Trends in Neurosciences
Volume 19, Issue 11, November 1996, Pages 497-501
Journal home page for Trends in Neurosciences

Immune responses to adenovirus vectors in the nervous system

https://doi.org/10.1016/S0166-2236(96)10060-6Get rights and content

Abstract

Non-replicating adenovirus vectors are being developed as vehicles for gene transfer into cells of the nervous system. An important requirement for successful gene transfer is the absence of deleterious cytotoxic or inflammatory side effects of the delivery system. Despite offering relatively stable reporter gene expression, currently available adenovirus vectors also elicit immune responses in the brain, both at the site of vector delivery and at synaptically linked distant sites. However, although an anti-viral T-lymphocyte response eliminates the vector and damages local tissue in many peripheral organs, the immune response to adenovirus in the brain is less effective and enables the vector to persist. Nevertheless, in this persistent state the adenovirus vector remains a potential target for a destructive immune response that can also cause local demyelination. The development of strategies to minimize this damaging immune response, through either vector modification or immunomodulation, will be crucial for the future success of genetic therapies in the brain. Trends Neurosci. (1996) 19, 497–501

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.

References (47)

  • G. Karpati

    Trends Neurosci.

    (1996)
  • T. Friedmann

    Trends Genet.

    (1994)
  • A.P. Byrnes

    Neuroscience

    (1995)
  • B.L. Davidson

    Exp. Neurol.

    (1994)
  • V.H. Perry et al.

    Trends Neurosci.

    (1993)
  • D.J. Sloan et al.

    Trends Neurosci.

    (1991)
  • M.J.A. Wood

    Exp. Neurol.

    (1994)
  • V. Ridoux

    Brain Res.

    (1994)
  • H. Kuo

    Brain Res.

    (1995)
  • G.R. Nemerow et al.

    Trends Cell Biol.

    (1994)
  • T.J. Wickham

    Cell

    (1993)
  • D.J. McFarland et al.

    J. Neurol. Sci.

    (1986)
  • M.K. Matyszak et al.

    Neuroscience

    (1995)
  • D.W. Mason

    Neuroscience

    (1986)
  • W-M. Duan

    Neuroscience

    (1995)
  • E. Joly et al.

    Neuron

    (1992)
  • Y. Yang et al.

    Immunity

    (1994)
  • A. Tishon

    Virology

    (1995)
  • J.C. Glorioso et al.

    Sem. Virol.

    (1992)
  • M.G. Kaplitt

    Nat. Genet.

    (1994)
  • S. Akli

    Nat. Genet.

    (1993)
  • B.L. Davidson

    Nat. Genet.

    (1993)
  • G. Le Gal La Salle

    Science

    (1993)
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