Bifunctional Peptide Inhibitors Suppress Interleukin-6 Proliferation and Ameliorates Murine Collagen-Induced Arthritis

Abstract

The objective of this study is to evaluate the efficacy and potential mechanism of action of type-II collagen bifunctional peptide inhibitor (CII-BPI) molecules in suppressing rheumatoid arthritis in the collagen-induced arthritis (CIA) mouse model. CII-BPI molecules (CII-BPI-1, CII-BPI-2, and CII-BPI-3) were formed through conjugation between an antigenic peptide derived from type-II collagen and a cell adhesion peptide LABL (CD11a237-246) from the I-domain of LFA-1 via a linker molecule. The hypothesis is that the CII-BPI molecules simultaneously bind to MHC-II and ICAM-1 on the surface of APC and block maturation of the immunological synapse. As a result, the differentiation of naïve T cells is altered from inflammatory to regulatory and/or suppressor T cells. The efficacies of CII-BPI molecules were evaluated upon intravenous injections in CIA mice. Results showed that CII-BPI-1 and CIIBPI-2 suppressed the joint inflammations in CIA mice in a dose-dependent manner and were more potent than the respective antigenic peptides alone. CII-BPI-3 was not as efficacious as CII-BPI-1 and CII-BPI-2. Significantly less joint damage was observed in CII-BPI-2 and CII-2 treated mice than in the control. The production of IL-6 was significantly lower at the peak of disease in mice treated with CII-BPI-2 compared to those treated with CII-2 and control. In conclusion, this is the first proof-of-concept study showing that BPI molecules can be used to suppress RA and may be a potential therapeutic strategy for the treatment of rheumatoid arthritis.

Evaluation of LFA-1 Peptide-Methotrexate Conjugates in Modulating Endothelial Cell Inflammation and Cytokine Regulation

“…37 In addition, CII-BPI molecules that are conjugates between LABL and collagen-II peptides suppressed rheumatoid arthritis (RA) in collageninduce arthritis (CIA) mice. 38 The concept of BPI was extended to protein and polymer conjugates such as Fc-BPI, I-domain antigen conjugate (IDAC), and soluble antigen array (SAgA) molecules; they are composed of LABL and antigenic peptides. 31 These large conjugates have been shown to effectively suppress EAE in the mouse model.…”

“…Previous work has implied that LABL-antigenic peptide conjugates can alter autoimmune inflammatory response to an antigenspecific tolerogenic responses. 31,[35][36][37][38] Our previous work had shown that cLABL peptide (cyclo1,12-PenITDGEATDSGC) derived from the LFA-1 I-domain interacted with the ICAM-1 D1 domain 23,39 to inhibit adhesion of lymphocytes 29,30 in an in vitro model of epithelial cell inflammation. 22 This peptide was synthesized by incorporating cysteine (Cys) and penicillamine (Pen) residues to the C-and N-termini, respectively, on the Ile 237 -Gly 246 sequence of the I-domain.…”