• Autoimmune neuroprotection – a physiological self-repair mechanism


Neurodegenerative disorders are commonly associated with ongoing neuronal loss in the central nervous system (CNS) [1 and 2]. Following the loss of neurons caused by primary risk factors, additional (‘secondary’) neuronal loss is mediated by self-compounds, such as glutamate, nitric oxide or reactive oxygen species, that exceed their physiological concentrations. These compounds are implicated in various types of neurological disorders and acute CNS injuries [3, 4, 5, 6 and 7]. It is interesting to note that destructive components common to neurodegenerative diseases have also been identified in autoimmune diseases such as multiple sclerosis (MS); in this disease, myelin damage in the CNS is accompanied by subsequent neuronal loss [8, 9, 10 and 11].

Immune activity in the CNS has long been considered detrimental, and patients with neurodegenerative disorders and acute injuries are therefore commonly treated with immunosuppressive drugs [12, 13, 14, 15, 16 and 17]. This negative view of inflammation derives largely from the fact that the presence of immune cells in the brain has been reported mainly in pathological situations. Indeed, these cells came to be regarded as the cause of the pathology, not as the result, and certainly not as cells recruited for the purpose of physiological repair.

Thus, for example, the immune components (e.g. activated microglia, blood-borne macrophages, CD8+ and CD4+ T cells) found in damaged regions and plaques in patients with neurodegenerative syndromes were assumed to be causatively associated with the syndrome [18 and 19]. However, studies in the past few years have shown that immune cells, in particular autoimmune T cells, play an essential role in protecting the injured CNS from the ongoing spread of damage [20, 21, 22, 23, 24 and 25].

Moreover, it has proved possible to boost protective immunity in rats and mice without risk of inducing neurodegenerative disease, as will be discussed here.
Autoimmune neuroprotection – a physiological self-repair mechanism

In certain strains of rats, passive transfer of autoimmune T cells reactive to myelin-related self-antigens induces a transient autoimmune syndrome known as experimental autoimmune encephalomyelitis (EAE) [26 and 27]. If these strains of rats are subjected either to partial crush injury of the optic nerve or to contusive injury of the spinal cord, the autoimmune cell transfer not only induces EAE but also confers neuroprotection by reducing secondary degeneration of the damaged neural tissue [21 and 23]. Recent studies have provided persuasive evidence that the observed autoimmune neuroprotection is not merely the outcome of an experimental manipulation, but is a physiological response evoked systemically by the CNS injury [20 and 28]. Furthermore, in several strains of mice and rats, an absence of mature T cells (e.g. in nude mice or in rats subjected to thymectomy at birth) results in a worse outcome from CNS injury than in their wild-type counterparts [20 and 28].

The way in which autoimmune T cells prevent the degenerative consequences of CNS insults or protect the injured nerve from self-destructive mediators of toxicity is currently under intensive investigation. Studies have shown that active autoimmune T cells engage in a dialogue with CNS-resident microglia or with infiltrating macrophages [29]. Among the effects attributed to such dialogue is activation, through MHC class II interaction, of the affected cells, enabling them to clear the injury site of potentially harmful factors, such as destructive self-compounds.

On the basis of the ability of activated T cells and monocytes to produce neurotrophic factors, it was further suggested [30 and 31] that macrophages might serve as a source of neurotrophins. Thus, T cells might participate in the activation of macrophages, through MHC class II interaction, for the production of such factors. However, it was recently shown that the autoimmune T cells are not the only T cells participating in autoimmune neuroprotection, but that another population of CD4+ T cells (probably of a regulatory phenotype) is also an essential participant (J. Kipnis et al., unpublished).

The phenotype of the T cells that regulate neuroprotection is still unknown. The most promising candidates are naturally occurring CD4+CD25+ regulatory T cells, which are antigen specific, and natural killer cells, which play an important role in terminating EAE [32]. In view of the results described above, it is reasonable to suggest that nonspecific therapeutic suppression of the immune response to CNS trauma (e.g. by depriving the body of proinflammatory cytokines) might be harmful for neurons in the long term. This might be the case even though the immune involvement appears to be at some cost in terms of neuronal loss to the tissue, since the benefit of neuroprotection afforded by the ongoing immune activity, if well controlled, will eventually outweigh the cost. It therefore seems that a preferable therapy would be antigen-specific immunomodulation aimed at boosting and regulating the inflammatory response [33 and 34] to a CNS insult [24].

It was recently discovered that it is possible to boost protective immunity in rats and mice without the risk of inducing EAE, by vaccinating the injured animal with glatiramer acetate (Cop-1) [35], a drug used clinically to alleviate the symptoms of MS.

Vaccination with Cop-1 emulsified in a strong adjuvant reduced glutamate-mediated cytotoxicity in the rodent retinal ganglion cell (RGC) model and attenuated the symptoms of a chronic neurodegenerative disorder (simulating glaucoma) in a rat model of high intraocular pressure [35 and 36]. The following sections discuss the dual effects of Cop-1 in protecting against ‘destructive’ autoimmunity (seen in patients with autoimmune diseases such as MS) and in inducing or boosting ‘protective’ autoimmunity, thereby promoting neuronal survival in cases of neurodegenerative disorders.