A therapeutic DNA vaccination strategy for autoimmunity and transplantation.
De novo autoimmunity induced by an allograft may play a significant role in chronic organ rejection, which remains a major barrier to successful transplantation. Accordingly, immunization with non-polymorphic antigens found in both donor allograft and recipient would be an attractive means to prevent long-term graft rejection, because it would rely on recipient mechanisms of immune homeostasis and could minimize the need to identify appropriate donor polymorphic antigens for induction of graft tolerance. Here we show that intradermal injection of plasmid DNA encoding glutamic acid decarboxylase (GAD) polypeptide, which is synthesized in both pancreatic islet and skin tissue, ameliorated new-onset type 1 diabetes in NOD mice and increased skin allograft survival in a BALB/c-C57BL/6 model system in a donor-specific manner. Successful therapy of autoimmune diabetes required CpG-methylation of plasmid DNA and co-delivery of a cDNA coding for the pro-apoptotic BAX protein, which was shown previously to induce Foxp3(+) regulatory T cells in NOD mice. In contrast, significantly increased skin allograft survival after immunization of recipient only required CpG-methylation of plasmid DNA coding for GAD alone. Injection of unmethylated plasmid DNA coding for BAX alone near the allograft also promoted graft survival, but induced a pro-inflammatory response to self-antigens. Our results reveal a promising potential for autoimmunity-targeting DNA vaccination to be applied to transplantation.
Li
Alice
A
Center for Transplant Immunology Research, School of Medicine and Medical Center, Loma Linda University, Loma Linda, CA 92354, USA.
Chen
Jianfeng
J
Hattori
Masahiro
M
Franco
Edson
E
Zuppan
Craig
C
Ojogho
Okechukwu
O
Iwaki
Yuichi
Y
Escher
Alan
A
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010957:Plasmids; D016038:Skin Transplantation; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D019444:Vaccines, DNA / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology
C494827:Bax protein, mouse; D010446:Peptide Fragments; D019444:Vaccines, DNA; D051028:bcl-2-Associated X Protein; C501056:glutamate decarboxylase 65 (202-221); D005968:Glutamate Decarboxylase