Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease
Ehud Hauben, Eugenia Agranov, Amalia Gothilf, Uri Nevo, Avi Cohen, Igor Smirnov, Lawrence Steinman, Michal Schwartz
Ehud Hauben, Eugenia Agranov, Amalia Gothilf, Uri Nevo, Avi Cohen, Igor Smirnov, Lawrence Steinman, Michal Schwartz
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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 MBP-derived 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.

Authors

Ehud Hauben, Eugenia Agranov, Amalia Gothilf, Uri Nevo, Avi Cohen, Igor Smirnov, Lawrence Steinman, Michal Schwartz

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Retrograde labeling of cell bodies in the red nucleus. Spinal contusion ...
Retrograde labeling of cell bodies in the red nucleus. Spinal contusion was preceded 7 days earlier by immunization with spinal cord homogenate emulsified in CFA (containing 0.5 mg/ml bacteria) or by injection with PBS in the same adjuvant (Figure 2a). Three months later, two rats from each group were reanesthetized and the dye rhodamine dextran amine (Fluoro-ruby) was applied below the site of contusion. Five days later, the rats were sacrificed and their brains were excised, processed, and cryosectioned. Sections taken through the red nucleus were inspected and analyzed qualitatively and quantitatively by fluorescence and confocal microscopy. Significantly more labeled rubrospinal neurons were seen in slices from the immunized rats (bottom) (BBB score = 8) than from the PBS-treated rats (top) (BBB score = 5.5).