Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice.
نویسندگان
چکیده
We previously demonstrated that administration of plasmid DNAs (pDNAs) encoding IL-4 and a fragment of glutamic acid decarboxylase 65 (GAD65) fused to IgGFc induces GAD65-specific Th2 cells and prevents insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To assess the general applicability of pDNA vaccination to mediate Ag-specific immune deviation, we examined the immunotherapeutic efficacy of recombinants encoding murine insulin A and B chains fused to IgGFc. Insulin was chosen based on studies demonstrating that administration of insulin or insulin B chain by a variety of strategies prevents IDDM in NOD mice. Surprisingly, young NOD mice receiving i.m. injections of pDNA encoding insulin B chain-IgGFc with or without IL-4 exhibited an accelerated progression of insulitis and developed early diabetes. Exacerbation of IDDM correlated with an increased frequency of IFN-gamma-secreting CD4(+) and CD8(+) T cells in response to insulin B chain-specific peptides compared with untreated mice. In contrast, treatment with pDNAs encoding insulin A chain-IgGFc and IL-4 elicited a low frequency of IL-4-secreting Th cells and had no effect on the progression of IDDM. Vaccination with pDNAs encoding GAD65-IgGFc and IL-4, however, prevented IDDM. These results demonstrate that insulin- and GAD65-specific T cell reactivity induced by pDNA vaccination has distinct effects on the progression of IDDM.
منابع مشابه
A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice.
Several studies have provided indirect evidence in support of a role for beta cell-specific Th2 cells in regulating insulin-dependent diabetes (IDDM). Whether a homogeneous population of Th2 cells having a defined beta cell Ag specificity can prevent or suppress autoimmune diabetes is still unclear. In fact, recent studies have demonstrated that beta cell-specific Th2 cell clones can induce IDD...
متن کاملThe type and frequency of immunoregulatory CD4+ T-cells govern the efficacy of antigen-specific immunotherapy in nonobese diabetic mice.
Antigen-specific immunotherapy, an approach to selectively block autoimmune diabetes, generally declines in nonobese diabetic (NOD) mice as disease progresses. To define the parameters influencing the efficacy of antigen-specific immunotherapy once diabetes is established, plasmid DNA (pDNA) vaccination was used to suppress autoimmune-mediated destruction of syngeneic islet grafts in diabetic N...
متن کاملT-cell Tolerance Following Bacterial Glutamic Acid Decarboxylase (GAD) Feeding in Streptozotocin-induced Diabetes
Background: Autoimmune type 1 diabetes mellitus is caused by T-cell mediated immune destruction of the insulin-producing β-cell in pancreatic islets of Langerhans. Specificity of the auto-antibodies and of the auto-reactive T-cells has been investigated, in which several auto-antigens were proposed. Objective: To determine whether glutamic acid decarboxylase (GAD) feeding would induce oral tol...
متن کاملMice Autoimmune Diabetes in Nonobese Diabetic Th2 Cell Clone Immunoregulates A Glutamic Acid Decarboxylase 65-Specific
متن کامل
Intramuscular injection of plasmid DNA encoding intracellular or secreted glutamic acid decarboxylase causes decreased insulitis in the non- obese diabetic mouse
O u r g o a l i s t o determine whether gene vaccination can be used for the treatment of insulindependent diabetes mell i tus (IDDM), an autoimmune disease. In this work, weanling non-obese diabetic (NOD) mice, an animal model system for the study of IDDM, received intramuscular injections of “naked” plasmid DNA encoding either intracellular or secreted human glutamic acid decarboxylase (GAD),...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of immunology
دوره 167 1 شماره
صفحات -
تاریخ انتشار 2001