86 encoding fo r the extracellular domains of CD86 along with a plasmid encoding for the g lycoprotein 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, whe n p Delta 86 was coadministered together with a plasmid encoding for the ov albumin (pOVA) (a soluble protein), a strong inhibition of the cell-mediate d immune response was observed in draining lymph nodes and only a partial i nhibition was found in the spleen. Furthermore, only a partial down-regulat ion of the humoral immune response was observed. The mechanism involved cou ld be a preferential engagement of Delta CD86 to GTLA-4 leading to the tran smission of a negative signal to T lymphocytes. (C) 2001 Academic Press.