Suppression of EAE and prevention of blood–brain barrier breakdown after vaccination with novel bifunctional peptide inhibitor

Abstract

The efficacy of bifunctional peptide inhibitor (BPI) in preventing blood-brain barrier (BBB) breakdown during onset of experimental autoimmune encephalomyelitis (EAE) and suppression of the disease was evaluated in mice. The mechanism that defines how BPI prevents the disease was investigated by measuring the in vitro cytokine production of splenocytes. Peptides were injected 5 to 11 days prior to induction of EAE, and the severity of the disease was monitored by a standard clinical scoring protocol and change in body weight. The BBB breakdown in diseased and treated mice was compared to that in normal control mice by determining deposition of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) in the brain using magnetic resonance imaging (MRI). Mice treated with PLP-BPI showed no or low indication of EAE as well as normal increase in body weight. In contrast, mice treated with the control peptide or PBS showed a decrease in body weight and a high disease score. The diseased mice had high deposition of Gd-DTPA in the brain, indicating breakdown in the BBB. However, the deposition of Gd-DTPA in PLP-BPI-treated mice was similar to that in normal control mice. Thus, PLP-BPI can suppress EAE when administered as a peptide vaccine and maintain the integrity of the BBB.

Controlling immune response and demyelination using highly potent bifunctional peptide inhibitors in the suppression of experimental autoimmune encephalomyelitis

“…Secondly, lovastatin can inhibit ICAM-1/LFA-1-mediated immune cell adhesion via binding to the I-domain of CD11a of LFA-1 [26]. As shown previously with BPI molecules, the PLP-cIBR molecule could prevent the infiltration of leucocytes by blocking ICAM-1/LFA-1-mediated immune cell adhesion to the vascular endothelial cells of the BBB as well as preventing BBB leakiness [16]. Finally, the underlying mechanisms of in-vivo activity of Ac-PLP-cIBR-NH2-1 and lovastatin were investigated by determining cytokine secretion phenotypes and their effect on pathologies of the brain.…”

“…Co-capping experiments showed that I-A g7 and ICAM-1 receptors were co-localized on the surface of GAD-BPI-treated APC, and binding of GAD-BPI on the APC was blocked by either anti-I-A g7 or anti-ICAM-1, suggesting that the BPI molecule can bridge MHC-II and ICAM-1 on the surface of APC [15]. The inhibition of immunological synapse formation alters the differentiation of T cells from inflammatory to regulatory cells [2,16].…”

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

“…Addition of antigen specificity to such an approach may reduce undesired side effects associated with global immunosuppression that accompanies many of the current immunomodulatory therapies available (4-7). Indeed, several groups have begun investigating antigen-specific immunotherapies to treat autoimmune disorders (22)(23)(24)(25)(26)(27)(28)(32)(33)(34)(35)(36).…”

“…Previously, a bifunctional peptide inhibitor (BPI) demonstrated the importance of co-delivering both antigenic peptide and a peptide inhibiting T cell activation by blocking immune cell adhesion (22,23,(26)(27)(28). Applying this codelivery approach of autoantigen and peptide inhibitor to a multivalent delivery vehicle (SAgA PLP:LABL ), i.e., multiple copies of peptide per therapeutic molecule, has also suppressed EAE (24,25).…”

“…The creation of an antigen-specific treatment capable of suppressing the immune response by co-delivery of autoantigen and immune inhibitor may improve the safety and efficacy of autoimmune therapies. Several previous studies have shown that co-delivering autoantigen and immune inhibitory peptide can inhibit autoimmune disease in animal models (22)(23)(24)(25)(26)(27)(28).…”