Streptococcal wall component OK432 restores sensitivity of non-obese diabetic (NOD) thymocytes to apoptotic signals. 2000

B Decallonne, and L Overbergh, and K M Casteels, and C Gysemans, and R Bouillon, and C Mathieu
Laboratory for Experimental Medicine and Endocrinology, Catholic University Leuven, Belgium.

OBJECTIVE The streptococcal wall component, OK432, prevents diabetes in NOD mice and BB rats by elimination of effector cells. Based on the knowledge of a link between autoimmunity and resistance of immune cells to elimination by apoptosis, we investigated whether OK432 treatment restored the sensitivity of NOD lymphocytes to apoptotic signals centrally (thymus) or peripherally (spleen) or both and we examined the pathways for the enhanced apoptosis rate. METHODS We treated NOD mice with OK432 (0.1 mg/kg i.p. weekly from 21 to 70 days). Apoptosis was measured by TUNEL 16 h after cyclophosphamide (70 mg/kg) and 24 h after dexamethasone (0.2 mg/mouse). Real time quantitative RT-PCR was used to investigate changes in gene expression. RESULTS Thymocyte apoptosis levels after cyclophosphamide were restored by OK432 treatment to levels observed in C57BL/6 mice: in NOD males apoptosis increased from 8 +/- 1% to 18 +/- 5% (p < 0.05) compared with 20 +/- 4% in C57BL/6 males, and in NOD females from 6+/- 2% to 11 +/- 2% (p < 0.05) compared with 12 +/- 2% in C57BL/6 females. The dexamethasone-induced thymocyte apoptosis rate was equally restored by OK432 treatment (58 +/- 4% vs 41 +/- 3% in control males (p < 0.0005) and 39 +/- 5% vs 26 +/- 3% in control females (p < 0.05)]. No change in apoptosis levels was on the contrary observed in splenocytes after OK432 treatment. By RT-PCR analysis of a panel of apoptosis-related genes in thymocytes we showed a down-regulation of anti-apoptotic Bcl-xL and c-myc by OK432 treatment. CONCLUSIONS Our data suggest that OK432 prevents diabetes in NOD mice by better elimination of effector cells through increased sensitivity to apoptotic signals centrally in the thymus.

UI MeSH Term Description Entries
D007166 Immunosuppressive Agents Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. Immunosuppressant,Immunosuppressive Agent,Immunosuppressants,Agent, Immunosuppressive,Agents, Immunosuppressive
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D010844 Picibanil A lyophilized preparation of a low-virulence strain (SU) of Streptococcus pyogenes (S. hemolyticus), inactivated by heating with penicillin G. It has been proposed as a noncytotoxic antineoplastic agent because of its immune system-stimulating activity. NSC-B116209,OK-432,Picibanyl,Streptococcal OK-432,Streptococcal Preparation OK-432,NSC B116209,NSCB116209,OK 432,OK432,Streptococcal OK 432,Streptococcal OK432,Streptococcal Preparation OK 432,Streptococcal Preparation OK432
D003520 Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. (+,-)-2-(bis(2-Chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-Oxide Monohydrate,B-518,Cyclophosphamide Anhydrous,Cyclophosphamide Monohydrate,Cyclophosphamide, (R)-Isomer,Cyclophosphamide, (S)-Isomer,Cyclophosphane,Cytophosphan,Cytophosphane,Cytoxan,Endoxan,NSC-26271,Neosar,Procytox,Sendoxan,B 518,B518,NSC 26271,NSC26271
D003907 Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Hexadecadrol,Decaject,Decaject-L.A.,Decameth,Decaspray,Dexasone,Dexpak,Hexadrol,Maxidex,Methylfluorprednisolone,Millicorten,Oradexon,Decaject L.A.
D003922 Diabetes Mellitus, Type 1 A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence. Diabetes Mellitus, Brittle,Diabetes Mellitus, Insulin-Dependent,Diabetes Mellitus, Juvenile-Onset,Diabetes Mellitus, Ketosis-Prone,Diabetes Mellitus, Sudden-Onset,Diabetes, Autoimmune,IDDM,Autoimmune Diabetes,Diabetes Mellitus, Insulin-Dependent, 1,Diabetes Mellitus, Type I,Insulin-Dependent Diabetes Mellitus 1,Juvenile-Onset Diabetes,Type 1 Diabetes,Type 1 Diabetes Mellitus,Brittle Diabetes Mellitus,Diabetes Mellitus, Insulin Dependent,Diabetes Mellitus, Juvenile Onset,Diabetes Mellitus, Ketosis Prone,Diabetes Mellitus, Sudden Onset,Diabetes, Juvenile-Onset,Diabetes, Type 1,Insulin Dependent Diabetes Mellitus 1,Insulin-Dependent Diabetes Mellitus,Juvenile Onset Diabetes,Juvenile-Onset Diabetes Mellitus,Ketosis-Prone Diabetes Mellitus,Sudden-Onset Diabetes Mellitus
D005260 Female Females
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D005938 Glucocorticoids A group of CORTICOSTEROIDS that affect carbohydrate metabolism (GLUCONEOGENESIS, liver glycogen deposition, elevation of BLOOD SUGAR), inhibit ADRENOCORTICOTROPIC HORMONE secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system. Glucocorticoid,Glucocorticoid Effect,Glucorticoid Effects,Effect, Glucocorticoid,Effects, Glucorticoid

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