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Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell
1Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, CA 94305, USA.
Abstract:
Usually we rely on vaccination to promote an immune response to a pathogenic microbe. In this study, we demonstrate a suppressive from of vaccination, with DNA encoding a minigene for residues 139-151 of myelin proteolipid protein (PLP139-151), a pathogenic self-Ag. This suppressive vaccination attenuates a prototypic autoimmune disease, experimental autoimmune encephalomyelitis, which presents clinically with paralysis. Proliferative responses and production of the Th1 cytokines, IL-2 and IFN-gamma, were reduced in T cells responsive to PLP139-151. In the brains of mice that were successfully vaccinated, mRNA for IL-2, IL-15, and IFN-gamma were reduced. A mechanism underlying the reduction in severity and incidence of paralytic autoimmune disease and the reduction in Th1 cytokines involves altered costimulation of T cells; loading of APCs with DNA encoding PLP139-151 reduced the capacity of a T cell line reactive to PLP139-151 to proliferate even in the presence of exogenous CD28 costimulation. DNA immunization with the myelin minigene for PLP-altered expression of B7.1 (CD80), and B7.2 (CD86) on APCs in the spleen. Suppressive immunization against self-Ags encoded by DNA may be exploited to treat autoimmune diseases.
Insights
This study introduces suppressive vaccination using DNA encoding a myelin protein fragment to treat autoimmune diseases like experimental autoimmune encephalomyelitis. This novel approach reduces T cell responses and disease severity by altering immune cell signaling.
Area of Science:
- Immunology
- Neuroscience
- Vaccinology
Background:
- Traditional vaccination promotes immune responses against pathogens.
- Autoimmune diseases involve the immune system attacking self-antigens.
- Experimental autoimmune encephalomyelitis (EAE) is a model for paralytic autoimmune disorders.
Purpose of the Study:
- To investigate suppressive vaccination using DNA encoding a self-antigen.
- To evaluate the efficacy of this approach in an autoimmune disease model.
- To elucidate the underlying mechanisms of immune modulation.
Main Methods:
- DNA immunization with a minigene encoding myelin proteolipid protein (PLP139-151).
- Assessment of experimental autoimmune encephalomyelitis (EAE) incidence and severity.
- Analysis of T cell proliferation and cytokine production (IL-2, IFN-gamma).
- Evaluation of antigen-presenting cell (APC) costimulatory molecule expression (B7.1, B7.2).
Main Results:
- Suppressive vaccination attenuated EAE, reducing paralysis.
- Reduced T cell proliferation and Th1 cytokine (IL-2, IFN-gamma) production observed.
- Decreased mRNA expression of IL-2, IL-15, and IFN-gamma in the brain.
- Altered APC costimulation, with reduced capacity for T cell proliferation.
Conclusions:
- DNA immunization with self-antigen minigenes can induce suppressive immunity.
- This approach effectively treats experimental autoimmune encephalomyelitis by modulating T cell responses.
- Targeting APC costimulation is a key mechanism in DNA-mediated immune suppression.
- Suppressive immunization against self-antigens holds potential for treating autoimmune diseases.