Immune-mediated destruction of transfected myocytes following DNA vaccination occurs via multiple mechanisms.
The delivery of antigenic proteins in the context of a DNA vaccine leads to the intracellular synthesis of antigen and the induction of both humoral and cellular immune responses. Subsequent to immune activation, any transfected cell expressing the immunogenic protein should, by the rules of immunology, become a legitimate target for removal by immune-mediated mechanisms. Herein, we have used an indirect assay of myocyte integrity following intra-muscular (i.m.) delivery of a DNA vaccine, in mice with various immune deficiencies, to determine which immunological mechanisms may be involved in destruction of antigen-expressing cells. We demonstrate that destruction of antigen- expressing myocytes following i.m. injection of a DNA vaccine is dependent on major histocompatibility complex (MHC) class II restricted CD4+ T cell activation, but is not mediated solely by MHC I-restricted or perforin-mediated lysis and appears to have a component that is antibody-mediated. Although we studied myocytes, the results likely represent what happens to any transfected cell expressing a foreign antigen. This study underscores the ability of DNA vaccines at inducing antigen-specific immune responses that include a number of effector mechanisms. From the perspective of gene therapy, this study highlights the significance of immune activation when considering strategies where maintenance of therapeutic gene expression is desired.
Payette
P J
PJ
Loeb Health Research Institute, Ottawa, Canada.
Weeratna
R D
RD
McCluskie
M J
MJ
Davis
H L
HL
D000704:Analysis of Variance; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D007273:Injections, Intramuscular; D008156:Luciferases / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
D006514:Hepatitis B Surface Antigens; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D008156:Luciferases