The ability of rats or mice to withstand the consequences of injury to myelinated axons in the CNS was previously shown to depend on the ability to manifest a T cell-mediated protective immune response, which is amenable to boosting by myelin-specific T cells. Here we show that this ability, assessed by retinal ganglion cell survival after optic nerve injury or locomotor activity after spinal cord contusion, is decreased if the animals were immunized as neonates with myelin proteins (resulting in their nonresponsiveness as adults to myelin proteins) or injected with naturally occurring regulatory CD4 ؉ CD25 ؉ T cells immediately after the injury, and is improved by elimination of these regulatory T cells. In nude BALB͞c mice replenished with a splenocyte population lacking CD4 ؉ CD25 ؉ regulatory T cells, significantly more neurons survived after optic nerve injury than in nude mice replenished with a complete splenocyte population or in matched wild-type controls. In contrast, neuronal survival in wildtype BALB͞c mice injected with CD4 ؉ CD25 ؉ regulatory T cells immediately after injury was significantly worse than in noninjected controls. These findings suggest that the ability to cope with the sequelae of a CNS insult is affected unfavorably by nonresponsiveness to myelin self-antigens and favorably by conditions allowing rapid expression of an autoimmune response. The regulatory T cells might represent an evolutionary compromise between the need to avoid autoimmune diseases and the need for autoimmunity on alert for the purpose of tissue maintenance.

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Immune cells have been shown to contribute to spontaneous recovery from central nervous system (CNS) injury. Here we show that adult female rats and mice recover significantly better than their male littermates from incomplete spinal cord injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult mice deprived of mature T cells. After spinal cord contusion in adult rats, functional recovery (measured by locomotor scores in an open field) was significantly worse in females treated with dihydrotestosterone prior to the injury than in placebo-treated controls, and significantly better in castrated males than in their noncastrated male littermates. Post-traumatic administration of the testosterone receptor antagonist flutamide promoted the functional recovery in adult male rats. These results, in line with the known inhibitory effect of testosterone on cell-mediated immunity, suggest that androgen-mediated immunosuppression plays a role in ISCI-related immune dysfunction and can therefore partly explain the worse outcome of ISCI in males than in female. We suggest that females, which are more prone to develop autoimmune response than males, benefit from this response in cases of CNS insults.

To benefit damaged neurons, immune neuroprotection should be directed against immunodominant antigens that reside in the site of damage. In a rat model of high IOP, RGCs can benefit from vaccination with peptides derived from proteins that are immunodominant in the eye but not from myelin-associated proteins. This suggests that the site of primary degeneration in IOP-induced RGC loss is in the eye. Cop-1 vaccination apparently circumvents the site-specificity barrier and provides protection without risk of inducing autoimmune disease.

Land snails are subject to daily and seasonal variations in temperature and in water availability and depend on a range of behavioral and physiological adaptations for coping with problems of maintaining water, ionic, and thermal balance. Heat shock proteins (HSPs) are a multigene family of proteins whose expression is induced by a variety of stress agents. We used experimental desiccation to test whether adaptation to different habitats affects HSP expression in two closely related Sphincterochila snail species, a desiccation-resistant, desert species Sphincterochila zonata, and a Mediterranean-type, desiccation-sensitive species Sphincterochila cariosa. We examined the HSP response in the foot, hepatopancreas, and kidney tissues of snails exposed to normothermic desiccation. Our findings show variations in the HSP response in both timing and magnitude between the two species. The levels of endogenous Hsp72 in S. cariosa were higher in all the examined tissues, and the induction of Hsp72, Hsp74, and Hsp90 developed earlier than in S. zonata. In contrary, the induction of sHSPs (Hsp25 and Hsp30) was more pronounced in S. zonata compared to S. cariosa. Our results suggest that land snails use HSPs as part of their survival strategy during desiccation and as important components of the aestivation mechanism in the transition from activity to dormancy. Our study underscores the distinct strategy of HSP expression in response to desiccation, namely the delayed induction of Hsp70 and Hsp90 together with enhanced induction of sHSPs in the desert-dwelling species, and suggests that evolution in harsh environments will result in selection for reduced Hsp70 expression.

The myelin-associated protein Nogo-A has received more research attention than any other inhibitor of axonal regeneration in the injured central nervous system (CNS). Circumvention of its inhibitory effect, by using antibodies specific to Nogo-A, has been shown to promote axonal regrowth. Studies in our laboratory have demonstrated that active or passive immunization of CNS-injured rats or mice with myelin-associated peptides induces a T-cellmediated protective autoimmune response, which promotes recovery by reducing posttraumatic degeneration. Here, we show that neuronal degeneration after incomplete spinal-cord contusion in rats was substantially reduced, and hence recovery was significantly promoted, by posttraumatic immunization with p472, a peptide derived from Nogo-A. The observed effect seemed to be mediated by T cells and could be reproduced by passive transfer of a T cell line directed against the Nogo-A peptide. Thus, it seems that after incomplete spinal-cord injury, immunization with a variety of myelin-associated peptides, including those derived from Nogo-A, can be used to evoke a T cell-mediated response that promotes recovery. The choice of peptide(s) for clinical treatment of spinalcord injuries should be based on safety considerations; in particular, the likelihood that the chosen peptide will not cause an autoimmune disease or interfere with essential functions of this peptide or other proteins. From a therapeutic point of view, the fact that the active cellular agents are T cells rather than antibodies is an advantage, as T cell production commences within the time window required for a protective effect after spinal-cord injury, whereas antibody production takes longer.

Vaccination with peptides derived from interphotoreceptor retinoid-binding protein (a self-Ag that can cause experimental autoimmune uveoretinitis) resulted in protection of retinal ganglion cells from glutamate-induced death or death as a consequence of optic nerve injury. In the case of glutamate insult, no such protection was obtained by vaccination with myelin Ags (self-Ags associated with an autoimmune disease in the brain and spinal cord that evokes a protective immune response against consequences of injury to myelinated axons). We suggest that protective autoimmunity is the body’s defense mechanism against destructive self-compounds, and an autoimmune disease is the outcome of a failure to properly control such a response. Accordingly, the specific self-Ag (although not necessarily its particular epitopes) used by the body for protection against potentially harmful self-compounds (e.g., glutamate) can be inferred from the specificity of the autoimmune disease associated with the site at which the stress occurs (irrespectively of the type of stress) and is in need of help.