Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues.
First-generation adenovirus vectors will have limited application in gene therapy for chronic diseases because of destructive host immune responses. Important immune effectors include CD8+ T cells, which mediate target cell destruction and ablate transgene expression, and B cells, which produce neutralizing antibodies that block effective readministration of vector. Previous studies indicated that activation of CD4+ T cells by virus capsid proteins is necessary for full realization of effector function of CD8+ T cells and B cells. In this paper, we present a strategy for preventing CD4+ T-cell activation by an adenovirus vector delivered to mouse liver and lung tissues which is based on interfering with T-cell priming via CD40 ligand-CD40 interactions. Adenovirus transgene expression was stabilized in mice genetically deficient in CD40 ligand (CD40L), and neutralizing antibody to adenovirus did not develop, allowing efficient readministration of vector. A transient blockade of T-cell activation with an antibody to CD40L infused into the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished production of neutralizing antibody, allowing readministration of vector. In vitro T-cell assays suggested that a block in the primary activation of CD4+ T cells was responsible for the lack of B-cell- and cytotoxic-T-cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.
Yang
Y
Y
Institute for Human Gene Therapy, University of Pennsylvania Health System, Philadelphia, USA.
Su
Q
Q
Grewal
I S
IS
Schilz
R
R
Flavell
R A
RA
Wilson
J M
JM
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000256:Adenoviridae / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000906:Antibodies; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002645:Chickens; D003602:Cytotoxicity, Immunologic; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000199:Actins; D000906:Antibodies; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D000469:Alkaline Phosphatase