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Faresjö, Maria
Alternative names
Publications (10 of 34) Show all publications
Rydén, A. & Faresjö, M. (2013). Altered immune profile from pre-diabetes to manifestation of type 1 diabetes. Diabetes Research and Clinical Practice, 100(1), 74-84
Open this publication in new window or tab >>Altered immune profile from pre-diabetes to manifestation of type 1 diabetes
2013 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 1, p. 74-84Article in journal (Refereed) Published
Abstract [en]

Background: While the mechanisms leading to beta-cell destruction and clinical onset of T1D are still unclear, the composition of the immune profile is probably important for the outcome of immune activity. The aim of this study was to investigate the composition and possible changes of the immunological profile, spontaneously and following stimulation with the autoantigens GAD(65), and HSP60, at high-risk and T1D onset and further to 8 months post diagnosis. Methods: Fifteen first-degree relatives of T1D patients with a high risk of developing the disease within five years, 25 children approximately four days and 8 months after diagnosis of T1D and 16 healthy children were included in the study. Cytokines (IL-1 beta, -6, -7, -10, -13, -17, IFN-gamma and TNF-alpha) and chemokines (CCL2, -3, -4, -5 and CXCL10) associated with Th1, Th2, Tr1 and inflammatory cells were detected in cell culture supernatants by Luminex-technique, and markers associated with regulatory T-cells (FOXP3, CTLA-4 and TGF-beta) by real-time RT-PCR. Results: High-risk individuals differed in immunity from that seen in healthy and T1D children. High-risk individuals had a low TNF-alpha response and fewer responders from mitogen exposure as well as low spontaneous secretions of IL-13 compared to healthy children. High-risk individuals that later developed T1D, had a lower FOXP3 and CTLA-4 mRNA expression, following stimulation with GAD(65), in combination with higher secretion of the pro-inflammatory chemokine CCL4. Conclusion: Changes in immunity seen in individuals with high risk of developing T1D points to alterations/actions in the immune system already early in the pre-diabetic phase.

Keywords
Type 1 diabetes, pre-diabetes, Th1, Th2, cytokines, chemokines
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71941 (URN)10.1016/j.diabres.2013.01.014 (DOI)000317744300019 ()
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
Stechova, K., Halbhuber, Z., Hubackova, M., Kayserova, J., Petruzelkova, L., Vcelakova, J., . . . Sumnik, Z. (2012). Case report: type 1 diabetes in monozygotic quadruplets. European Journal of Human Genetics, 20(4), 457-462
Open this publication in new window or tab >>Case report: type 1 diabetes in monozygotic quadruplets
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2012 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 4, p. 457-462Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-alpha further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called fertile-field hypothesis proposing that genetic predisposition to anti-islet autoimmunity is fertilized and precipitated by a viral infection leading to a fully blown T1D.

Place, publisher, year, edition, pages
Nature Publishing Group, 2012
Keywords
type 1 diabetes, monozygotic quadruplets, enteroviral infection, gene expression array, cytokine array, genetic predisposition to diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76613 (URN)10.1038/ejhg.2011.212 (DOI)000301736600015 ()
Note
Funding Agencies|Czech Ministry of Education|NPVII 2B06019|Ministry of Education, Youth and Sports of the Czech Republic|VZ MSM 0021620812|Ministry of Health|MZOFNM2005|project GACR|P302/10/1679|Czech Ministry of Education, Youth and Sports|NPVII 2B08066|Academy of Sciences of the Czech Republic|AVOZ50520514|Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07
Rydén, A., Bolmeson, C., Jonson, C.-O., Cilio, C. M. & Faresjö, M. (2012). Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children. Diabetes/Metabolism Research Reviews, 28(1), 84-96
Open this publication in new window or tab >>Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children
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2012 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 28, no 1, p. 84-96Article in journal (Refereed) Published
Abstract [en]

High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full length CTLA-4 and other Treg associated markers in T1D children and in individuals with high or low risk of developing the disease.

T1D children were studied at four days, one and two years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells (PBMC) were stimulated with the T1D-associated glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA). Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.

Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel to a negative relation in healthy subjects. Further, low mitogen-induced soluble CTLA-4 was accompanied by low C-peptide, together indicating an inverse relation of soluble CTLA-4 between health and disease. Moreover, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high-risk individuals, indicating an alteration in activation and downregulating immune mechanisms already during the pre-diabetic phase.

Place, publisher, year, edition, pages
Wiley, 2012
Keywords
soluble CTLA-4; PBMC; Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71942 (URN)10.1002/dmrr.1286 (DOI)000298736800008 ()
Note
funding agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Schelin Foundation||Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
Rydén, A. & Faresjö, M. (2011). Efficient expansion of cryopreserved CD4+CD25+CD127lo/- cells in Type 1 diabetes. Results in Immunology, 1(1), 36-44
Open this publication in new window or tab >>Efficient expansion of cryopreserved CD4+CD25+CD127lo/- cells in Type 1 diabetes
2011 (English)In: Results in Immunology, ISSN 2211-2839, Vol. 1, no 1, p. 36-44Article in journal (Refereed) Published
Abstract [en]

Increased attention has been drawn to the important role played by regulatory T-cells (Treg) in immune homoeostasis. However, the small numbers of Tregs make them elusive to study. We investigated the cryostability of Tregs and whether they can be expanded from cryopreserved peripheral blood mononuclear cells (PBMCs). Further, to elucidate if there is a difference in ex-vivo frequency or in vitro expansion of Tregs among T1D children (n=9), high-risk (n=7) and healthy (n=10) individuals, Tregs defined as CD4+CD25+CD127lo/− were isolated from cryopreserved PBMCs.

Cryopreserved PBMCs maintained a stable expression of Treg-markers. Tregs were efficiently expanded in vitro from all donors and Tregs from T1D children acquired higher FOXP3 expression compared to healthy subjects. T1D children had a significantly lower percentage of Tregs among CD4+ T-cells and also lower Treg to CD4+CD25 cell ratios compared to healthy individuals.

Place, publisher, year, edition, pages
Elsevier, 2011
Keywords
Cryopreservation; Regulatory T-cells; Expansion; Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71943 (URN)10.1016/j.rinim.2011.08.001 (DOI)
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2014-09-23Bibliographically approved
Hjorth, M., Axelsson, S., Ryden, A., Faresjo, M., Ludvigsson, J. & Casas, R. (2011). GAD-alum treatment induces GAD(65)-specific CD4(+)CD25(high)FOXP3(+) cells in type 1 diabetic patients. CLINICAL IMMUNOLOGY, 138(1), 117-126
Open this publication in new window or tab >>GAD-alum treatment induces GAD(65)-specific CD4(+)CD25(high)FOXP3(+) cells in type 1 diabetic patients
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2011 (English)In: CLINICAL IMMUNOLOGY, ISSN 1521-6616, Vol. 138, no 1, p. 117-126Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes results from autoimmune destruction of insulin producing pancreatic beta-cells. We have shown that treatment with alum-formulated glutamic acid decarboxylase 65 (GAD-alum) preserved residual insulin secretion and induced antigen-specific responses in children with recent onset type 1 diabetes. The aim of this study was to further investigate the immunomodulatory effect of GAD-alum, focusing on CD4(+)CD25(high) cells and their association to cytokine secretion. Samples obtained 21 and 30 months after the initial injection of GAD-alum or placebo were included in the present study. GAD(65)-stimulation enhanced the percentage of CD4(+)CD25(high)FOXP3(+) cells, but reduced the percentage of CD4(+)CD25(+) cells, in samples from the GAD-alum treated group. Further, the GAD(65)-induced secretion of IL-5, -10, and -13 correlated with the expression of CD4(+)CD25(high)FOXP3(+) cells, but inversely with CD4(+)CD25(+) cells. These new data suggest that GAD-alum treatment induced GAD(65)-specific T cells with regulatory features.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keywords
Type 1 diabetes, Immunotherapy, GAD(65), Antigen-specific cell, FOXP3, Cytokine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65953 (URN)10.1016/j.clim.2010.10.004 (DOI)000286714000015 ()
Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2011-02-28
Kivling, A., Nilsson, L. & Faresjö, M. (2009). How and when to pick up the best signals from markers associated with T-regulatory cells?. JIM - Journal of Immunological Methods, 345(1-2), 29-39
Open this publication in new window or tab >>How and when to pick up the best signals from markers associated with T-regulatory cells?
2009 (English)In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 345, no 1-2, p. 29-39Article in journal (Refereed) Published
Abstract [en]

Regulatory T (Treg) cells are important tools with the purpose to control and regulate the immune system. These cells use FOXP3, TGF-beta, CTLA-4 and sCTLA-4 to regulate other T-cells. Since cryopreservation of peripheral blood mononuclear cells (PBMC) is a convenient way to handle samples, we investigated whether these cells will change their mRNA expression of Treg associated markers, as well as secretion of TGF-beta1, after cryopreservation. Additionally, we aimed to investigate the mRNA expression after two different time intervals of in vitro antigen stimulation. PBMC from healthy adults were stimulated either fresh (48/96 h) or after cryopreservation (48 h), with PHA, tetanus toxoid, beta-lactoglobulin, ovalbumin or in culture medium exclusively (spontaneous). The mRNA expression of FOXP3, TGF-beta, CTLA-4 and sCTLA-4 were studied with multiplex real-time RT-PCR and TGF-beta1 with ELISA. Cryopreserved PBMC were appropriate for detection of the Treg associated markers FOXP3, TGF-beta, CTLA-4 and sCTLA-4 expressed spontaneously. Also antigen-induced mRNA expression of CTLA-4, sCTLA-4 and TGF-beta and secreted TGF-beta1, with the exception of FOXP3, preserved a stable transcription activity after cryopreservation. Further, a stimulation period of 48 h in general revealed the highest mRNA expression of the markers studied. In conclusion, cryopreserved cells are in general suitable for studying Treg associated markers.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18986 (URN)10.1016/j.jim.2009.03.010 (DOI)19341742 (PubMedID)
Available from: 2009-06-07 Created: 2009-06-07 Last updated: 2017-12-13Bibliographically approved
Stechova, K., Spalova, I., Durilova, M., Bartaskova, D., Cerny, M., Cerna, M., . . . Faresjo, M. (2009). Influence of Maternal Hyperglycaemia on Cord Blood Mononuclear Cells in Response to Diabetes-associated Autoantigens. SCANDINAVIAN JOURNAL OF IMMUNOLOGY, 70(2), 149-158
Open this publication in new window or tab >>Influence of Maternal Hyperglycaemia on Cord Blood Mononuclear Cells in Response to Diabetes-associated Autoantigens
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2009 (English)In: SCANDINAVIAN JOURNAL OF IMMUNOLOGY, ISSN 0300-9475, Vol. 70, no 2, p. 149-158Article in journal (Refereed) Published
Abstract [en]

Perfect maternal diabetes compensation is crucial for the outcome of the baby. However, little is known how hyperglycaemia influences the specific immune response. Furthermore, babies of type 1 diabetes (T1D) mothers have less risk of development T1D than babies with a T1D father. This study aimed to analyze the effect of maternal hyperglycaemia on newborns with focus on the response to diabetes-associated autoantigens. Populations: (1) Newborns of T1D mothers split into groups according to maternal diabetes compensation during the 3rd trimester: perfect (n = 15) or acceptable (n = 25) compensation. (2) newborns with T1D father (n = 12) (3) newborns with a mother treated for either gestational or type 2 diabetes (n = 10) (4) control newborns (n = 25). Spontaneous as well as diabetes-associated autoantigen-stimulated production of 23 cytokines and chemokines were tested using protein microarray. In addition, the influence of glucose on cytokine and chemokine responsiveness was analyzed in vitro. The study groups differed in their spontaneous as well as stimulated cytokine and chemokine spectra. A prominent Th1 response (high IFN-gamma) from autoantigen stimulation was observed especially in babies of T1D fathers (P = 0.001) and also in mothers with perfect diabetes compensation during the 3rd trimester (P = 0.016) in comparison with control newborns. By contrast, cord blood mononuclear cells cultivated in vitro in high glucose concentration decreased the diabetogenic stimulated Th1 cytokine response. Maternal sweet as well as autoimmune environment may both lead to lower occurrence of T1D within their offspring. Further studies will reveal the exact immunological mechanism of this observation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20131 (URN)10.1111/j.1365-3083.2009.02282.x (DOI)
Available from: 2009-08-31 Created: 2009-08-31 Last updated: 2009-08-31
Rydén, A., Stechova, K., Durilova, M. & Faresjö, M. (2009). Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes. Diabetes/Metabolism Research Reviews, 25(4), 335-343
Open this publication in new window or tab >>Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes
2009 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 335-343Article in journal (Refereed) Published
Abstract [en]

Background: Type 1 diabetes (T1D) is all autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This Study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the Study focused on spontaneous as well as autoantigen-induced immune profile.

Methods: Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA andgt;= 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, turnout necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).

Results: High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.

Conclusion: A dominant Thl-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.

Keywords
Type 1 diabetes, high-risk children, T-helper cells, T-regulatory cells, cytokines, chemokines
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19142 (URN)10.1002/dmrr.958 (DOI)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
Axelsson, S., Faresjö, M., Hedman, M., Ludvigsson, J. & Casas, R. (2008). Cryopreserved peripheral blood mononuclear cells are suitable for the assessment of immunological markers in type 1 diabetic children. Cryobiology, 57(3), 201-208
Open this publication in new window or tab >>Cryopreserved peripheral blood mononuclear cells are suitable for the assessment of immunological markers in type 1 diabetic children
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2008 (English)In: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 57, no 3, p. 201-208Article in journal (Refereed) Published
Abstract [en]

Cryopreserved peripheral blood mononuclear cells (PBMC) are commonly used when assessing immune responses in clinical trials, both for practical reasons and to minimize interassay variation, as samples are often collected and studied over time. This study investigated the effect of cryopreservation on cytokine and chemokine secretion, and on expression of regulatory T-cell associated markers, in samples from children with type 1 diabetes. PBMC were cultured before and after cryopreservation either with GAD(65) or PHA. Secretion of cytokines (IL-5, -6, -10, -12, -13 -17, IFN-gamma and TNF-alpha) and chemokines (IP-10, MCP-1, MIP-1 alpha, MIP-1 beta and RANTES) was analysed in cell supernatants using multiplex fluorochrome technique (Luminex). Expression of FOXP3 and TGF-beta mRNA was detected by multiplex real-time RT-PCR. Increased spontaneous secretion of IL-6, -10, -12, -13, IFN-gamma and MCP-1, and mRNA expression of FOXP3 and TGF-beta, was detected after cryopreservation. Stimulation with GAD65 induced higher levels of IL-6, IFN-gamma, TNF-alpha and MIP-1 alpha, whereas lower secretion was found for IL-10 and IL-13 in cryopreserved PBMC. Stimulation with PHA induced lower secretion of IP-10, MCPA and RANTES and FOXP3 mRNA expression after cryopreservation. Thus, cryopreserved PBMC were suitable to assess the immunological markers included in this study, even though their expression could differ from freshly handled cells.

Keywords
Cryopreservation, BMC, Cytokine, Chemokine, Multiplex fluorochrome technique, Real-time RT-PCR, Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16224 (URN)10.1016/j.cryobiol.2008.08.001 (DOI)
Available from: 2009-01-12 Created: 2009-01-09 Last updated: 2017-12-14
Kivling, A., Nilsson, L., Fälth-Magnusson, K., Sollvander, S., Johanson, C. & Faresjö, M. (2008). Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease. Annals of the New York Academy of Sciences, 1150, 273-277
Open this publication in new window or tab >>Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease
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2008 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, p. 273-277Article in journal (Refereed) Published
Abstract [en]

Imbalance between different types of T lymphocytes, such as T helper (Th) and regulatory T cells (Tregs), has been reported to play a part in the pathogenesis behind such autoimmune diseases as type 1 diabetes (T1D) and celiac disease (CD). Defects in Tregs are proposed to at least partly explain the imbalance of Th cells found in children with immunologic diseases. Peripheral blood mononuclear cells from 24 children with T1D and/or CD, and reference children (that is, those without any of these diseases) were stimulated with disease-associated antigens (insulin, gluten, transglutaminase [tTG]), and phytohemagglutinin (PHA). The mRNA expression of the Treg-associated marker FOXP3 was analyzed with multiplex real-time RT-PCR. Children with T1D showed both a low spontaneous (P < 0.05) and PHA-induced (P < 0.01) expression of FOXP3 mRNA compared to children with CD. Children with T1D also had a low PHA-induced FOXP3 mRNA expression compared to the group of children diagnosed with both T1D and CD (P < 0.05). Spontaneous (P < 0.05) and PHA-induced (P < 0.05) FOXP3 mRNA expression was high in children with CD compared to reference children. In contrast, stimulation with insulin tended to induce high FOXP3 mRNA expression in T1D children compared to reference children (P = 0.057). In conclusion, children with only T1D generally showed a lower FOXP3 mRNA expression than did children with CD, or with T1D in combination with CD, which suggests impaired regulation of the immune system in children with T1D.

Keywords
type 1 diabetes, celiac disease, immune regulation, FOXP3
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16622 (URN)10.1196/annals.1447.018 (DOI)
Note
Volume 1150 Issue: Immunology of Diabetes V From Bench to Bedside.Available from: 2009-02-08 Created: 2009-02-06 Last updated: 2017-12-14
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