PMID- 26757712 OWN - NLM STAT- MEDLINE DCOM- 20161006 LR - 20181113 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 18 DP - 2016 Jan 12 TI - The CII-specific autoimmune T-cell response develops in the presence of FTY720 but is regulated by enhanced Treg cells that inhibit the development of autoimmune arthritis. PG - 8 LID - 10.1186/s13075-015-0909-6 [doi] LID - 8 AB - BACKGROUND: Fingolimod (FTY720) is an immunomodulating drug that inhibits sphingosine-1-phosphate binding and blocks T-cell egress from lymph nodes. We analyzed the effect of FTY720 on the autoimmune T- and B-cell response in autoimmune arthritis and studied the mechanisms by which it alters the function of T cells. METHODS: Human leukocyte antigen (HLA)-DR1 humanized mice were immunized with type II collagen (CII) and treated with FTY720 three times per week for 3 weeks. Arthritis was evaluated and autoimmune T- and B-cell responses were measured using proliferation assays, enzyme-linked immunosorbent assays, HLA-DR tetramers, and flow cytometry. The functional capacity of regulatory T (Treg) cells from FTY720-treated mice was measured using an in vitro suppression assay, and the role of Treg cells in inhibiting arthritis in FTY720-treated mice was evaluated using mice treated with anti-CD25 to deplete Treg cells. RESULTS: Treatment with FTY720 delayed the onset of arthritis and significantly reduced disease incidence. FTY720 did not prevent the generation of a CII-specific autoimmune T-cell response in vivo. However, as the treatment continued, these T cells became unresponsive to restimulation with antigen in vitro, and this anergic state was reversed by addition of interleukin 2. Measurements of CD4(+)CD25(+)Foxp3(+) cells in the lymph nodes revealed that the ratio of Treg to helper T (Th) cells increased twofold in the FTY720-treated mice, and in vitro assays indicated that the regulatory function of these cells was enhanced. That FTY720 stimulation of Treg cells played a major role in arthritis inhibition was demonstrated by a loss of disease inhibition and restitution of the T-cell proliferative function after in vivo depletion of the Treg cells. CONCLUSIONS: While FTY720 affects the recirculation of lymphocytes, its ability to inhibit the development of autoimmune arthritis involves several mechanisms, including the enhancement of Treg cell function by increasing the Treg/Th ratio and increased regulatory function on a per-cell basis. FTY720 did not inhibit the development of the autoimmune T-cell response, but disease inhibition appeared to be mediated by Treg cell-mediated suppression of the CII-specific T cells. These data suggest that specific targeting of Treg cells with FTY720 may be a novel therapy for autoimmunity. FAU - Miller, David C AU - Miller DC AD - Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. dmille26@uthsc.edu. AD - Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. dmille26@uthsc.edu. FAU - Whittington, Karen B AU - Whittington KB AD - Memphis VA Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104, USA. kwhittington@uthsc.edu. FAU - Brand, David D AU - Brand DD AD - Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. dbrand@uthsc.edu. AD - Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. dbrand@uthsc.edu. AD - Memphis VA Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104, USA. dbrand@uthsc.edu. FAU - Hasty, Karen A AU - Hasty KA AD - Memphis VA Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104, USA. khasty@uthsc.edu. AD - Department of Orthopaedic Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. khasty@uthsc.edu. FAU - Rosloniec, Edward F AU - Rosloniec EF AD - Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. erosloniec@uthsc.edu. AD - Memphis VA Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104, USA. erosloniec@uthsc.edu. AD - Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. erosloniec@uthsc.edu. LA - eng GR - I01 BX001045/BX/BLRD VA/United States GR - IP1 BX001607/BX/BLRD VA/United States PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20160112 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Collagen Type II) RN - 0 (Immunosuppressive Agents) RN - G926EC510T (Fingolimod Hydrochloride) SB - IM MH - Animals MH - Arthritis, Experimental/chemically induced/drug therapy/*immunology MH - Autoimmune Diseases/chemically induced/drug therapy/*immunology MH - Autoimmunity/drug effects/*immunology MH - Collagen Type II/*toxicity MH - Fingolimod Hydrochloride/*pharmacology/therapeutic use MH - Humans MH - Immunosuppressive Agents/pharmacology/therapeutic use MH - Mice MH - Mice, 129 Strain MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - T-Lymphocytes, Regulatory/drug effects/*immunology PMC - PMC4718028 EDAT- 2016/01/14 06:00 MHDA- 2016/10/08 06:00 PMCR- 2016/01/12 CRDT- 2016/01/14 06:00 PHST- 2015/01/27 00:00 [received] PHST- 2015/12/29 00:00 [accepted] PHST- 2016/01/14 06:00 [entrez] PHST- 2016/01/14 06:00 [pubmed] PHST- 2016/10/08 06:00 [medline] PHST- 2016/01/12 00:00 [pmc-release] AID - 10.1186/s13075-015-0909-6 [pii] AID - 909 [pii] AID - 10.1186/s13075-015-0909-6 [doi] PST - epublish SO - Arthritis Res Ther. 2016 Jan 12;18:8. doi: 10.1186/s13075-015-0909-6.