Abstract
Most of the current therapies used in the treatment of multiple sclerosis (MS) are either ineffective or have adverse side effects. As such, there is a need to develop better therapies that specifically target myelin-specific aberrant immune cells involved in CNS inflammation without compromising the general immune system. In the present study, we developed a new bifunctional peptide inhibitor (BPI) that is effective and specific. Our BPI (PLP-B7AP) is composed of an antigenic peptide from myelin proteolipid protein (PLP139–151) and a B7 antisense peptide (B7AP) derived from CD28 receptor. The main hypothesis is that PLP-B7AP simultaneously targets MHC-II and B7-costimulatory molecules on the surface of antigen presenting cells (APC) and possibly alters the differentiation of naïve T cells from inflammatory to regulatory phenotypes. Results showed that PLP-B7AP was very effective in suppressing experimental autoimmune encephalomyelitis (EAE) compared to various controls in a mouse model. PLP-B7AP was effective when administered both before and after disease induction. Secreted cytokines from splenocytes isolated during periods of high disease severity and remission indicated that PLP-B7AP treatment induced an increased production of anti-inflammatory cytokines and inhibited the production of pro-inflammatory cytokines. Further, analysis of cortical brain tissue sections showed that PLP-B7AP treated mice had significantly lower demyelination compared to the control group. All these taken together indicate that the T cell receptor (TCR) and the CD28 receptor can be targeted simultaneously to improve efficacy and specificity of potential MS therapeutics.
Highlights
Inflammation of the central nervous system (CNS) is one of the main hallmarks of multiple sclerosis (MS), a neurodegenerative disease that leads to damage of neuronal axons [1]
The B7 antisense peptide (B7AP) peptide suppressed disease significantly when compared to phosphate-buffered saline (PBS) (p
The loss in body weight correlated well with what was reported from the clinical scores (Figure 2B) except that the group treated with the PLP and B7AP mixture had significantly lower loss of body weight compared to the B7AP-treated mice (p
Summary
Inflammation of the central nervous system (CNS) is one of the main hallmarks of multiple sclerosis (MS), a neurodegenerative disease that leads to damage of neuronal axons [1]. In the case of MS, a specific immune trigger in the periphery is thought to cause antigens related to myelin to be processed by dendritic cells in the lymphoid system and presented to T-cells on the surface of antigen-presenting cells (APC); leading to activation and clonal expansion of antigen-specific T cells. These T cells can cross the blood-brain barrier (BBB) and enter the CNS, where they are reactivated by the target antigen on myelin. Activation of inflammatory CD4+ T cell response requires two signals that must be delivered to the T cell by APC; an antigenspecific signal and a costimulatory signal [3,4,5]
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