The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding rat.
BACKGROUND
Autoimmune diabetes of the diabetes-resistant biobreeding (DRBB) rat shares similarities with diabetes in humans and has stages of diabetes that can be controlled and compared. FTY720 is an immunomodulator that has been efficacious in transplant and autoimmune models without inducing an immunosuppressed state. We determined the stages of diabetes that are affected by FTY720 in the DRBB rat.


METHODS
Autoimmune diabetes was induced with RT6.1 T-cell-depleting antibody and polyIC starting at 4 weeks of age. FTY720 (1 mg/kg/d) was started at day 0, 5, 7, and 14 following the start of depletion. The rats that did not develop diabetes were maintained for 60 d following the last dose of FTY720 before undergoing a second course of depletion.


RESULTS
FTY720 starting at day 0, 5, 7, and 14 of depletion prevented diabetes in 100, 100, 50, and 20% of the DRBB rats compared to 0% of the control rats. The surviving rats in the 5-, 7-, and 14-d groups developed diabetes after FTY720 treatment was stopped. Histological examination indicated insulitis in the control rats between day 7 and 11 of depletion and end-stage insulitis by day 18 of depletion compared to negligible insulitis in rats without diabetes. Redepletion in the surviving day 0 rats resulted in development of diabetes in 25% of these rats compared to none of the age-matched controls.


CONCLUSIONS
FTY720 can prevent autoimmune diabetes, if administered before and/or during stimulation and expansion of the autoreactive T cells or in the early stages of insulitis. The effectiveness diminishes with each successive stage of diabetes.
Popovic
Jadranka
J
Children's Mercy Hospital, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA. jpopovic@cmh.edu
Kover
Karen L
KL
Moore
Wayne V
WV
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D000068876:Fingolimod Hydrochloride; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011913:Rats, Inbred BB; D013110:Sphingosine / Q000031:analogs & derivatives; D016019:Survival Analysis
D000276:Adjuvants, Immunologic; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine