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.
The objective of this study was to optimize the in vivo activity of proteolipid protein (PLP)-bifunctional peptide inhibitor (BPI) molecule to suppress experimental autoimmune encephalomyelitis (EAE) in SJL/J mice and evaluate pharmacokinetic profiles of PLP-BPI. PLP-BPI is constructed via conjugation of myelin PLP 139-151 with CD11a 237-246 -derived peptide (LABL) via a spacer. The hypothesis is that PLP-BPI binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule-1 on the antigen-presenting cell (APC) and inhibits the formation of the immunological synapse during T-cell and APC interactions. In this study, the structure of BPI was modified by varying the spacer and was evaluated in the EAE model.Intravenous injections of BPI derivatives inhibited the onset, severity, and incidence of EAE more effectively and induced a lower incidence of anaphylaxis than that produced by unmodified PLP-BPI. As anticipated, production of interleukin-17, a proinflammatory cytokine commonly found in elevated levels among multiple sclerosis (MS) patients, was significantly lower in Ac-PLP-BPI-PEG6-or Ac-PLP-BPI-NH 2 -2-treated mice than in phosphate-buffered saline-treated mice. These results suggest that BPI-type molecules can be modified to achieve more efficient and better tolerated BPI-based derivatives for the treatment of MS.
SummaryIn this study, we investigated the efficacy of new bifunctional peptide inhibitors (BPIs) in suppressing experimental autoimmune encephalomyelitis (EAE) in an animal model. BPI [e.g. proteolipid protein-cyclo(1,8)-CPRGGSVC-NH2 (PLP-cIBR)] is a conjugate between the PLP139-151 peptide derived from proteolipid protein (PLP) and the cIBR7 peptide derived from domain-1 (D1) of intercellular adhesion molecule-1 (ICAM-1). PLP-cIBR is designed to bind to major histocompatibility complex (MHC)-II and leucocyte function-associated antigen-1 (LFA-1) simultaneously to inhibit the formation of the immunological synapse and alter the differentiation and activation of a subpopulation of T cells, thus inducing immunotolerance. The results show that PLP-cIBR is highly potent in ameliorating EAE, even at low concentrations and less frequent injections. Mice treated with PLPcIBR had a higher secretion of cytokines related to regulatory and/or suppressor cells compared to phosphate-buffered saline (PBS)-treated mice. In contrast, T helper type 1 (Th1) cytokines were higher in mice treated with PBS compared to PLP-cIBR, suggesting that it suppressed Th1 proliferation. Also, we observed significantly less demyelination in PLP-cIBR-treated mice compared to the control, further indicating that PLP-cIBR promoted protection against demyelination.
Latar belakang: Bayamduri (Amaranthus spinosus L.) dan sambiloto (Andrographis paniculata Burm F) adalah herbal tradisional yang digunakan untuk pengobatan malaria. Tujuan penelitian ini adalah untuk menentukan aktivitas anti malaria skizontisidal kombinasi kedua ekstrak terhadap mencit yang diinfeksi Plasmodium berghei. Metode: Mencit jantan (galur Balb/c) dengan berat 28-30 g, 7-8 minggu, dibagi menjadi 5 kelompok secara acak, tiap kelompok terdiri atas 4 ekor mencit. Kelompok A: kontrol negatif, kelompok perlakuan dengan ekstrak tanaman (kelompok B, C, D) diberikan 1 kali per hari selama 7 hari. Kelompok B: Amaranthus 10 mg/kgBB, kelompok C: Andrographis 2 mg/ kgBB, kelompok D: kombinasi ekstrak Amaranthus + Andrographis 10 mg + 2 mg/kgBB, dan kelompok E: diberi klorokuin 10 mg/kgBB sekali sehari selama 3 hari. Hasil: Terjadi peningkatan berat badan hanya pada kelompok D, peningkatan kadar hemoglobin pada semua kelompok perlakuan (C, D dan E secara bermakna dibandingkan dengan kontrol, p < 0,05). Aktivitas skizontisidal darah terlihat pada semua kelompok perlakuan, aktivitas tertinggi hampir 90% terlihat pada kelompok D dan E. Tingkat survival adalah 100% pada semua kelompok. Kesimpulan: Kombinasi ekstrak Amaranthus dan Andrographis (10 mg + 2 mg/kgBB) menunjukkan aktivitas skizontisidal darah sama baiknya dengan pemberian klorokuin 10 mg/kgBB.
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