Trends in Immunology
Volume 23, Issue 1, 1 January 2002, Pages 23-30
Journal home page for Trends in Immunology

Opinion
Immunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective

https://doi.org/10.1016/S1471-4906(01)02063-4Get rights and content

Abstract

The immune system imposes limitations on gene transfer into the brain. Viral vectors injected into the brain's ventricular system elicit innate and adaptive immune responses. However, when injected directly into the brain parenchyma, they elicit only transient inflammation owing to the absence of dendritic cells, which transport antigen to lymph nodes and present it to naive T cells to initiate adaptive immune responses. This article explores the evolutionary and developmental basis of brain immune responses and their implications for viral-vector-mediated neurological gene therapy. Elucidating the cellular and molecular basis of these differential reactions is essential to the long-term success of neurological gene therapy.

Section snippets

The anatomy of brain immune responses

Immune responses, immune cells and immune-specific tissues are organ specific; examples of this include skin-associated lymphoid tissue (SALT) [8], nasal-mucosa-associated lymphoid tissue (NALT) [9], gut-associated lymphoid tissue (GALT) [10] and the eye-specific immune responses [11]. Regional immune responses result from the need to maintain effective immune surveillance while preserving organ function 12, 13. Although these local lymphoid tissues are certainly important in generating quick

Why are adaptive immune responses not primed after parenchymal brain injections of viral vectors?

The lack of adaptive cellular immune responses to infectious particulate Ags injected into the naive brain can be most easily explained as a consequence of the absence of priming of naive T cells. This results from an anatomical or functional absence of afferent professional Ag-presenting cells (APCs) or dendritic cells (DCs) in the brain (Box 2). Lack of priming of naive T cells following the administration of infectious particulate Ags into the brain parenchyma could be a consequence of: (1)

Gene transfer into different brain compartments: an evolutionary and developmental perspective

The evolutionary appearance of the brain (in amphioxus and cyclostomes) pre-dates the appearance of the adaptive immune system in chondrichthyes by ∼50–100 million years 33, 34, 35 (Fig. 1; Table 1, Table 2). Thus, during its early phylogeny, the brain co-evolved with the phylogenetically older innate immune system. Innate immune mechanisms are present in all animals preceding the cartilaginous fishes 33, 34, 35, as well as in insects and plants [36]. Thus, during the early stages of brain

Does the brain's capacity for Ag presentation change during inflammation?

During brain inflammation, cells displaying immunocytochemical, molecular or functional characteristics of DCs become detectable within the brain parenchyma. The appearance of DCs in the brain parenchyma, in experimental allergic encephalomyelitis (EAE), delayed-type hypersensitivity (DTH) or brain infection, or following the administration of the DC growth factor Flt3 ligand 17, 30, 31, 32, 46, 47, 48, suggests three possible mechanisms. These are: (1) DCs enter the brain after the induction

Conclusion: clinical implications for the use of viruses as gene-therapy vectors for the treatment of brain diseases

This article proposes that the ‘immune privilege’ of the brain is a result of the co-evolution of the brain and the immune system (Fig. 1; Table 1, Table 2), maintained through phylogeny by constraints on the developmental programs (Table 3), as proposed by Gould and Lewontin [1]. This hypothesis is supported strongly by the parallel appearance of immune and nervous structures during ontogeny, following a time-course perfectly compatible with their evolutionary appearance.

The brain walks a

Acknowledgements

I wish to acknowledge the following for critical discussions of the ideas presented in this manuscript: M. Castro, C.A. Janeway, Jr, E. Bell, S. Ali, P. Walden and, especially, H. Lassmann, who has helped shape some of the ideas presented herein. I particularly wish to thank T. Southgate for his creative assistance in translating some of the essential ideas of this manuscript into its pictorial depiction in Fig. 1. I was supported by a Research Fellowship from The Lister Institute of Preventive

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