The anti-inflammatory compound lisofylline prevents Type I diabetes in non-obese diabetic mice.
OBJECTIVE
Pro-inflammatory cytokines are increased during the active stages of Type I (insulin-dependent) diabetes mellitus. The aim of this study was to investigate the applicability of using a new anti-inflammatory compound, Lisofylline, to prevent diabetes in non-obese diabetic (NOD) mice. Lisofylline has previously been shown to block Th1 cell differentiation and to reduce IL-1 beta-induced dysfunction in rat islets.


METHODS
Lisofylline was added to isolated NOD islets in vitro, with or without IL-1 beta. Insulin secretion and DNA damage of the islets was assessed. Lisofylline was administered to female non-obese diabetic mice starting at 4, 7 and 17 weeks of age for 3 weeks. Cytokines and blood glucose concentrations were monitored. Histology and immunohistochemistry were carried out in pancreatic sections. Splenocytes isolated from donor mice were intravenously injected into immunodeficient NOD (NOD.scid) mice.


RESULTS
In vitro, Lisofylline preserved beta-cell insulin secretion and inhibited DNA damage of islets in the presence of IL-1 beta. In vivo, Lisofylline suppressed IFN-gamma production, reduced the onset of insulitis and diabetes, and inhibited diabetes after transfer of splenocytes from Lisofylline-treated donors to NOD.scid recipients. However, cotransfer of splenocytes from both Lisofylline-treated and diabetic NOD donors did not suppress diabetes in recipient mice.


CONCLUSIONS
Lisofylline prevents the onset of autoimmune diabetes in NOD mice by a mechanism that does not seem to enhance the function of regulatory T cells, but could be associated with suppression of proinflammatory cytokines and reduction of cellular infiltration in islets. This study suggests that Lisofylline could have therapeutic benefits in preventing the onset of Type I diabetes.
Yang
Z-D
ZD
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908-1405, USA.
Chen
M
M
Wu
R
R
McDuffie
M
M
Nadler
J-L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004249:DNA Damage; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000517:prevention & control*; D005260:Female; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D017710:Lymphocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; C025189:lisofylline; D010431:Pentoxifylline