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 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.
Fló
J
J
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Tisminetzky
S
S
Baralle
F
F
D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D004247:DNA / Q000276:immunology*; D004279:DNA, Viral / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D006566:Herpesviridae Infections / Q000517:prevention & control; D007111:Immunity, Cellular; D018796:Immunoconjugates; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D004279:DNA, Viral; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; C040570:glycoprotein D-herpes simplex virus type 2; D000069594:Abatacept; D004247:DNA