Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease

Abstract

Spinal cord injury results in a massive loss of neurons, and thus of function. We recently reported that passive transfer of autoimmune T cells directed against myelin-associated antigens provides acutely damaged spinal cords with effective neuroprotection. The therapeutic time window for the passive transfer of T cells was found to be at least 1 week. Here we show that posttraumatic T cell-based active vaccination is also neuroprotective. Immunization with myelin-associated antigens such as myelin basic protein (MBP) significantly promoted recovery after spinal cord contusion injury in the rat model. To reduce the risk of autoimmune disease while retaining the benefit of the immunization, we vaccinated the rats immediately after severe incomplete spinal cord injury with MBPderived altered peptide ligands. Immunization with these peptides resulted in significant protection from neuronal loss and thus in a reduced extent of paralysis, assessed by an open-field behavioral test. Retrograde labeling of the rubrospinal tracts and magnetic resonance imaging supported the behavioral results. Further optimization of nonpathogenic myelin-derived peptides can be expected to lead the way to the development of an effective therapeutic vaccination protocol as a strategy for the prevention of total paralysis after incomplete spinal cord injury.

CNS‐infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

“…Interestingly, Schwartz et al have reported that passive administration of T lymphocytes specific to self antigens, at selected times, could promote the recovery from both post partial optic nerve crush injury [29] and post incomplete spinal cord injury [30] in rodents, supporting the concept of protective autoimmunity. Whether the observed CD4 + T lymphocytes in the spinal cord post L5Tx respond to specific CNS antigen(s) and whether this possible T cell specificity plays a role in maintaining behavioral hypersensitivity requires further investigation.…”

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

“…Individuals differ in their ability to spontaneously evoke such an immune response (13). However, all individuals can benefit from boosting of the response, provided that intervention occurs at the right time, and uses the right antigen in optimal formulation so that the anti-self response is intensified, yet does not increase the risk of autoimmune disease (12,17,33). We further demonstrated that the same T cells (T helper 1) could apparently be responsible both for autoimmune disease and for protection from the detrimental effects of destructive self-compounds.…”

“…Thus, T helper 1 cells directed against immunodominant proteins were shown to be capable of inducing autoimmune disease, as well as neuroprotection (34). Disease-free protection was achieved by inducing an immune response against cryptic epitopes residing within the same potentially pathogenic immune-abundant protein, or by using an altered pathogenic peptide to eliminate the potential pathogenicity of the peptide (17,32).…”

“…In acute neurodegenerative conditions caused by mechanical (e.g., crush injury or axotomy) (12,14) or biochemical insults (e.g., glutamate or oxidative stress) (15), more neurons survive in the presence of an evoked anti-self T cell-mediated response than in its absence, provided that the evoked response is well regulated (13,(16)(17)(18)(19). The protective T cell-mediated response can be boosted, without risk of antoimmune disease induction, by administration of copolymer-1 (Cop-1; Copaxone), a synthetic polypeptide consisting of the amino acids tyrosine, glutamate, alanine, and lysine (15,20).…”

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

“…Therefore, boosting the immune responses to CNS injury under certain conditions may be more beneficial than harmful to functional regeneration (58) . Implantation of activated macrophages (86) or T-lymphocyte mediated immune activity, achieved by either adoptive transfer or active immunization (87)(88)(89)(90) , enhances recovery from spinal cord injury by conferring neuroprotection or regeneration. Although the concept of neuroprotective autoimmunity is intriguing, there is no definitive mechanism that explains its efficacy.…”