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Review
. 2002 Mar;109(5):581-4.
doi: 10.1172/JCI15198.

Degeneracy, as opposed to specificity, in immunotherapy

David A Hafler  1
Affiliations
Review

Degeneracy, as opposed to specificity, in immunotherapy

David A Hafler. J Clin Invest. 2002 Mar.
No abstract available

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Figures

Figure 1
Figure 1
Autoimmune mechanism of MS. Naive, myelin reactive T cells are activated by microbes that: 1) induce the innate immune system to provide costimulatory signals necessary for clonal expansion of naive CD4+ T cells and, 2) contain epitopes that are cross-reactive with self antigens. Activated CD4+ T cells cross the blood-brain barrier and recognize self antigen presented by microglia, local antigen-presenting cells (APC) that sample self antigens. The reactivation of autoreactive CD4+ cells leads to a cascade of events including recruitment of macrophages, antibody secretion, and eventual destruction of myelin and axons.
Figure 2
Figure 2
The CD4+ T cell model of action by glatiramer acetate (GA). GA induces strong MHC class II restricted proliferative responses by T cells. Daily injections of GA induces a moderate loss of responsiveness to the antigen accompanied by a shift to a more Th2 type of CD4+ T cell. The surviving GA-reactive T cells show a greater degree of degeneracy, as measured by cross-reactive responses to combinatorial peptide libraries. Highly cross-reactive Th2 cells with degenerate T cell receptors migrate to the site CNS, recognize self antigens as weak agonists or “altered peptide ligands”. In response, they begin to secrete Th2/Th3 cytokines, and suppress inflammation by the mechanism of bystander suppression.
Figure 3
Figure 3
The CD8+ T cell model of action by GA. MHC class I restricted CD8+ T cell responses to GA, which are significantly lower at baseline in MS patients than in healthy controls, increase significantly following treatment, as seen in the greater number of IFN-γ–positive, GA responsive CD8+ T cells. GA treatment is proposed to restore CD8+ suppressor function, which is dependent upon IFN-γ secretion. The mechanism for CD8+ suppression of the immune response is unknown. Shown in the figure is a CD8+ T cell migrating to the CNS, regulating a CD4+ autoreactive T cell.
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