Summary
The efficacy of the diabetogenic drags 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 ≤ 14 mmol/l) had no adverse effects on lymphoid activity, while exposure to streptozotocin was routinely toxic at concentrations ≥ 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. Thus, alloxan- but not streptozotocin-diabetes provides a useful model for evaluating immunological changes associated with hyperglycaemia and diabetes.
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References
Johnson JE III (1983) Infection and diabetes. In: Ellenberg M, Rifkin H (eds) Diabetes millitus: Theory and practice. McGraw-Hill, New York, pp 734–7452
Louria DB (1967) Deep-seated mycotic infections, allergy to fungi and mycotoxins. N Engl J Med 277: 1065–1071
MacCuish AC, Jordan J, Campbell CJ, Duncan LJP, Irvine WJ (1974) Cell-mediated immunity to human pancrease in diabetes mellitus. Diabetes 23: 693–697
Buse JB, Rowley RF, Eisenbarth GS (1982) Disordered cellular immunity in type I diabetes of man and the BB rat. Surv Immunol Res 1: 339–351
Coleman DL (1979) Diabetes mellitus in rodents. In: Andrews EJ, Ward BC, Altman NH (eds) Spontaneous animal models of human disease, vol 1. Academic Press, New York, pp 126–131
Rerup CC (1970) Drugs producing diabetes through damage of the insulin secreting cells. Pharm Rev 22: 485–518
Weiss RB (1982) Streptozotocin: a review of its pharmacology, efficacy, and toxicity. Cancer Treatment Reports 66: 427–436
Malaisse-Lagae F, Sener A, Malaisse WJ (1981) Biochemical basis of a species difference in sensitivity to alloxan. FEBS Lett 133: 181–182
Yamamoto H, Uchigata Y, Okamoto H (1981) Streptozotocin and alloxan induce DNA strand breaks and poly(ADP-ribose) synthetase in pancreatic islets. Nature 294: 284–286
Ptak W, Hanczakowska M, Rozycka R, Rozycka D (1977) Impaired antibody responses in alloxan diabetic mice. Clin Exp Immunol 29: 140–146
Ptak W, Czarnik Z, Hanczakowska M (1975) Contact sensitivity in alloxan-diabetic mice. Clin Exp Immunol 19: 319–325
Mahmoud AAF, Rodman HM, Mandel MA, Warren KS (1976) Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. J Clin Invest 57: 362–367
Nevalainen DE, Hoftiezer U (1977) The response of C3H mice to streptozotocin. I. Thymic depression and leukocyte toxicity. Am J Med Technol 43: 417–418
Nichols WK, Spellman JB, Vann LL, Daynes RA (1979) Immune responses of diabetic animals: direct immunosuppressant effects of streptozotocin in mice. Diabetologica 16: 51–57
Hyvarinen A, Nikkila E (1962) Specific determination of blood glucose with 0-toluidine. Clin Chim Acta 1: 140–143
Yoon JW, Onodera T, Nokins AL (1978) Virus-induced diabetes mellitus. XV. Beta cell damage and insulin-dependent hyperglycemia in mice infected with Coxsackie B4. J Exp Med 148: 1068–1080
Onodera T, Toniolo A, Ray UR, Jenson AB, Knazek RA, Notkins AL (1981) Virus-induced diabetes mellitus XX. Polyendocrinopathy and autoimmunity. J Exp Med 153: 1457–1473
Bernstein SE (1966) Physiological characteristics. In: Green EL (ed) Biology of the laboratory mouse, 2nd edn. McGraw-Hill, New York, pp 337–350
Lee JM, DeWitt S Jr (1952) Studies in alloxan metabolism. J Biol Chem 197: 205–214
Lacy PE, Kostianovsky M (1967) Method for the isolation of intact islets of langerhans from the rat pancreas. Diabetes 16: 35–39
Cowing C, Schwartz BD, Dickler HB (1978) Macrophage Ia antigens. I. Macrophage populations differ in their expression of Ia antigens. J Immunol 120: 378–384
Grankvist K, Lernmark A, Taljedal I-B (1977) Microscope photometric analyses of trypan blue uptake by pancreatic islet cells in suspension. Biochem J 162: 19–24
Cunningham AJ (1965) A method of increased sensitivity for detecting single antibody-forming cells. Nature 207: 1106–1107
Eardley DD, Murphy DB, Kemp JD, Shen FW, Cantor H, Gershon RK (1980) Ly-1 inducer and ly-1,2 acceptor Tcells in the feedback suppressor circuit bear an I-J subregion determinant. Immunogenetics 11: 549–553
Gillis S, Ferm MM, Ou W, Smith KA (1978) T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol 120: 2027–2032
Mizel SB, Oppenheim JJ, Rosenstreich DL (1978) Characterization of lymphocyte-activating factor (LAF) produced by the macrophage cell line P388D1. 1. Enhancement of LAF production by activated T lymphocytes. J Immunol 120: 1497–1503
Bach BA, Sherman L, Benacerraf B, Greene MI (1978) Mechanisms of regulation of cell-mediated immunity. II. Induction and suppression of delayed-type hypersensitivity to azobenzene-arsonate-coupled syngeneic cells. J Immunol 121: 1460–1468
Nichols WK, Spellmann JB, Daynes RA (1978) Immune responses of diabetic animals: comparison of genetically obese and streptozotocin-diabetic mice. Diabetologica 14: 343–349
Jackson R, Rassi N, Crump T, Haynes B, Eisenbarth GS (1981) The BB Diabetic rat: profound T-cell lymphocytopenia. Diabetes 30: 887–889
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Gaulton, G.N., Schwartz, J.L. & Eardley, D.D. Assessment of the diabetogenic drugs alloxan and streptozotocin as models for the study of immune defects in diabetic mice. Diabetologia 28, 769–775 (1985). https://doi.org/10.1007/BF00265026
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DOI: https://doi.org/10.1007/BF00265026