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Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and
Y Yang1, Q Su, I S Grewal
1Institute for Human Gene Therapy, University of Pennsylvania Health System, Philadelphia, USA.
Abstract:
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.
Insights
Blocking CD40 ligand (CD40L) interactions prevents immune responses to adenovirus vectors. This strategy stabilizes transgene expression and allows vector re-administration, improving gene therapy for chronic diseases.
Area of Science:
- Immunology
- Gene Therapy
- Virology
Background:
- First-generation adenovirus vectors elicit destructive host immune responses, limiting their use in gene therapy.
- CD8+ T cells destroy target cells, while B cells produce neutralizing antibodies, both hindering effective gene therapy.
- CD4+ T cell activation by adenovirus capsid proteins is crucial for CD8+ T cell and B cell effector functions.
Purpose of the Study:
- To develop a strategy to prevent CD4+ T cell activation by adenovirus vectors.
- To investigate the role of CD40 ligand-CD40 interactions in T cell priming against adenovirus vectors.
- To assess the impact of blocking CD40L on transgene expression and immune responses.
Main Methods:
- Adenovirus vectors were delivered to mouse liver and lung tissues.
- Mice genetically deficient in CD40 ligand (CD40L) were used.
- An antibody to CD40L was administered to block T cell activation during gene transfer.
- In vitro T cell assays were performed.
Main Results:
- Adenovirus transgene expression was stabilized in CD40L-deficient mice.
- Neutralizing antibodies to adenovirus did not develop in CD40L-deficient mice, allowing vector re-administration.
- Transient blockade of T cell activation with anti-CD40L antibody stabilized transgene expression and reduced neutralizing antibody production.
- In vitro assays indicated a block in primary CD4+ T cell activation, leading to diminished B cell and cytotoxic T cell responses.
Conclusions:
- Interfering with CD40 ligand-CD40 interactions prevents CD4+ T cell activation by adenovirus vectors.
- Blocking CD40L at the time of gene transfer improves adenovirus vector efficacy and allows for re-administration.
- This strategy holds promise for enhancing the potential of adenovirus vectors in gene therapy.
