Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro.
We have shown previously that incorporation of a cDNA coding for the pro-apoptotic protein BAX into plasmid DNA coding for a secreted form of the pancreatic beta-cell antigen glutamic acid decarboxylase (GAD) promotes prevention of type 1 diabetes in non-obese diabetic (NOD) mice. Here we present evidence indicating that injection of the same vaccine at time of early diabetes onset could ameliorate the disease with efficacy, with 42% of mice overtly diabetic by 40 weeks of age compared to 92% in control groups. In addition, immunological analysis revealed that the DNA vaccine induced CD4(+)CD25(+) T cells cultured from draining lymph nodes that had immunosuppressive function in vitro. The induced regulatory T cells (Tregs) expressed the foxp3 gene and showed cell-contact-dependent as well as TGF-beta- and IL-10-independent immunosuppressive activity. Data also revealed that CD4(+)CD25(-) T cells from mice immunized with the DNA vaccine yielded a cell population that was foxp3(+), showed increased expression of CD25 compared to control, and had immunosuppressive function in vitro, indicating that Tregs could have developed from antigen-induced, peripheral T lymphocytes. In contrast, injection of DNA coding for SGAD55 or BAX alone did not induce Tregs. Altogether, our data confirm that pro-apoptotic DNA vaccination can be used as an immunosuppressive strategy and demonstrate its potential for therapy of pathological autoimmunity.
Li
Alice
A
Center for Transplant Immunology Research, Loma Linda University and Medical Center, CA 92354, USA.
Ojogho
Okechukwu
O
Franco
Edson
E
Baron
Pedro
P
Iwaki
Yuichi
Y
Escher
Alan
A
D000375:Aging; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000276:immunology
C494827:Bax protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D019444:Vaccines, DNA; D051028:bcl-2-Associated X Protein; D016753:Interleukin-10