Prophylactic and therapeutic suppression of experimental autoimmune encephalomyelitis by a novel bifunctional peptide inhibitor

Abstract

The objective was to optimize and evaluate the in vivo activities of our novel bifunctional peptide inhibitor (BPI), which alters immune response in autoimmune diseases by modulating the immunological synapse formation. Previously, we have designed PLP-BPI and GAD-BPI by conjugating myelin proteolipid protein (PLP) 139-151 and glutamic acid decarboxylase (GAD) [208][209][210][211][212][213][214][215][216][217] , respectively, with CD11a 237-246 via a spacer peptide. PLP-BPI and GAD-BPI suppressed the disease progression in experimental autoimmune encephalomyelitis (EAE) and in type-1 diabetes, respectively. In this study, various PLP-BPI derivatives were synthesized and evaluated in the EAE model. Intravenous injections of PLP-BPI derivatives prevented the disease progression more efficiently than did unmodified PLP-BPI. Production of interleukin-17, a potent pro-inflammatory cytokine found commonly among MS patients, was significantly low in Ac-PLP-BPI-NH 2 -2-treated mice. Treatment given after the disease onset could dramatically ameliorate the disease. BPI induced anaphylactic responses at a lower incidence than PLP 139-151 . In conclusion, PLP-BPI derivatives can effectively suppress the disease severity and morbidity of EAE by postonset therapeutic treatment as well as prophylactic use.

Antigen-Specific Suppression of Experimental Autoimmune Encephalomyelitis by a Novel Bifunctional Peptide Inhibitor: Structure Optimization and Pharmacokinetics

“…A combination of central SMAC (signal 1) and peripheral SMAC (signal 2) is called the immunological synapse (Monks et al, 1998;Grakoui et al, 1999;Lee et al, 2002). We discovered a novel and selective way to suppress autoimmune diseases (i.e., MS and type 1 diabetes) by using a bifunctional peptide inhibitor (BPI), which consists of an antigen peptide epitope and an ICAM-1-binding peptide conjugated via a spacer (Kobayashi et al, , 2008Murray et al, 2007). Although the mechanism of action of BPI is still unknown, we hypothesize that BPI molecules block the formation of the immunological synapse by simultaneously binding to the MHC-II and ICAM-1 on the APC to prevent the translocation and segregation of signal 1 and signal 2 during the formation of the immunological synapse (Kobayashi et al, , 2008Murray et al, 2007).…”

“…Although the mechanism of action of BPI is still unknown, we hypothesize that BPI molecules block the formation of the immunological synapse by simultaneously binding to the MHC-II and ICAM-1 on the APC to prevent the translocation and segregation of signal 1 and signal 2 during the formation of the immunological synapse (Kobayashi et al, , 2008Murray et al, 2007). In this case, the antigenic-peptide epitope 139-151 derived from the proteolipid protein ) was conjugated to LABL peptide derived from ␣ L integrin (CD11a [237][238][239][240][241][242][243][244][245][246] ) to make BPI molecules (Kobayashi et al, , 2008. To optimize the efficacy and lower the potential side effects of PLP-BPI molecules, the linker between the PLP and LABL peptides was modified, and the pharmacokinetic properties of the BPI molecule were evaluated.…”

“…We discovered a novel and selective way to suppress autoimmune diseases (i.e., MS and type 1 diabetes) by using a bifunctional peptide inhibitor (BPI), which consists of an antigen peptide epitope and an ICAM-1-binding peptide conjugated via a spacer (Kobayashi et al, , 2008Murray et al, 2007). Although the mechanism of action of BPI is still unknown, we hypothesize that BPI molecules block the formation of the immunological synapse by simultaneously binding to the MHC-II and ICAM-1 on the APC to prevent the translocation and segregation of signal 1 and signal 2 during the formation of the immunological synapse (Kobayashi et al, , 2008Murray et al, 2007). In this case, the antigenic-peptide epitope 139-151 derived from the proteolipid protein ) was conjugated to LABL peptide derived from ␣ L integrin (CD11a [237][238][239][240][241][242][243][244][245][246] ) to make BPI molecules (Kobayashi et al, , 2008.…”

Peptides and Proteins for Treatment and Suppression of Type 1 Diabetes

“…EAE is an animal model for multiple sclerosis (MS). PLP-BPI derivatives are able to suppress EAE better than the parent PLP peptide (PLP 139-151 ), indicating that the presence of LABL peptide alters the mechanisms of action of PLP-BPI compared to PLP peptide alone (Kobayashi et al, 2008;Kobayashi et al, 2007;Ridwan et al, 2010;Zhao et al, 2010). Cytokine studies indicated that PLP-BPI treatment induced the differentiation and proliferation of T-reg and Th2 cells and suppressed the proliferation of Th17 cells.…”

“…Using the distance estimate, a combination of glycine (G) and amino caproic acid (Acp) was used to connect LABL to GAD peptides. In general, BPI molecules are effective in suppressing different autoimmune diseases; for example, GAD-BPI, PLP-BPI, and CII-BPI molecules (Table 1) have excellent efficacy to suppress T1D (Murray et al, 2007), EAE (Kobayashi et al, 2008;Kobayashi et al, 2007;Ridwan et al, 2010;Zhao et al, 2010), and RA, respectively. The central hypothesis is that binding of BPI molecules simultaneously to MHC-II and ICAM-1 on the surface of APC blocks the immunological synapse formation at the interface of APC-T cells.…”