CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice.
The nonobese diabetic (NOD) mouse spontaneously develops T cell-dependent autoimmune diabetes. Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this disease. Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the age at which insulitis typically begins) completely prevented the insulitis and diabetes. In contrast, treatment of such mice with anti-CD40L at >9 wk of age did not inhibit the disease process. These results suggest that a costimulatory signal by CD40L is required early but not in the effector phase of disease development. Anti-CD40L treatment affected the priming of islet Ag-specific T cell responses in vivo. Cytokine analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from anti-CD40L-treated mice. Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40L was not associated with switching of the response from a Th1 to a Th2 profile. Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly prevented the insulitis by inhibiting the development and further accumulation of pathogenic Th1 cells to islets of Langerhans, we conclude that CD40L-CD40 costimulation is required for early events in the development of spontaneous autoimmune diabetes.
Balasa
B
B
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Krahl
T
T
Patstone
G
G
Lee
J
J
Tisch
R
R
McDevitt
H O
HO
Sarvetnick
N
N
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D010182:Pancreatic Diseases / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand