Journal Article

Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

Kang, Jin Hee, Hwang, Seung Rim, Byun, Young Ro, Sung, Shijin, Al Faruque, Hasan, Nam, Eon Jeong, Kang, Young Mo, Alam, Md. Mahmudul, Sa, Keum Hee

2017

Overview

Identification of the structure-function relationship of heparin, particularly between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory activities, is critical in order to evaluate the biological effects of heparin, especially in conjunction with modifications for oral formulation. In this study, we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic modifications have differential effects on the blocking of interactions between sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore, 6DSHbD coated on the apical surface of inflamed endothelium directly blocked the adhesive interactions of circulating T cells, which was confirmed in vivo by suppressing T cell adhesion at post-capillary venular endothelium. Thus, in series with our previous study demonstrating inhibition of transendothelial migration, oral delivery of low anticoagulant LMWH to venular endothelium of inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell recruitment and provides a rationale for the development of modified oral heparins as innovative agents for the treatment of chronic inflammatory arthritis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adhesion / Adjuvants / Affinity / Animals / Anti-inflammatory agents / Anti-Inflammatory Agents - chemistry / Anti-Inflammatory Agents - pharmacology / Anti-Inflammatory Agents - therapeutic use / Antibodies / Anticoagulants / Anticoagulants - chemistry / Anticoagulants - pharmacology / Anticoagulants - therapeutic use / Antithrombin / Arthritis / Arthritis - drug therapy / Arthritis - immunology / Arthritis - pathology / Assaying / Attenuation / Bioavailability / Biochemistry / Biological effects / Biology / Biology and Life Sciences / Bovine serum albumin / Carbodiimide / Carboxyfluorescein diacetate / CCL21 protein / CD3 antigen / Cell adhesion & migration / Cell Adhesion - drug effects / Cell adhesion molecules / Cellular biology / Chemokines / Chiron / Clinical trials / Cloning / Collagen / Complications and side effects / Cues / Degradation / Development and progression / Dosage and administration / Drug therapy / Effectiveness / Egress / Epithelium / Ethanol / Ethylenediaminetetraacetic acids / Gastrointestinal tract / Genetic aspects / Growth factors / Health aspects / Heart / Heparan sulfate / Heparin / Heparin - chemistry / Heparin - pharmacology / Heparin - therapeutic use / Heparin, Low-Molecular-Weight - chemistry / Heparin, Low-Molecular-Weight - pharmacology / Heparin, Low-Molecular-Weight - therapeutic use / Humans / Immune response / Immune system / Immunological memory / Infiltration / Inflammation / Inflammatory diseases / Inhibition / Interleukin 2 / Interleukin 6 / Internal medicine / Intestine / Lungs / Lymphocytes / Lymphocytes T / Male / Medicine / Medicine and Health Sciences / Metabolism / Mice / Mice, Inbred DBA / Modulation / Neutralization / P-selectin glycoprotein ligand 1 / Pharmaceutical sciences / Pharmacology / Pharmacy / Physiological aspects / Probes / Rats / Reagents / Rheumatoid arthritis / Rheumatology / Sulfates - chemistry / Sulfuric acid / T cells / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Tissues / Transendothelial and Transepithelial Migration - drug effects / Venules - drug effects / Venules - immunology / Venules - pathology