A blocking anti-CD28-specific antibody induces long-term heart allograft survival by suppression of the PKC theta-JNK signal pathway.
This study investigated the effects of a blocking anti-CD28 antibody (Anti-CD28-PV1-IgG3) in vitro and in vivo. Anti-CD28-PV1-IgG3, a hamster-mouse chimeric antibody against murine CD28, which does not provide CD28-positive signaling during TCR-driven T cell activation, enabled long-term survival of heart allografts across a complete mismatch of the MHC in rats. Among the T cell signaling proteins tested in the spleens from recipients, we found that recipients treated with anti-CD28-PV1-IgG3 exhibited suppression of alloantigen-initiated proximal TCR signaling events, including Lck, Zap70, Vav, and PI3K expression, and their PKC theta- and JNK-regulated expression/activation. This leads to attenuation of intragraft T cell infiltration and expression of T cell effector molecules. These results indicate that targeting the CD28 receptor with a blocking antibody leads to long-term allograft survival by reducing activation of alloantigen-mediated key signaling events in T cells that might be crucial for full T cell activation.
Jang
Mei-Shiang
MS
Astellas Research Institute of America, Skokie, IL 60077, USA.
Pan
Fan
F
Erickson
Laurie M
LM
Fisniku
Ogert
O
Crews
Gladys
G
Wynn
Carmen
C
Hong
In Chul
IC
Tamura
Kouichi
K
Kobayashi
Masakazu
M
Jiang
Hongsi
H
D000818:Animals; D000918:Antibody Specificity; D018106:CD28 Antigens / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
D018106:CD28 Antigens; D007527:Isoenzymes; C489591:Prkcq protein, rat; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048670:MAP Kinase Kinase 4