Assessment of the diabetogenic drugs alloxan and streptozotocin as models for the study of immune defects in diabetic mice.
The efficacy of the diabetogenic drugs streptozotocin and alloxan were evaluated as models for the study of immune defects associated with diabetes. Streptozotocin- or alloxan-treated mice, with a stable hyperglycaemia of 25-33 mmol/l plasma glucose, were severely impaired in their ability to mount antibody forming, mitogenic, or delayed-type hypersensitivity responses in vivo. Treatment of alloxan-diabetic mice with insulin in vivo completely reversed all immune defects, while insulin treatment of streptozotocin-diabetic mice restored immune function to only 70-80% of normal levels. Results obtained by viability measurements and in vitro biological assays of lymphoid function, including proliferation in response to T- and B-cell mitogens, the production of interleukin-2 by T cells, and the production of interleukin-1 by macrophages indicated that direct exposure to alloxan for 48 h (at concentrations less than or equal to 14 mmol/l) had no adverse effects on lymphoid activity, while exposure to streptozotocin was routinely toxic at concentrations greater than or equal to 1 mmol/l. Both alloxan and streptozotocin exhibited strong toxicity in vitro for isolated pancreatic islet cells. Finally, lymphocytes from streptozotocin-diabetic mice, or cells incubated in vitro with streptozotocin, contained numerous chromosomal abnormalities indicative of DNA strand breakage. Such abnormalities were absent in alloxan-diabetic mice and in cells incubated with alloxan in vitro. These results indicate that immune dysfunction associated with streptozotocin is attributable to direct and irreversible impairment of lymphoid cell function and viability. In contrast, immune dysfunction associated with alloxan-diabetes appears to be a consequence of the diabetic state.(ABSTRACT TRUNCATED AT 250 WORDS)
Gaulton
G N
GN
Schwartz
J L
JL
Eardley
D D
DD
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000473:pathology; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular; D007153:Immunologic Deficiency Syndromes / Q000209:etiology* / Q000276:immunology; D007328:Insulin / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000473:pathology; D013311:Streptozocin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000473:pathology
D007328:Insulin; D013311:Streptozocin; D000496:Alloxan; D004247:DNA