Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice

ArticleinEuropean Journal of Immunology 18(3):481-4 · March 1988with10 Reads
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.
    • "[12] It has been suggested that CY preferentially depletes regulatory (suppressor) cells. [13] The nature of these suppressors is largely unknown. There is growing evidence that Th2-like cells secreting interleukin (IL-4) and IL-10 provide protection, whereas pathogenic cells are Th1-like cell which secretes interferons alpha (IFN-α). "
    [Show abstract] [Hide abstract] ABSTRACT: Breast cancer is the leading cause of death in women. Epirubicin and cyclophosphamide (EC) is one of the chemotherapeutic regimens used for the treatment of breast cancer. We describe a case treated with EC regimen and who presented to us with symptoms suggestive of diabetes mellitus postchemotherapy. Absence of family history of diabetes and normal blood sugar level, prechemotherapy points toward drug‑induced hyperglycemia. These chemotherapeutic agents capable of altering immune response and might act synergistically to cause immunological damage to the islets of pancreas which might precipitate diabetes mellitus. Causality analysis on Naranjo's scale indicates a possible association with regimen.
    Full-text · Article · Sep 2016
    • "In that model, cyclophosphamide is used as a neutropenic agent to establish an A. baumannii persistent infection. Yet, cyclophosphamide also preferentially depletes suppressor or regulatory T cells (Yasunami and Bach, 1988; Ghiringhelli et al., 2004) and affects circulating macrophages (Santosuosso et al., 2002). The advantage of using the mAb 1A8 over cyclophosphamide to deplete neutrophils is that it acts preferentially on these cells of innate immunity, making neutrophil function studies more reliable. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Nov 2015
    • "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). A. baumannii is an extremely successful opportunistic pathogen of immunosuppressed individuals. "
    [Show abstract] [Hide abstract] 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.
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