As mentioned, the environmental deficiency or toxicity created by
the degenerating nerve causes further neuronal damage. It seems,
however, that the primary and secondary causative factors trigger not
only destructive processes but also mechanisms of self-repair. The
latter may partly account for the self-limiting nature of the
progressive neurodegeneration seen in models of partially injured optic
nerves.
11 In the case of glaucoma, however, it seems that
these self-repair mechanisms are either too weak or too transient to
override the harmful effects.
In this connection, it is interesting to note that for glutamate, which
exhibits essential physiological activity or lethal neurotoxicity
depending on its concentration, there is an intermediate level at which
it is not only not detrimental but is even beneficial in triggering an
intracellular mechanism of self-protection. We found that in naive
neurons exposed to above-normal—although subtoxic—levels of
glutamate, increased resistance develops to further toxicity and not
necessarily to glutamate toxicity only.
12 That the
resistance induced by such glutamate levels is not restricted to
glutamate toxicity has a number of implications: A ubiquitous amino
acid that is potentially neurotoxic may be safe at a certain
intermediate level; a mechanism of self-repair may operate
constitutively after insults to the nerve; and by gaining an
understanding of a physiologically beneficial mechanism of repair, such
as that mediated by glutamate, it may be possible to simulate it by
appropriate drug therapy.
Another possible mechanism of intracellular self-repair is the
induction of immediate early genes (such as c-
jun), which
are found to be triggered immediately after optic nerve
injury,
13 apparently as a result of trophic factor
deprivation. The increase is transient and can be sustained by a
peripheral nerve graft, known to increase the survival rate and to
promote regrowth of injured optic nerve axons. A transient increase in
BDNF was also found to occur soon after optic nerve mechanical insult
or as an early response of the retina to low levels of
N-methyl-
d-aspartate.
14
In the course of our studies we recently came across another mechanism,
traditionally viewed as detrimental, that may be similar to the
physiological self-repair mechanisms described—that is, normally too
weak to be effective, yet amenable to exogenous boosting, and
potentially lethal to the tissue if it gets out of control. The
self-repair mechanism in this case is mediated by autoimmune T cells
directed against myelin-associated proteins of the central nervous
system (CNS). We suggested that the endogenous T cell immune response
to optic nerve damage is beneficial, but limited. Our findings showed,
against all expectations, that exogenous administration of T cells
directed against the CNS self-antigen, myelin basic protein (MBP),
significantly reduces the injury-induced spread of
degeneration.
15 16 Interestingly, the observed
protection of neurons from secondary degeneration was not related to
the intrinsic pathogenicity of the anti-MBP T cells. Thus, induction of
clinical autoimmune disease was not a prerequisite for the protection
against secondary degeneration mediated by the anti-MBP T cells. It is
conceivable that the endogenous T cells that accumulate spontaneously
at sites of CNS injury arise from an injury-triggered autoimmune
response.
17 Such a response may be beneficial but too weak
to be effective and in need of boosting. It may therefore be worth
seeking ways to augment therapeutically a beneficial autoimmune
response without triggering a persisting autoimmune disease. Such
boosting might be achieved, for example, by using T cells specific to
the self-antigenic epitopes normally sequestered in the intact CNS.
These autoimmune T cells would not accumulate in or interact with
undamaged sites and thus would not induce disease, yet they might be
able to assist in the repair of injured CNS tissue, if the covert
epitope is exposed by the injury.
T cells can synthesize cytokines and neurotrophic
factors.
18 19 We have suggested that the accumulated
autoimmune T cells may provide a source of neurotrophic factors. If so,
these could compensate for the deprivation in supply or local
production of trophic factors after injury to the optic nerve. Such an
effect would illustrate the advantage of immune neuroprotection
mediated by cells, rather than by pharmaceutical or physiological
compounds. The immune neuroprotection may represent an extracellular
mechanism of self-repair.