Trends in Neurosciences
Immune responses to adenovirus vectors in the nervous system
Section snippets
Immune responses to adenovirus vectors
The immune system plays a crucial role in peripheral organs in limiting the duration of transgene expression from adenoviral vectors9, 10. For example, in normal mouse liver, transgene expression declines dramatically over the initial few weeks and is accompanied by inflammation; both of these effects are due to anti-vector immune responses10, 11. In sharp contrast, transgene expression occurs for considerably longer in young animals with underdeveloped immune systems or in those that are
Immune responses in distant synaptically linked brain sites
An important and interesting property of viral vectors is their capacity for rapid retrograde axonal transport in the brain, which suggests that they might be useful for gene delivery to distant synaptically linked brain regions. This behaviour has been particularly well characterized for HSV vectors[22]and, more recently, for adenovirus5, 23, 24, a virus that is not naturally neurotropic. While most cell types in the brain appear to be susceptible to adenovirus infection, it is not yet clear
Quantification of immune responses to non-replicating vectors
The development of methods to quantify immunological parameters following the injection of non-replicating viral vectors into the brain is important for several reasons. Such techniques will enable standard functional immune assays to be applied to questions of viral vector neuroimmunology, and will therefore give further insight into important aspects of immune regulation in the brain. Perhaps more crucially, the advent of such methods will be vital for the accurate evaluation of the
Role of T-cell subsets in the immune response
From the quantitative studies referred to above, the predominant T cells present during the adaptive phase of the immune response to adenovirus vectors in the brain are CD4+ T lymphocytes. To examine the functional role of CD4+ and CD8+ cells more closely, monoclonal antibodies were used to deplete each subset in turn[21]. Significantly, the early inflammatory response was undiminished even when both subsets of T cells were depleted. Given that irradiation of the adenovirus vector with UV also
Immune responses to adenovirus vectors in sensitized animals
The conclusion drawn at the end of the previous section prompts the obvious question of why the T-cell immune response to a non-replicating adenovirus vector in the brain is ineffective and incapable of clearing the virus from the brain. Where precisely is the defect in this response? Alternatively, under what conditions might the immune system act effectively to clear the vector and eliminate transgene expression from the brain, and what effector mechanisms might be used in so doing?
It is
Concluding remarks
Since the T-cell response to adenovirus in the brain is generally ineffective, long-term transgene expression is possible with currently available vectors. Furthermore, adenovirus vectors can deliver genes to synaptically linked brain areas, which is valuable potential strategy for gene targeting in the complex environment of the adult brain. However, against these putative advantages must be set the definite disadvantage that long-lasting transgene expression in the brain is seriously at risk
Acknowledgements
We thank P. Belk for his help in the preparation of the manuscript and M. McMenamin for her assistance with some of the figures. This work is supported by grants from the MRC (UK), BBSRC (UK), the Wellcome Trust and by the award of a Wellcome Prize Studentship to APB.
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