Physiological approaches to neuroprotection. boosting of protective autoimmunity

Abstract

In glaucoma, as in other degenerative diseases of the central nervous system (CNS), there are some neurons which, although susceptible to degeneration, are amenable to neuroprotection. Until very recently, attempts to attenuate the spread of damage after CNS trauma or in neurodegenerative diseases did not include recruitment of the immune system, because it was assumed that in the CNS any immune activity, particularly autoimmune activity, would be harmful. Using the injured optic nerve of the rat as a model, we recently showed, however, that this 'secondary degeneration' can be slowed down by a well-controlled adaptive immune response, which is mediated by T cells against CNS self-antigens, such as myelin basic protein (MBP), and can be achieved either by passive transfer of MBP-activated T cells or by active immunization with MBP. Accordingly, we suggested that autoimmune T cells can be neuroprotective. We further showed that the neuroprotective autoimmunity is a physiological response to the injury, perhaps insufficient in its natural state, but amenable to boosting. The neuroprotective activity of these T cells probably depends on their reactivation by their specific antigen after they are targeted to the injured nerve. As nerve degeneration is initiated and sustained by many factors, it would probably best be counteracted by a comprehensive type of therapy rather than treatment that addresses only some aspects of nerve damage. T cell therapy, being physiological rather than pharmaceutical in nature, may provide a global answer. However, since the neuroprotective immune response is directed against the self, it must be rigorously regulated to avoid inducing an autoimmune disease. We showed that the synthetic copolymer Cop-1 can passively or actively evoke T cell-mediated neuroprotection, probably by cross-reacting with MBP. Safe synthetic peptides that resemble self-antigens and are cross-activated by CNS-associated self antigens may be a useful starting point for the development of anti-self immunity for neuroprotective purposes.