ABSTRACT
PURPOSE: Invasive breast carcinoma is the most common cancer in women as in non-ovariectomised pet dogs, which are already identified as a valuable spontaneous preclinical model for that disease. Geographical and time trends suggest that environmental factors may play an important role in the etiology and pathogenesis of breast cancer. Persistent organic pollutants (POPs) fit perfectly with these trends and are known to interact with hormonal receptors implicated in breast cancer subtyping. The aim of this innovating study was to evaluate the interest of the companion dog model in assessing chemical exposure and breast cancer associations, in order to identify common etiological features with the human disease in a context of comparative oncology. METHODS: We monitored a hundred of molecules belonging to a large panel of POPs (dioxins, dioxin-like and non dioxin-like polychlorobisphenyls, organochlorine pesticides, brominated flame retardants, perfluorinated alkylated substances) in companion dogs diagnosed for mammary adenocarcinoma (n = 54) and non cancer controls (n = 47). RESULTS: All targeted chemical families were able to be detected in canine samples. We identified pollutants associated with mammary cancer belonging to the dioxin like-PCB family (notably PCB-118, -156, -105, -114) that were already pointed out in human epidemiological studies on breast cancer, and that fit with the fundamental role of the Aryl Hydrocarbon Receptor in the promotion of breast cancer. CONCLUSIONS: Similarities observed in the spontaneous dog model are very helpful to progress in interpretation of human breast cancer-environment relationships. This study provides a new insight focusing on this discrete but recurrent signature.
ABSTRACT
Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells. CD8(+) T cells have recently been assigned a major role in beta cell injury. Consequently, the identification of autoreactive CD8(+) T cells in humans remains essential for development of therapeutic strategies and of assays to identify aggressive cells. However, this identification is laborious and limited by quantities of human blood samples available. We propose a rapid and reliable method to identify autoantigen-derived epitopes recognized by human CD8(+) T lymphocytes in T1D patients. Human histocompatibility leukocyte Ags-A*0201 (HLA-A*0201) transgenic mice were immunized with plasmids encoding the T1D-associated autoantigens: 65 kDa glutamic acid decarboxylase (GAD) or insulinoma-associated protein 2 (IA-2). Candidate epitopes for T1D were selected from peptide libraries by testing the CD8(+) reactivity of vaccinated mice. All of the nine-candidate epitopes (five for GAD and four for IA-2) identified by our experimental approach were specifically recognized by CD8(+) T cells from newly diagnosed T1D patients (n = 19) but not from CD8(+) T cells of healthy controls (n = 20). Among these, GAD(114-123), GAD(536-545) and IA-2(805-813) were recognized by 53%, 25%, and 42% of T1D patients, respectively.
Subject(s)
Autoantigens/immunology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , HLA-A Antigens/genetics , Immunodominant Epitopes/immunology , Vaccines, DNA/immunology , Adolescent , Adult , Animals , Autoantigens/genetics , Autoantigens/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Diabetes Mellitus, Type 1/diagnosis , Female , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/immunology , HLA-A Antigens/administration & dosage , HLA-A Antigens/immunology , HLA-A Antigens/metabolism , HLA-A2 Antigen , Humans , Immunodominant Epitopes/metabolism , Injections, Subcutaneous , Isoenzymes/genetics , Isoenzymes/immunology , Male , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Transgenic , Middle Aged , Peptide Fragments/genetics , Peptide Fragments/immunology , Protein Binding/genetics , Protein Binding/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/immunology , Receptor-Like Protein Tyrosine Phosphatases, Class 8 , Vaccines, DNA/administration & dosageABSTRACT
During the past decade, glutamic acid decarboxylase (GAD) has been considered a crucial beta-cell autoantigen involved in type 1 diabetes in the NOD mouse and human. Recently, the etiological role of GAD has remained controversy. In the NOD mouse, some previous studies argued in favor of a regulatory role for GAD-specific CD4+ T cells, and no diabetogenic CD8+ T cells specific for GAD have been identified so far, discrediting the importance of GAD in beta-cell injury. Here, we identified, in the NOD model, a relevant GAD CD8+ T cell epitope (GAD(90-98)) using immunization with a plasmid encoding GAD, a protocol relying on in vivo processing of peptides from the autoantigenic protein. In pancreatic lymph nodes of naïve female NOD mice, CD8+ T lymphocytes recognizing GAD(90-98) peptide were detected during the initial phase of invasive insulitis (between 4 and 8 weeks of age), suggesting an important role for these cells in the first stage of the disease. GAD(90-98) specific CD8+ lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NOD(SCID) mice (100%). Finally, diabetes was accelerated greatly in 3-week-old female NOD mice injected i.p. with GAD(90-98), strengthening the role of GAD-specific CTLs in diabetes pathogenesis.
