Paradoxical antidiabetogenic effect of gamma-interferon in DP-BB rats.
Previous studies have shown that anti-gamma-interferon (IFN-gamma) antibody reduces the frequency of autoimmune IDDM in the DP-BB rat. We tested the effects of systemically administered recombinant rat IFN-gamma in both DP-BB and DR-BB rats. Unexpectedly, IFN-gamma markedly reduced the incidence of IDDM as compared with control rats when administered six times per week at a dosage of 280,000 U between ages 30-35 to 105 days or ages 60-64 to 105 days. A lower dosage (28,000 U on alternate days) was also protective when administered to DP-BB rats between birth and age 60 days. However, long-lasting protection against IDDM development over the 1-year study period was achieved only by the highest dosage of IFN-gamma administered from age 30 to 105 days. Ex vivo production of tumor necrosis factor-alpha from splenic lymphoid cells (SLCs) and peritoneal macrophages of the rats treated with IFN-gamma was comparable with that of controls; however, SLCs from the IFN-gamma-treated animals secreted lower amounts of IFN-gamma after stimulation with concanavalin A. IFN-gamma treatment also markedly reduced the frequency of phenotypically activated SLC-expressing class II antigens and interleukin-2 receptor. Finally, in agreement with the observed antidiabetogenic effects, exogenously administered IFN-gamma induced neither insulitis nor IDDM development in DR-BB rats, a subline of DP-BB rats in which autoimmune diabetes rarely occurs spontaneously but can be induced by administration of polyinosinic-polycytidilic acid.
Nicoletti
F
F
Institute of Microbiology, University of Milan, Italy. fnicol@herganet.it
Zaccone
P
P
Di Marco
R
R
Magro
G
G
Grasso
S
S
Stivala
F
F
Calori
G
G
Mughini
L
L
Meroni
P L
PL
Garotta
G
G
D000375:Aging / Q000502:physiology; D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015994:Incidence; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D010641:Phenotype; D011897:Random Allocation; D051381:Rats; D011913:Rats, Inbred BB; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma; D016559:Tacrolimus