title: Programmed death-1 ligands-transfected dendritic cells loaded with glutamic acid decarboxylase 65 (GAD65) inhibit both the alloresponse and the GAD65-reactive lymphocyte response.
abstract: Type 1 diabetes (T1D) is due to a loss of immune tolerance to islet antigens, such as glutamic acid decarboxylase 65 (GAD65), for which islet transplantation is a promising therapy. Therefore, the generation of tolerance aiming at both alloantigen and GAD65 will help therapeutic intervention greatly in T1D. In this study, we tested the effect of programmed death-1 ligands (PD-L1)-transfected dendritic cells (DC) loaded with GAD65 on the alloresponse and GAD65-reactive lymphocyte response. The DC2.4 cell line was transfected with PD-L1 and co-cultured with GAD65. BALB-c mice were primed, respectively, by intraperitoneal injection with GAD65, PD-L1-transfected- or non-transfected DC (PD-L1/DC or DC), and PD-L1-transfected- or non-transfected DC loaded with GAD65 (PD-L1/DC/GAD65 or DC/GAD65). Splenocytes of treated mice were isolated and restimulated in vitro with GAD65 or the various DC populations above being used as stimulators, respectively. In the mixed lymphocyte reaction, DC/GAD65 were able to stimulate both allogeneic and GAD65-reactive lymphocytes. However, PD-L1/DC/GAD65 were poorer than DC/GAD65 at activating the GAD65-reactive lymphocyte response. Further, although PD-L1/DC could inhibit the alloresponse, PD-L1/DC/GAD65 were more effective at down-regulating the GAD65-reactive lymphocyte response. More importantly, PD-L1/DC/GAD65-primed lymphocytes exhibited the weakest proliferation when again restimulated in vitro by PD-L1/DC/GAD65. Additionally, PD-L1/DC/GAD65 down-regulated interferon-gamma and up-regulated interleukin-10 production by activated lymphocytes. Therefore, combined stimulation in vivo and in vitro by PD-L1/DC/GAD65 could inhibit both the alloresponse and the GAD65-reactive lymphocyte response, which may contribute to controlling diabetes and islet transplant rejection.
authors.affiliation: Department of Immunology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: F-R
authors.initials: FR
authors.lastname: He
authors.forename: H-F
authors.initials: HF
authors.lastname: Zhu
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: Y D
authors.initials: YD
authors.lastname: Dai
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Xing
authors.forename: G-X
authors.initials: GX
authors.lastname: Shen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy; D004705:Endocytosis; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D007519:Isoantigens / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D061026:Programmed Cell Death 1 Receptor; D014162:Transfection / Q000379:methods; D019076:Transgenes
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D007519:Isoantigens; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2