title: Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis.
abstract: Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin-PC (TPC), a novel helminth-based compound in collagen-induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 µg/0.1 ml) or orally (250 µg/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme-linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (Treg ) and regulatory B (Breg ) cell phenotypes by fluorescence-activated cell sorter (FACS). TPC-treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC-treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL-10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)-α, interleukin (IL)-17 and IL-1β (P < 0.0001). TPC significantly expanded the CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) Treg cells and CD19(+) IL-10(+) CD5(high) CD1d(high) T cell immunoglobulin mucin-1 (TIM-1(+) ) Breg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti-inflammatory cytokine expression, as well as expansion of Treg and Breg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset.
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Bashi
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Shovman
authors.affiliation: Department of Organic Chemistry, The Weizmann Institute of Sciences, Rehovot, Israel, Tel-Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Fridkin
authors.affiliation: Institute of Pathology, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Volkov
authors.affiliation: Institute of Pathology, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Blank
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Shoenfeld
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000906:Antibodies / Q000097:blood*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D024043:Collagen Type II / Q000097:blood / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D000072596:Hepatitis A Virus Cellular Receptor 1; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D010767:Phosphorylcholine / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014405:Tuftsin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D024043:Collagen Type II; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; C556062:IL10 protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D010767:Phosphorylcholine; D016753:Interleukin-10; D014405:Tuftsin
keywords: collagen-induced arthritis; helminth; phosphorylcholine; rheumatoid arthritis; tuftsin