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: 4.03). 03/1988; 18(3):481-4. DOI: 10.1002/eji.1830180325
Source: PubMed


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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    • "Moreover , cyclophosphamide inhibits a suppressor response that normally prevents activation of effector T cells ( Yasunami and Bach , 1988 ) . The exacerbation of inflammatory responses and blockade of suppressive activity after cyclophosphamide treatment is consistent with the suggestion that this agent preferentially depletes suppressor or regulatory T cells ( Yasunami and Bach , 1988 ; Ghiringhelli et al . , 2004 ) . "
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    ABSTRACT: The Gram negative coccobacillus Acinetobacter baumannii has become an increasingly prevalent cause of hospital-acquired infections in recent years. The majority of clinical A. baumannii isolates display high-level resistance to antimicrobials, which severely compromises our capacity to care for patients with A. baumannii disease. Neutrophils are of major importance in the host defense against microbial infections. However, the contribution of these cells of innate immunity in host resistance to cutaneous A. baumannii infection has not been directly investigated. Hence, we hypothesized that depletion of neutrophils increases severity of bacterial disease in an experimental A. baumannii murine wound model. In this study, the Ly-6G-specific monoclonal antibody (mAb), 1A8, was used to generate neutropenic mice and the pathogenesis of several A. baumannii clinical isolates on wounded cutaneous tissue was investigated. We demonstrated that neutrophil depletion enhances bacterial burden using colony forming unit determinations. Also, mAb 1A8 reduces global measurements of wound healing in A. baumannii-infected animals. Interestingly, histological analysis of cutaneous tissue excised from A. baumannii-infected animals treated with mAb 1A8 displays enhanced collagen deposition. Furthermore, neutropenia and A. baumannii infection alter pro-inflammatory cytokine release leading to severe microbial disease. Our findings provide a better understanding of the impact of these innate immune cells in controlling A. baumannii skin infections.
    Frontiers in Microbiology 11/2015; 6:1134. DOI:10.3389/fmicb.2015.01134 · 3.99 Impact Factor
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    • "Moreover, CYP inhibits a suppressor response that normally prevents activation of effector T cells (Yasunami & Bach, 1988). The exacerbation of inflammatory responses and blockade of suppressive activity after CYP treatment is consistent with the suggestion that CYP preferentially depletes suppressor or regulatory T cells (Ghiringhelli et al., 2004; Yasunami & Bach, 1988). "
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    ABSTRACT: Acinetobacter baumannii is an opportunistic Gram-negative bacterium that affects critically ill hospitalized patients with breaches in skin integrity and airway protection leading to significant morbidity and mortality. Considering the paucity of well-established animal models of immunosuppression to study A. baumannii pathogenesis, we set out to characterize a murine model of immunosuppression using the alkylating agent cyclophosphamide (CYP). We hypothesize that CYP-induced immunosuppression would increase the susceptibility of C57BL/6 to develop A. baumannii-mediated pneumonia followed by systemic disease. We demonstrated that CYP intensified A. baumannii-mediated pulmonary disease, abrogated normal immune cell function and lead to altered pro-inflammatory cytokine release. The development of an animal model that mimics A. baumannii infection onset in immunosuppressed individuals is crucial for generating novel approaches to patient care and improving public health strategies to decrease susceptibility of infection for individuals at risk.
    Journal of Medical Microbiology 09/2013; 62(Pt_11). DOI:10.1099/jmm.0.060004-0 · 2.25 Impact Factor
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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 · 2.51 Impact Factor
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