The objective of this study is to evaluate the activity of a novel peptide, i.e., bifunctional peptide inhibitor (BPI), which targets the immunological synapse and inhibits autoimmune responses in an antigen-specific manner. Proteolipid protein (PLP)-BPI was designed by conjugating two peptides, an encephalitogenic epitope of proteolipid protein ) and an intercellular adhesion molecule-1-binding peptide derived from ␣ L integrin (CD11a 237-246 ), via a spacer peptide. The therapeutic effect of PLP-BPI was studied in experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice as a model for human multiple sclerosis. Mice that received i.v. injections of PLP-BPI showed significantly lower EAE disease scores and incidence than those treated with vehicle, PLP 139 -151 peptide only, CD11a 237-246 peptide only, unlinked mixture of PLP 139 -151 , and CD11a 237-246 peptides, or other control peptides. Multiple injections of antigenic peptide can produce anaphylactic responses; interestingly, PLP-BPI-treated animals have significantly lower anaphylactic response than do the PLP 139 -151 -treated group. Therefore, PLP-BPI can effectively inhibit the disease severity and incidence of EAE with a lower possibility of inducing fatal anaphylaxis. These results suggest that BPI-type molecules can be used to treat different autoimmune diseases in which antigenic epitopes have been identified. The overall assembly of Signal-1, Signal-2, and other costimulatory signals at the interface of T cell and APC is called the "immunological synapse". Grakoui et al. (1999) have demonstrated that the formation of the immunological synapse is a dynamic process. Initially, TCR/MHC-antigen complexes are found peripherally in a ring shape of the nascent synapse, whereas LFA-1/ICAM-1 molecules congregate toward the central cell-cell contacting region. As T-cell activation proceeds, both molecular complexes are rearranged (translocated) into a bull's-eye pattern with a central supramolecular activation cluster surrounded by a peripheral supramolecular activation cluster (Monks et al., 1998;Grakoui et al., 1999;Lee et al., 2002).To develop a novel method to alter immune response in an antigen-specific manner, we have designed a bifunctional peptide inhibitor (BPI) that targets the immunological synapse. The BPI is made of the following three peptide portions: 1) antigen epitope peptide and 2) ICAM-1-binding peptide, which are conjugated via 3) a spacer peptide. Our group has previously discovered the ICAM-1-binding peptide, named LABL, derived from ␣ L integrin (CD11a

IntroductionRheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease.MethodsRA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures.ResultsEighteen patients (78% female) with a mean age of 57 ± 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non-segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement.ConclusionsMyocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.

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.

Compared to controls, RA was associated with a higher prevalence and higher severity of atherosclerosis in the bulb-ICA but not the CCA. Our data suggest that future studies in RA that utilize carotid artery measurements should include assessment of the bulb-ICA.

TCZ treatment significantly increased EF and decreased LVMI associated with disease activity.