| 1. |
- Nowak, C., et al.
(författare)
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Intralymphatic GAD-Alum (Diamyd (R)) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2
- 2022
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:9, s. 2644-2651
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Tidskriftsartikel (refereegranskat)abstract
- Aims Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). Methods DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 mu g GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. Results We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. Conclusions Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.
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| 2. |
- Barcenilla, Hugo, et al.
(författare)
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Regulatory T-Cell Phenotyping Using CyTOF
- 2023. - 1
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Ingår i: Regulatory T-Cells. - New York : Humana Press. - 9781071626498 - 9781071626474 - 9781071626467 ; , s. 231-242
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Bokkapitel (refereegranskat)abstract
- Regulatory T cells are an important component of the immune system that plays a key role in maintaining homeostasis. Identification of distinct regulatory T cell subsets is essential to understand their function. Mass cytometry or CyTOF is a technology that enables the simultaneous measurement of up to 50 markers in single cells by using antibodies tagged with heavy metals, which are then detected with time-of-flight mass spectrometry. This chapter describes a mass cytometry approach for phenotypic characterization of regulatory T cells and determination of their master transcription factor Foxp3.
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| 3. |
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| 4. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Cat allergen-induced cytokine secretion and Fel d 1–immunoglobulin G immune complexes in cord blood
- 2004
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 34:4, s. 591-596
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Tidskriftsartikel (refereegranskat)abstract
- Background We have recently obtained evidence for the presence of immune complexes (IC) in cord blood from allergic and non-allergic mothers. Such complexes could conceivably provide the fetus with the initial trigger for the priming of the T cell system already in utero.Objective To relate the presence of Fel d 1–IgG IC to T cell cytokine production in cord blood mononuclear cells (CBMCs) after stimulation with cat allergen.Methods CBMC obtained from babies of 15 allergic and 22 non-allergic mothers were cultured in the presence of cat allergen. The production of IFN-γ, IL-5, IL-10 and IL-13 was determined by ELISA. Furthermore, IgG1 and IgG4 antibodies to cat allergen in cord blood samples were measured by ELISA. A more sensitive ELISA was used to measure Fel d 1–IgG IC.Results The prevalence and levels of IC were similar in cord blood from children of allergic and non-allergic mothers. The production of IL-5, IL-10. IL-13 and IFN-γ by CBMC was not influenced by maternal atopy, but IFN-γ was less commonly detected in samples with IC. There was no association between the presence of IC and any other cytokines. The levels of IgG1 and IgG4 antibodies were similar in both groups, and tended to be associated with the presence of IC.Conclusion Immune complexes in cord blood may represent a normal mechanism for inducing primary immune responses, as the responses in babies from allergic and non-allergic mothers were largely similar. Low levels of IFN-γ seems to be related with the presence of IC in cord blood.
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| 5. |
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| 6. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers
- 2001
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 12:2, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- It is an established fact that T-cell responses of fetal origin to inhalant allergens are present in most cord blood samples. These immune responses could be explained by trans-placental passage of peptides, either as free antigens or in complexes with immunoglobulin G (IgG), providing the fetus with a trigger for priming the T-cell system already present in utero. The aim of this study was to investigate the presence of the major cat allergen, Fel d 1, in complexes with IgG in cord blood and maternal sera. Serum samples from 75 mothers (38 allergic, 37 non-allergic), and cord blood from their infants, were investigated for the presence of Fel d 1–IgG immune complexes (ICs) by using an amplified enzyme-linked immunosorbent assay (ELISA). Three monoclonal antibodies to Fel d 1 were used for coating. The specificity of the method was confirmed by inhibition experiments. ICs of Fel d 1–IgG were detected in the sera of 45% allergic and 49% non-allergic mothers, and in, respectively, 34% and 41% of their infants. Therefore, neither the prevalence nor the level of ICs were affected by maternal allergy. Low levels of trans-placentally transferred ICs can provide the fetus with a signal for the priming of T-cell responses to inhalant allergens. However, this is not necessarily related to allergic disease.
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| 7. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Detection of IgA antibodies to cat, β-lactoglobulin, and ovalbumin allergens in human milk
- 2000
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 105:6 part 1, s. 1236-1240
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between the development of allergy during infancy and breast-feeding remains controversial. This controversy may be due to individual variations in the composition of human milk. Antibodies to food antigens to which the mother is commonly exposed are present in the milk, but their relationship to allergy is still unknown. IgA antibodies to inhalant allergens have not been previously detected.Objective: Our purpose was to analyze secretory IgA antibody levels to cat, β-lactoglobulin, and ovalbumin allergens in colostrum and mature milk in relation to maternal allergy.Methods: Colostrum and samples of mature milk were obtained after 1 and 3 months of lactation from 53 nursing mothers (17 allergic and 36 nonallergic mothers) and were analyzed for total secretory IgA levels by ELISA and secretory IgA antibodies to cat, β-lactoglobulin, and ovalbumin by an enzyme-amplified ELISA. The specificity of the assays was confirmed by inhibition experiments.Results: Secretory IgA to cat, β-lactoglobulin, and ovalbumin allergens were detected in colostrum as well as mature milk. The levels of secretory IgA to ovalbumin were lower in colostrum from allergic mothers with P = .016, whereas the levels to β-lactoglobulin and cat were similar in the 2 groups. IgA antibodies to ovalbumin were detected in 94% of the colostrum samples from allergic and in all samples from nonallergic mothers, in 82% and 96%, respectively at 1 month, and 53% and 65% at 3 months. Fewer samples had detectable secretory IgA antibodies to β-lactoglobulin than to ovalbumin and cat, and only 33% and 10% of the samples from the allergic and nonallergic mothers, respectively, remained positive at 3 months. All the allergic mothers had detectable IgA to cat in colostrum, whereas 83% and 73% of the samples were positive at 1 and 3 months. The corresponding numbers were 93%, 81%, and 81% in the nonallergic mothers (not significant).Conclusion: Even a low level of exposure of the mucosa (eg, by inhalant allergens) can induce antibody secretion into the milk, both in allergic and nonallergic mothers. (J Allergy Clin Immunol 2000;105:1236-40.)
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| 8. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Downregulation of CXCR6 and CXCR3 in lymphocytes from birch-allergic patients
- 2008
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 68:3, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Preferential expression of chemokine receptors on Th1 or Th2 T-helper cells has mostly been studied in cell lines generated in vitro or in animal models, however, results are less well characterized in humans. We determined T-cell responses through chemokine receptor expression on lymphocytes, and cytokine secretion in plasma from birch-allergic and healthy subjects. The expression of CCR2, CCR3, CCR4, CCR5, CCR7, CXCR3, CXCR4, CXCR6, IL-12 and IL-18R receptors was studied on CD4+ and CD8+ cells from birch-allergic (n = 14) and healthy (n = 14) subjects by flow cytometry. The concentration of IL-4, IL-5, IL-10, IL-12, IFN-γ and TNF-α cytokines was measured in plasma from the same individuals using a cytometric bead array human cytokines kit. The similar expression of CCR4 in T cells from atopic and healthy individuals argues against the use of the receptor as an in vivo marker of Th2 immune responses. Reduced percentages of CD4+ cells expressing IL-18R, CXCR6 and CXCR3 were found in the same group of samples. TNF-α, IFN-γ, IL-10, IL-5, IL-4 and IL-12 cytokines were elevated in samples from allergic individuals. Reduced expression of Th1-associated chemokine receptors together with higher levels of Th1, Th2 and anti-inflammatory cytokines in samples from allergic patients indicate that immune responses in peripheral blood in atopic diseases are complex and cannot be simplified to the Th1/Th2 paradigm. Not only the clinical picture of atopic diseases but also the clinical state at different time points of the disease might influence the results of studies including immunological markers associated with Th1- or Th2-type immune responses. © 2008 The Authors.
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| 9. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Impaired maturation of monocyte-derived dendritic cells from birch allergic individuals in association with birch-specific immune responses
- 2007
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 66:5, s. 591-598
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Tidskriftsartikel (refereegranskat)abstract
- Optimal activation of T lymphocytes requires a costimulatory signal provided by the interaction of molecules on the surface of T cells with their ligands expressed on dendritic cells (DC). We investigated whether DC differentiated from monocytes from healthy and birch allergic asthmatic individuals and further maturated by stimulation with cat and birch allergens and LPS differ in their phenotypic receptor expression. Similar expression of DC surface markers, including HLA-DR, CD80, CD86, CD83, CD1a and CD11c, was detected in monocyte-derived DC from allergic and healthy individuals. Cells from healthy donors stimulated either antigen showed a similar activation of the CD80 and double CD80/CD86 costimulatory molecules when compared with non-stimulated cells. In the case of cells from allergic individuals, birch allergen was unable to produce the same increased expression of CD80 alone or in combination with CD80/CD86, in comparison with cells stimulated with cat and LPS. Levels of IL-6, IL-8, IL-10, MCP-1/MCAF and MIP-1β were similar in the supernatant of non-stimulated DC from both groups of subjects. By contrast, the spontaneous secretion of IL-12p70 and TNF-α was higher in the supernatant of DC from healthy subjects when compared with that from allergic individuals. Stimulation with birch and LPS resulted in an increased secretion of IL-12p70 in samples from healthy when compared with that in allergic individuals. The results suggest an impaired specific maturation of DC from birch allergic individuals in association with birch-specific immune responses. Lower secretion of IL-12p70 from birch-stimulated DC from allergic individuals suggests that not only maturation, but also the specific Th1 function of these cells seems to be affected in those individuals.
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| 10. |
- Casas, Rosaura, 1954-, et al.
(författare)
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Intra-lymphatic administration of GAD-alum in type 1 diabetes : long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial)
- 2022
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Ingår i: Acta Diabetologica. - : Springer. - 0940-5429 .- 1432-5233. ; 59:5, s. 687-696
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To evaluate the long-term effect of intra-lymphatic administration of GAD-alum and a booster dose 2.5 years after the first intervention (DIAGNODE Extension study) in patients with recent-onset type 1 diabetes.Methods: DIAGNODE-1: Samples were collected from 12 patients after 30 months who had received 3 injections of 4 μg GAD-alum into a lymph node with one-month interval. DIAGNODE Extension study: First in human, a fourth booster dose of autoantigen (GAD-alum) was given to 3 patients at 31.5 months, who were followed for another 12 months. C-peptide was measured during mixed meal tolerance tests (MMTTs). GADA, IA-2A, GADA subclasses, GAD65-induced cytokines, PBMCs proliferation and T cells markers were analyzed.Results: After 30-month treatment, efficacy was still seen in 8/12 patients (good responders, GR). Partial remission (IDAA1c < 9) had decreased compared to 15 months, but did not differ from baseline, and HbA1c remained stable. GAD65-specific immune responses induced by the treatment started to wane after 30 months, and most changes observed at 15 months were undetectable. GADA subclasses IgG2, IgG3 and IgG4 were predominant in the GR along with IgG1. A fourth intra-lymphatic GAD-alum dose to three patients after 31.5 months gave no adverse events. In all three patients, C-peptide seemed to increase the first 6 months, and thereafter, C-peptide, HbA1c, insulin requirement and IDAA1c remained stable.Conclusion: The effect of intra-lymphatic injections of GAD-alum had decreased after 30 months. Good responders showed a specific immune response. Administration of a fourth booster dose after 31.5 months was safe, and there was no decline in C-peptide observed during the 12-month follow-up.
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