ABSTRACT
In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury1-4. Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.
Subject(s)
Celiac Disease , Duodenum , Interleukin-7 , Intestinal Mucosa , Models, Biological , Organoids , Humans , Autoantibodies/immunology , Autoimmunity , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biopsy , Celiac Disease/immunology , Celiac Disease/pathology , Celiac Disease/metabolism , Duodenum/immunology , Duodenum/pathology , Duodenum/metabolism , Epitopes/immunology , Glutens/immunology , Glutens/metabolism , GTP-Binding Proteins/metabolism , GTP-Binding Proteins/immunology , HLA-DQ Antigens/immunology , HLA-DQ Antigens/metabolism , Interleukin-7/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Killer Cells, Natural/immunology , Myeloid Cells/immunology , Organoids/immunology , Organoids/metabolism , Organoids/pathology , Protein Glutamine gamma Glutamyltransferase 2/immunology , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, B-Cell/metabolism , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Chronic inflammatory enteropathy (CIE) is a common condition in dogs causing recurrent or persistent gastrointestinal clinical signs. Pathogenesis is thought to involve intestinal mucosal inflammatory infiltrates, but histopathological evaluation of intestinal biopsies from dogs with CIE fails to guide treatment, inform prognosis, or correlate with clinical remission. We employed single-cell RNA sequencing to catalog and compare the diversity of cells present in duodenal mucosal endoscopic biopsies from 3 healthy dogs and 4 dogs with CIE. Through characterization of 35,668 cells, we identified 31 transcriptomically distinct cell populations, including T cells, epithelial cells, and myeloid cells. Both healthy and CIE samples contributed to each cell population. T cells were broadly subdivided into GZMAhigh (putatively annotated as tissue resident) and IL7Rhigh (putatively annotated as non-resident) T cell categories, with evidence of a skewed proportion favoring an increase in the relative proportion of IL7Rhigh T cells in CIE dogs. Among the myeloid cells, neutrophils from CIE samples exhibited inflammatory (SOD2 and IL1A) gene expression signatures. Numerous differentially expressed genes were identified in epithelial cells, with gene set enrichment analysis suggesting enterocytes from CIE dogs may be undergoing stress responses and have altered metabolic properties. Overall, this work reveals the previously unappreciated cellular heterogeneity in canine duodenal mucosa and provides new insights into molecular mechanisms which may contribute to intestinal dysfunction in CIE. The cell type gene signatures developed through this study may also be used to better understand the subtleties of canine intestinal physiology in health and disease.
Subject(s)
Dog Diseases , Duodenum , Gene Expression Profiling , Single-Cell Analysis , Transcriptome , Animals , Dogs , Duodenum/pathology , Duodenum/immunology , Duodenum/metabolism , Dog Diseases/genetics , Dog Diseases/immunology , Dog Diseases/pathology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Chronic Disease , Male , Female , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.
Subject(s)
Celiac Disease , Diet, Gluten-Free , GTP-Binding Proteins , Gene Expression Profiling , Glutens , Intestinal Mucosa , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases , Celiac Disease/immunology , Humans , Glutens/immunology , Transglutaminases/metabolism , Transglutaminases/antagonists & inhibitors , GTP-Binding Proteins/metabolism , GTP-Binding Proteins/antagonists & inhibitors , GTP-Binding Proteins/genetics , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/drug effects , Female , Male , Adult , Transcriptome , Duodenum/pathology , Duodenum/immunology , Duodenum/metabolism , Interferon-gamma/metabolism , Middle Aged , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , Young Adult , Adaptive Immunity/drug effectsABSTRACT
BACKGROUND: Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM: To improve overall understanding of this disease's diagnosis and prognosis. METHODS: We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS: Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin's lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION: Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.
Subject(s)
Glucocorticoids , Humans , Female , Male , Retrospective Studies , Adult , Middle Aged , Prognosis , Biopsy , Glucocorticoids/therapeutic use , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/immunology , Polyendocrinopathies, Autoimmune/pathology , Polyendocrinopathies, Autoimmune/drug therapy , Polyendocrinopathies, Autoimmune/therapy , Ileum/pathology , Ileum/immunology , Duodenum/pathology , Duodenum/immunology , Diarrhea/etiology , Diarrhea/diagnosis , Diarrhea/immunology , Intestinal Mucosa/pathology , Intestinal Mucosa/immunology , Immunosuppressive Agents/therapeutic use , Aged , Young Adult , Endoscopy, GastrointestinalABSTRACT
Many antibody responses induced by infection, vaccination or autoimmunity show signs of convergence across individuals with epitope-dependent selection of particular variable region gene segments and complementarity determining region 3 properties. However, not much is known about the relationship between antigen-specific effector cells and antigen-specific precursors present in the naïve B-cell repertoire. Here, we sought to address this relationship in the context of celiac disease, where there is a stereotyped autoantibody response against the enzyme transglutaminase 2 (TG2). By generating TG2-specific monoclonal antibodies from both duodenal plasma cells and circulating naïve B cells, we demonstrate a discord between the naïve TG2-specific repertoire and the cells that are selected for autoantibody production. Hence, the naïve repertoire does not fully reflect the epitope preference and gene usage observed for memory B cells and plasma cells. Instead, distinct naïve B cells that target particular TG2 epitopes appear to be selectively activated at the expense of TG2-binding B cells targeting other epitopes.
Subject(s)
Autoantibodies , B-Lymphocytes , Celiac Disease , Epitopes, B-Lymphocyte , GTP-Binding Proteins , Lymphocyte Activation , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases , Celiac Disease/immunology , Humans , Autoantibodies/immunology , Transglutaminases/immunology , Epitopes, B-Lymphocyte/immunology , GTP-Binding Proteins/immunology , Lymphocyte Activation/immunology , B-Lymphocytes/immunology , Plasma Cells/immunology , Plasma Cells/metabolism , Female , Antibodies, Monoclonal/immunology , Epitopes/immunology , Male , Adult , Duodenum/immunology , Duodenum/pathologyABSTRACT
Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.
Subject(s)
Axl Receptor Tyrosine Kinase , Celiac Disease , Duodenum , Intercellular Signaling Peptides and Proteins , Intestinal Mucosa , Protein S , Receptor Protein-Tyrosine Kinases , c-Mer Tyrosine Kinase , Humans , Celiac Disease/immunology , Celiac Disease/metabolism , Celiac Disease/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/immunology , Male , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Female , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Adult , Duodenum/metabolism , Duodenum/immunology , Duodenum/pathology , c-Mer Tyrosine Kinase/genetics , c-Mer Tyrosine Kinase/metabolism , Protein S/metabolism , Protein S/genetics , Middle Aged , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Young Adult , Signal Transduction , Adolescent , Interferons/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
In its conventional form, celiac disease (CeD) is characterized by both positive serology and flat villi in the duodenum, and is well known by gastroenterologists and general practitioners. The aim of this review was to shed light on 2 neglected and not yet well-defined celiac phenotypes, that is, seronegative and ultrashort CeD. Seronegative CeD can be suspected in the presence of flat villi, positive HLA-DQ2 and/or HLA-DQ8, and the absence of CeD antibodies. After ruling out other seronegative enteropathies, the diagnosis can be confirmed by both clinical and histologic improvements after 1 year of a gluten-free diet. Ultrashort CeD is characterized by the finding of flat villi in the duodenal bulb in the absence of mucosal damage in the distal duodenum and with serologic positivity. Data on the prevalence, clinical manifestations, histologic lesions, genetic features, and outcome of seronegative and ultrashort CeD are inconclusive due to the few studies available and the small number of patients diagnosed. Some additional diagnostic tools have been developed recently, such as assessing intestinal transglutaminase 2 deposits, flow cytometry technique, microRNA detection, or proteomic analysis, and they seem to be useful in the identification of complex cases. Further cooperative studies are highly desirable to improve the knowledge of these 2 still-obscure variants of CeD.
Subject(s)
Celiac Disease , Diet, Gluten-Free , Duodenum , HLA-DQ Antigens , Celiac Disease/diagnosis , Celiac Disease/immunology , Celiac Disease/blood , Humans , HLA-DQ Antigens/genetics , HLA-DQ Antigens/blood , HLA-DQ Antigens/immunology , Duodenum/pathology , Duodenum/immunology , Phenotype , Transglutaminases/immunology , Intestinal Mucosa/pathology , Intestinal Mucosa/immunology , Protein Glutamine gamma Glutamyltransferase 2 , Biopsy , GTP-Binding Proteins/immunology , Biomarkers/blood , Autoantibodies/blood , Serologic Tests , Predictive Value of TestsABSTRACT
Toxoplasma gondii Korean isolate (KI-1) tachyzoites were inoculated intraduodenally to BALB/c mice using a silicon tube, and the course of infection and immune responses of mice were studied. Whereas control mice, that were infected intraperitoneally, died within day 7 post-infection (PI), the intraduodenally infected mice survived until day 9 PI (infection with 1x10(5) tachyzoites) or day 11 PI (with 1x10(6) tachyzoites). Based on histopathologic (Giemsa stain) and PCR (B1 gene) studies, it was suggested that tachyzoites, after entering the small intestine, invaded into endothelial cells, divided there, and propagated to other organs. PCR appeared to be more sensitive than histopathology to detect infected organs and tissues. The organisms spread over multiple organs by day 6 PI. However, proliferative responses of splenocytes and mesenteric lymph node (MLN) cells in response to con A or Toxoplasma lysate antigen decreased significantly, suggesting immunosuppression. Splenic CD4+ and CD8+ T-lymphocytes showed decreases in number until day 9 PI, whereas IFN-gamma and IL-10 decreased slightly at day 6 PI and returned to normal levels by day 9 PI. No TNF-alpha was detected throughout the experimental period. The results showed that intraduodenal infection with KI-1 tachyzoites was successful but did not elicit significant mucosal immunity in mice and allowed dissemination of T. gondii organisms to systemic organs. The immunosuppression of mice included reduced lymphoproliferative responses to splenocytes and MLN cells to mitogen and low production of cytokines, such as IFN-gamma, TNF-alpha, and IL-10, in response to T. gondii infection.
Subject(s)
Animals , Mice , Cell Proliferation , Cytokines/metabolism , Disease Models, Animal , Duodenum/immunology , Endothelial Cells/parasitology , Histocytochemistry , Immune Tolerance , Lymph Nodes/immunology , Mice, Inbred BALB C , Polymerase Chain Reaction , Rodent Diseases/immunology , T-Lymphocyte Subsets/immunology , Toxoplasma/immunology , Toxoplasmosis, Animal/immunologyABSTRACT
INTRODUCTION: Visceral leishmaniasis (VL) is a neglected tropical disease with a complex immune response in different organs. This pattern of organ-specific immune response has never been evaluated in the gastrointestinal tract. The aim of this study was to determine the in situ immune response in duodenal biopsies on patients with VL. METHODS: A case-control study was conducted on 13 patients with VL in comparison with nine controls. The immune response was evaluated using immunohistochemistry, for CD4, CD8, CD68, IL-4, IFN-γ, TNF-α and IL-10. Histological findings from the villi, crypts and inflammatory process were analyzed. RESULTS: All the cases of VL presented Leishmania antigens. No antigen was detected in the control group. The villus size was greater in the VL patients (p < 0.05). CD68 (macrophages) and CD4 levels were higher in the VL patients (p < 0.05). No differences in the expression of CD8, TNF-α, IL-10 or IL-4 were demonstrated. The number of cells expressing IFN-γ was lower in the VL patients (p < 0.05). CONCLUSIONS: Low levels of cytokines were found in the gastrointestinal tract of patients with VL. This pattern was not found in other organs affected by the disease. Immunotolerance of this tissue against Leishmania could explain these findings, as occurs with intestinal bacteria.
INTRODUÇÃO: Leishmaniose visceral (LV) é uma doença tropical negligenciada com uma resposta imune complexa em diferentes órgãos. Este padrão de resposta imune órgão-específica nunca foi avaliada no trato gastrointestinal. O objetivo deste estudo foi determinar a resposta imune in situ em biópsias duodenais de pacientes com LV. MÉTODOS: Um estudo de caso controle com 13 pacientes com LV foi comparado com 9 controles. A resposta imune foi avaliada por imunohistoquímica para CD4, CD8, CD68, IL-4, IFN-γ, TNF-α e IL-10. Achados histológicos nos vilos, criptas e processo inflamatório foram analisados. RESULTADOS: Todos os casos de LV apresentaram antígenos de Leishmania. Nenhum antígeno foi encontrado no grupo controle. O tamanho do vilo foi maior em pacientes com LV (p < 0,05). CD68 (macrófagos) e CD4 estavam aumentados em pacientes com LV (p < 0,05). Nenhuma diferença foi demonstrada na expressão de CD8, TNF-α, IL-10 e IL-4. O número de células expressando IFN-γ foi mais baixo que no grupo controle (p < 0,05). CONCLUSÕES: Baixos níveis de citocinas foram encontrados no trato gastrointestinal de pacientes com LV. Este padrão não foi encontrado em outros órgãos acometidos pela doença. Uma imunotolerância do tecido contra Leishmania poderia explicar estes achados, como ocorre com as bactérias entéricas.
Subject(s)
Child , Child, Preschool , Humans , Infant , Cytokines/analysis , Duodenum/immunology , Intestinal Mucosa/immunology , Leishmaniasis, Visceral/immunology , Macrophages/immunology , T-Lymphocytes/immunology , Case-Control Studies , Cytokines/immunology , Duodenum/parasitology , Immunohistochemistry , Intestinal Mucosa/parasitology , Leishmaniasis, Visceral/pathologyABSTRACT
The objective of the present study was to evaluate the duodenal mucosa of HIV-infected patients during antiretroviral therapy. This was an observational study conducted on HIV-positive patients and a control group. Group 1 comprised 22 HIV-negative individuals while 38 HIV-positive individuals were classified according to the CDC 1993 classification into group 2 (A1 or A2) or group 3 (B2, A3, B3, C2, C3). All subjects were submitted to upper gastrointestinal endoscopy with duodenal biopsies. Qualitative, semi-quantitative and quantitative histological analyses were performed. Results were considered significant when P < 0.05. A higher prevalence of inflammatory infiltrate and eosinophilia was observed in the HIV group, together with a reduction in mucosal CD4+ lymphocyte (L) counts [median (lower-upper quartiles), 12.82 (8.30-20.33), 6.36 (1.75-11.66) and 1.75 (0.87-3.14) in groups 1, 2 and 3, respectively] which was not correlated with disease stage. The extent of CD4+L count reduction was similar in blood and duodenal mucosa. Normal CD8+L and CD45RO+L counts, and normal numbers of macrophages and antigen-presenting cells were also found in the HIV patients. The cytokine pattern did not differ among groups. Tissue HIV, assessed by p24 antigen, correlated with a higher CD45RO+L count (77.0 (61-79.8) and 43.6 (31.7-62.8) in p24+ and p24-, respectively, P = 0.003), and IL-4 positivity (100 and 48.2 percent in p24+ and p24-, respectively, P = 0.005). The duodenal mucosa of HIV+ patients showed a relatively preserved histological architecture. This finding may be characteristic of a population without opportunistic infections and treated with potent antiretroviral therapy, with a better preservation of the immune status.
Subject(s)
Humans , Male , Female , Antiretroviral Therapy, Highly Active , Anti-HIV Agents/therapeutic use , Duodenum/immunology , HIV Infections/drug therapy , Intestinal Mucosa/immunology , Reverse Transcriptase Inhibitors/therapeutic use , Case-Control Studies , /immunology , Duodenoscopy , Duodenum/pathology , HIV Infections/immunology , HIV Infections/pathology , Intestinal Mucosa/pathology , Viral LoadABSTRACT
Background: The prevalence of celiac disease (CD) is unknown in Chile. We have recently noted a rise in the number of cases diagnosed among adults. Aim: To describe the clinical characteristics of a group of adult celiac patients. Patients and methods: Clinical data of patients older than 15 years with positive antitransglutaminase or antiendomysial autoantibodies and a duodenal biopsy characteristic of CD were retrospectively reviewed. Age at diagnosis, symptoms and signs and laboratory, endoscopic and histological findings, were analyzed. Results: Thirty seven patients (28 women), were studied. Median age at diagnosis was 41 years (range 15-69). Main symptoms and signs were diarrhea (78%), weight loss (38%) and abdominal pain (38%). Anemia was found in 49%, elevation of ESR in 57%, elevation of alkaline phosphatases in 54%, elevation of aspartate aminotransferase in 38% and a rise in alanine aminotransferase in 27%. Antiendomysial antibodies were positive in 17/22 (77%) and antitransglutaminase in 19/22 (86%) patients. Endoscopic findings were suggestive of CD in 47% of cases and duodenal biopsy showed intestinal villi atrophy in 34 (92%) patients. The three patients with normal histology had positive serology and a good response to gluten free diet. Conclusions: CD should be considered in the differential diagnosis of patients with unespecific digestive symptons, even when they present late in adult life. Serologic markers are a good diagnostic tool. A normal duodenal pathology does not exclude the diagnosis, if other diagnostic features are present.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Celiac Disease/pathology , Duodenum/pathology , Biomarkers/blood , Biopsy , Celiac Disease/blood , Celiac Disease/immunology , Diagnosis, Differential , Duodenum/immunology , Fluorescent Antibody Technique, Indirect , Immunoglobulin A/blood , Immunoglobulin G/blood , Retrospective Studies , Transglutaminases/blood , Transglutaminases/immunologySubject(s)
Humans , Duodenum/immunology , Duodenum/microbiology , Gastrins/metabolism , Helicobacter Infections/physiopathology , Helicobacter pylori/pathogenicity , Hydrochloric Acid , Gastric Mucosa/immunology , Gastric Mucosa/microbiology , Duodenal Ulcer/physiopathology , Duodenal Ulcer/microbiologyABSTRACT
1. Forty-five outbred Wistar rats were randomly assigned to three experimental groups: GI, 10 non-diabetic control rats; GII, 10 alloxan-diabetic control rats; GIII, 25 alloxan-diabetic rats which received pancreaticoduodenal transplantation (PDT) from normal Wistar donor rats and were immunosuppressed with cyclosporin A (Cy-A), 10 mg kg body weight-1 day-1, administered intraperitoneally for 30 days. 2. In parallel, 15 alloxan-diabetic inbred Wistar rats received isogeneic PDT from normal Wistar donor rats. 3. Cy-A prevented graft rejection in the 15 surviving animals in group III. These observations were confirmed by clinical and biochemical parameters (body weight, urine output, water and food intake, blood and urinary glucose and plasma insulin) and by histology and immunohistochemistry of the pancreas. 4. However, Cy-A was associated with 60% of the infectious complications in transplanted rats leading to 40% mortality. Pulmonary infections were the main cause of death. There were no side effects of immunosuppression on the pancreas. Infections were not significant in inbred rats submitted to PDT