title: Immune Tolerance Induction against Experimental Autoimmune Encephalomyelitis (EAE) Using A New PLP-B7AP Conjugate that Simultaneously Targets B7/CD28 Costimulatory Signal and TCR/MHC-II Signal.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA ; KU Medical Center, The University of Kansas, Kansas City, KS 66160, USA.
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Badawi
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kiptoo
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
keywords: Bifunctional peptide inhibitor; Cytokines; Inflammation; Multiple Sclerosis; T cell Receptor