1. Inhibition of allogeneic islet graft rejection by VISTA-conjugated liposome
- Author
-
Meng Guo, Wen-yuan Guo, Xiao-Min Shi, Guoshan Ding, Liu Yanfang, Yuanyu Zhao, Quanxing Wang, Fang Liu, and Shu Han
- Subjects
Graft Rejection ,Male ,0301 basic medicine ,Immunoconjugates ,Islets of Langerhans Transplantation ,Gene Expression ,Lymphocyte proliferation ,Lymphocyte Activation ,Biochemistry ,law.invention ,Mice ,0302 clinical medicine ,Genes, Reporter ,law ,Medicine ,Lymphocytes ,Luciferases ,Receptor ,Mice, Inbred BALB C ,Liposome ,geography.geographical_feature_category ,Graft Survival ,Islet ,030220 oncology & carcinogenesis ,Half-Life ,Signal Transduction ,Biophysics ,Biotin ,Islets of Langerhans ,03 medical and health sciences ,Bacterial Proteins ,Animals ,Syk Kinase ,Transplantation, Homologous ,Proto-Oncogene Proteins c-vav ,Molecular Biology ,Cell Proliferation ,geography ,business.industry ,Membrane Proteins ,Cell Biology ,Fusion protein ,Blockade ,Mice, Inbred C57BL ,Transplantation ,030104 developmental biology ,Liposomes ,Cancer research ,Suppressor ,Lymphocyte Culture Test, Mixed ,business - Abstract
The Ig superfamily member V-domain Ig-containing suppressor of T-cell activation (VISTA) is a negative regulator with broad-spectrum activities and has reported that blockade of VISTA or combination with other negative checkpoint receptors sufficiently break tumor tolerance. However, it remains unclear whether VISTA could induce allogeneic T-cell hyporesponsiveness and inhibit allograft rejection. Here we found VISTA treatment significantly inhibited lymphocyte proliferation and activation in allogeneic MLR assay through impairing SYK-VAV pathway. Interestingly, though neither VISTA protein nor VISTA-Fc fusion protein administration exerted satisfactory immunosuppressive effect on allograft survival due to their short half-life in circulation, this problem was solved by conjugating VISTA protein on liposome by biotin-streptavidin system, which markedly prolonged its circulating half-life to 60 h. With islet transplant model, administration of VISTA-conjugated liposome could markedly prolong allograft survival by inhibition of SYK-VAV pathway, thus maintained the normal blood glucose level of recipients during treatment period. The results indicate VISTA is a promising therapeutic target to treat allograft rejection of islet transplantation.
- Published
- 2019