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1.
PLoS One ; 13(2): e0191360, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29415062

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 1/patologia , Heparitina Sulfato/metabolismo , Ilhotas Pancreáticas/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/metabolismo , Progressão da Doença , Feminino , Humanos , Lactente , Ilhotas Pancreáticas/citologia , Masculino , Sensibilidade e Especificidade , Adulto Jovem
2.
BMJ Open ; 3(9): e003411, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24065696

RESUMO

OBJECTIVE: To determine the potential of opportunistic glycated haemoglobin (HbA1c) testing of pathology samples to detect previously unknown diabetes. DESIGN: Pathology samples from participants collected for other reasons and suitable for HbA1c testing were utilised for opportunistic diabetes screening. HbA1c was measured with a Biorad Variant II turbo analyser and HbA1c levels of ≥6.5% (48 mmol/mol) were considered diagnostic for diabetes. Confirmation of previously unknown diabetes status was obtained by a review of hospital medical records and phone calls to general practitioners. SETTING: Hospital pathology laboratory receiving samples from hospital-based and community-based (CB) settings. PARTICIPANTS: Participants were identified based on the blood sample collection location in the CB, emergency department (ED) and inpatient (IP) groups. Exclusions pretesting were made based on the electronic patient history of: age <18 years, previous diabetes diagnosis, query for diabetes status in the past 12 months, evidence of pregnancy and sample collected postsurgery or transfusion. Only one sample per individual participant was tested. RESULTS: Of the 22 396 blood samples collected, 4505 (1142 CB, 1113 ED, 2250 IP) were tested of which 327 (7.3%) had HbA1c levels ≥6.5% (48 mmol/mol). Of these 120 (2.7%) were determined to have previously unknown diabetes (11 (1%) CB, 21 (1.9%) ED, 88 (3.9%) IP). The prevalence of previously unknown diabetes was substantially higher (5.4%) in hospital-based (ED and IP) participants aged over 54 years. CONCLUSIONS: Opportunistic testing of referred pathology samples can be an effective method of screening for diabetes, especially in hospital-based and older persons.

3.
Transplantation ; 79(12): 1674-82, 2005 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-15973168

RESUMO

BACKGROUND: Identification of the antigens that stimulate transplant rejection can help develop graft-specific antirejection strategies. The xenoantigens recognized during rejection of porcine cellular xenografts have not been clearly defined, but it has been assumed that major histocompatibility complex (MHC) xenoantigens are involved. METHODS: The role of porcine endogenous retrovirus (PERV) as a source of xenoantigens was examined. The authors used morphometry to compare the kinetics of swine leukocyte antigen (SLA) pig thyroid xenograft rejection in control mice and mice immunized with PERV PK15 cells (porcine kidney epithelial cells), PERV SLA pig peripheral blood lymphocytes (PBL), PERV virions purified from PK15 cells, and PERV or PERV A pseudotypes produced from infected human 293 cells. The tempo of rejection for cellular xenografts of PERV A pseudotype-producing human 293 cells, uninfected human 293 cells, and PK15 cells in PERV-preimmunized and control mice was also compared. RESULTS: Mice immunized with PK15 cells rejected pig thyroid xenografts significantly faster at day 5 than control mice and mice immunized with pig PBL. This correlated with the amount of PERV RNA and virions produced, but not with the amount of SLA class I MHC expressed by PK15 cells. Immunization of mice with PERV virions purified from porcine PK15 cells and with PERV virions or PERV A pseudotypes produced by human 293 cells also induced accelerated xenograft rejection by 5 days. Accelerated rejection induced by virus pretreatment was CD4 T-cell dependent and restricted to PERV-expressing cellular xenografts of porcine or nonporcine origin. CONCLUSIONS: PERV acts as a significant source of xenoantigens that target porcine cellular xenografts for rejection.


Assuntos
Antígenos Heterófilos/imunologia , Antígenos Virais/imunologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/isolamento & purificação , Rejeição de Enxerto/virologia , Glândula Tireoide/transplante , Transplante Heterólogo/patologia , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Rejeição de Enxerto/patologia , Humanos , Complexo Principal de Histocompatibilidade , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos SCID , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Porco Miniatura , Vírion/genética , Vírion/isolamento & purificação
4.
Xenotransplantation ; 9(3): 169-82, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11983015

RESUMO

The rejection of pig proislet xenografts in mice is a CD4 T cell-dependent process in which macrophages play an important role. To assess the potential for activated macrophages to act as effector cells in xenograft destruction, we have examined the relationship between proislet xenograft rejection, two principal markers of macrophage activation, transcription of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO), and their temporal relationship to intragraft cytokine gene expression. Xenograft rejection in CBA/H mice correlated with early induction of intragraft host iNOS mRNA and marked intragraft production of NO (reactive nitrogen intermediates, RNI). Intragraft mRNA expression for IFN-gamma, IL-1beta and TNF, cytokines associated with macrophage activation, was also found. These findings suggested that activated macrophages could be contributing to xenograft destruction via local NO-mediated toxicity at the graft site. To test the role of NO in this model: (1) Q-fever antigen (QFA) was administered to recipient mice in order to induce high systemic RNI levels and (2) in another experiment, pig proislets were transplanted into iNOS-/- mice. Treatment with QFA correlated with prolonged xenograft survival at 7 days post-transplant. Splenocytes from QFA-treated, but not control mice at 7 and 22 days post-transplant, exhibited inhibition of secondary xenogeneic mouse antiporcine mixed lymphocyte reaction (MLR) that was reversed by culture with the NOS inhibitor N-methylarginine (NMA). Despite continued elevated NO production, xenograft protection was temporary with complete rejection by day 22. Evidence that locally produced NO was not contributing to rejection was seen when pig proislets transplanted into iNOS-/- mice were rejected with normal kinetics; in these animals intragraft NO production was not detected (despite porcine iNOS gene expression). Failure of activated macrophages to achieve indefinite xenograft survival suggests that other factors are also required. Macrophage potential to effect either destructive or protective roles after pig proislet xenotransplantation suggests that such functions may depend on the site and magnitude of macrophage activation. Together these findings clearly demonstrate that high NO levels in the periphery are not damaging to xenogeneic islet tissue, neither host nor donor NO production is essential for islet xenograft rejection and consequently elevated plasma RNI levels do not represent a direct marker for rejection.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Transplante das Ilhotas Pancreáticas/efeitos adversos , Óxido Nítrico/metabolismo , Animais , Citocinas/genética , Transplante de Tecido Fetal/efeitos adversos , Transplante de Tecido Fetal/imunologia , Transplante de Tecido Fetal/fisiologia , Rejeição de Enxerto/patologia , Transplante das Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/fisiologia , Ativação Linfocitária , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/genética , Espécies Reativas de Nitrogênio/metabolismo , Suínos , Linfócitos T/imunologia , Transplante Heterólogo
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