Yasunami, R. & Bach, J.F. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur. J. Immunol. 18, 481-484

INSERM U 25-CNRS UA 122-Hôpital, Necker, Paris.
European Journal of Immunology (Impact Factor: 4.52). 03/1988; 18(3):481-4. DOI: 10.1002/eji.1830180325
Source: PubMed

ABSTRACT In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes.

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    • "Cyclophosphamide (CTX) treatment was previously shown to enhance the autoimmune response and to synchronize diabetes onset when administrated to prediabetic non-obese diabetic (NOD) mice which is a well-documented animal model of spontaneous diabetes [1]. In agreement with the initial hypothesis suggesting that CTX actually induced the removal of a suppressor activity, Brode et al. have recently shown that CTX administration led to a reduction of T regulatory cell numbers [2]. "
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    ABSTRACT: Cyclophosphamide (CTX) was previously shown to induce the recruitment of immunosuppressive myeloid cells in mouse. In the non-obese diabetic (NOD) mouse, which develops spontaneously type I diabetes, CTX is widely known to accelerate the autoimmune process. Our data demonstrated that CTX actually did mobilize an immunosuppressive myeloid CD11b(+) Ly-6G(-) population in the NOD mouse spleen in addition to a well-identified neutrophil CD11b(+) Ly-6G(+) population. CD11b(+) Ly-6G(-) cells, in contrast with CD11b(+) Ly-6G(+) cells, were able to inhibit in vitro mitogen-induced syngeneic T cell proliferation. CD11b(+) Ly-6G(-) cells represented a heterogeneous population mainly made of CD31(hi) cells and Ly-6C(+) monocytes. Only these last ones supported the immunosuppressive in vitro activity and resembled circulating inflammatory monocytes according to flow cytometry, cytology and RT-PCR data. Although CD11b(+) Ly-6G(-) Ly-6C(+) cells exhibited immunosuppressive function in vitro, they were not able to control the autoimmune response following CTX injection. Our data show that these CTX-induced immunosuppressive myeloid cells actually behaved as very plastic cells in vitro. Likewise, in the model of prediabetic NOD/SCID mice, CD11b(+) Ly-6G(-) Ly-6C(+) were able to differentiate into CD11c+ cells after i.v. injection. Herein, we described a new mechanism by which CTX might induce diabetes acceleration in the NOD mouse. In summary, recruited immunosuppressive cells might participate in the immunopotentiating effect of CTX on the autoimmune response by their further differentiation into immunostimulatory cells.
    Immunology letters 02/2010; 129(2):85-93. DOI:10.1016/j.imlet.2010.01.009 · 2.37 Impact Factor
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    • "In particular, the accelerated diabetes onset in BDC2.5 transgenic NOD mice crossed onto RAG, SCID, and TCRa (Ca-deficient backgrounds, which lack endogenous (non-transgenic) T cells strongly supports the existence of T-cell populations that are capable of controlling T1D in wild-type NOD mice [7]. Similarly, administration of cyclophosphamide accelerates diabetes onset in NOD mice, probably through preferential deletion of regulatory T cells [8]. Two major, naturally occurring regulatory T-cell subsets have been identified, namely CD4 þ CD25 þ Treg and NKT cells. "
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    ABSTRACT: Type 1 diabetes is an autoimmune disease due to the destruction of insulin-producing pancreatic beta cells. Natural Killer T (NKT) cells are a T-cell subset that links the innate and adaptive immune systems. NKT cells play a key regulatory role in type 1 diabetes. The absence of NKT cells correlates with exacerbation of type 1 diabetes, whereas an increased frequency and/or activation of NKT cells prevents beta-cell autoimmunity. Various mechanisms are involved in the protective effect of NKT cells. The goal is now to translate knowledge gained from mouse models into human therapeutics.
    International Reviews Of Immunology 08/2009; 26(1-2):49-72. DOI:10.1080/08830180601070229 · 5.28 Impact Factor
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    • "The diabetic process can be accelerated and synchronized by the administration of cyclophosphamide (Cy), a drug that is thought to deplete immune regulatory cells [20]. In contrast to chemical induction of diabetes by STZ, the Cy accelerated destruction ensues from autoimmune attack and is associated with insulitis [20]. Both spontaneous NOD diabetes and cyclophosphamideaccelerated diabetes (CAD) are autoimmune disorders characterized by increased Th1 responses to several auto-antigens, including the 60 kDa heat-shock protein (HSP60) [21], glutamic acid decarboxylase (GAD) [22] [23] and insulin [24]. "
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) results from a specific autoimmune mediated destruction of the pancreatic beta-cells. PDX-1 induced developmentally redirected liver cells were suggested to restore the ablated pancreatic function in chemically induced diabetes. However, developmentally redirected liver cells, may have acquired along with the desired beta-cell characteristics and functions, also undesired sensitivity to autoimmune attack and therefore may be inefficient in ameliorating T1DM. This study analyzes whether subjects with beta-cell autoimmunity could benefit from Ad-CMV-PDX-1 gene therapy. Using the model of cyclophosphamide-accelerated diabetes in non-obese diabetic (CAD-NOD) mice, we report that recombinant adenovirus mediated PDX-1 gene therapy, ameliorates hyperglycemia in CAD-NOD mice. Our data demonstrate that 43% of the overtly diabetic CAD-NOD mice treated with Ad-CMV-PDX-1 became normoglycemic and maintained a stable body weight. Ectopic PDX-1 expression induced pancreatic gene expression and insulin production in the mice livers. The amelioration of hyperglycemia, in PDX-1 treated diabetic mice was associated with an immune modulation manifested by Th1 to Th2 shift in the autoimmune T-cell response to antigens associated with NOD diabetes. Thus, liver-to-pancreas transdifferentiation ameliorates T1DM in a process which is associated with a concomitant modulation of the autoimmune attack. Our findings suggest a beneficial therapeutic effect of the PDX-1 gene therapy for treating autoimmune type 1 diabetes mellitus (T1DM).
    Journal of Autoimmunity 03/2007; 28(2-3):134-42. DOI:10.1016/j.jaut.2007.02.010 · 7.02 Impact Factor
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