title: Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation.
abstract: The prevention of diabetes by the immunomodulatory agent FTY720 (fingolimod) was studied in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Immune cell subtypes and cytokine profiles in pancreatic islets, secondary lymphoid tissue, and serum were analyzed for signs of immune cell activation. Animals were treated with FTY720 (1 mg/kg body weight) for 40 d starting on d 50 of life. Changes in gene and protein expression of cytokines, CD8 markers, monocyte chemoattractant protein-1, inducible NO synthase, and caspase 3 were evaluated. Treatment with FTY720 prevented diabetes manifestation and islet infiltration around d 60 of life, the usual time of spontaneous diabetes development. On d 120, 30 d after the end of FTY720 therapy, diabetes prevention persisted. However, six of 12 treated animals showed increased gene expression of IL-1beta, TNF-alpha, and CD8 markers in pancreas-draining lymph nodes, indicating immune cell activation. In parallel, serum concentrations of these proinflammatory cytokines were increased. These six animals also showed macrophage infiltration without proinflammatory cytokine expression in a small minority (2-3%) of islets. Interestingly, regulatory T lymphocytes were significantly increased in the efferent vessels of the pancreas-draining lymph nodes only in animals without signs of immune cell activation but not in the rats with immune cell activation. This provides an indication for a lack of protective capacity in the animals with activated immune cells. Thus, FTY720 treatment prevented the manifestation of diabetes by promoting the retention of activated immune cells in the lymph nodes, thereby avoiding islet infiltration and beta-cell destruction by proinflammatory cytokines.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany. joerns.anne@mh-hannover.de
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Klaus Jan
authors.initials: KJ
authors.lastname: Rath
authors.forename: Taivankhuu
authors.initials: T
authors.lastname: Terbish
authors.forename: Tanja
authors.initials: T
authors.lastname: Arndt
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer Zu Vilsendorf
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005260:Female; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D007107:Immune System / Q000187:drug effects* / Q000276:immunology; D056747:Immunomodulation; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine