Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype
GAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compare...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1112570/full |
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| author | Sara Puente-Marin Fabrícia Dietrich Peter Achenbach Peter Achenbach Hugo Barcenilla Johnny Ludvigsson Johnny Ludvigsson Rosaura Casas |
| author_facet | Sara Puente-Marin Fabrícia Dietrich Peter Achenbach Peter Achenbach Hugo Barcenilla Johnny Ludvigsson Johnny Ludvigsson Rosaura Casas |
| author_sort | Sara Puente-Marin |
| collection | DOAJ |
| description | GAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype.MethodsGAD autoantibodies, GADA subclasses, GAD65-induced cytokine secretion (Luminex panel) and proliferation of peripheral mononuclear cells were analyzed in T1D patients (n=109) who received either three intra-lymphatic injections (one month apart) with 4 µg GAD-alum and oral vitamin D supplementation (2000 IE daily for 120 days), or placebo.ResultsHigher GADA, GADA subclasses, GAD65-induced proliferation and cytokine secretion was observed in actively treated patients after the second injection of GAD-alum compared to the placebo group. Following the second injection of GAD-alum, actively treated subjects with DR3DQ2 haplotype had higher GAD65-induced secretion of several cytokine (IL4, IL5, IL7, IL10, IL13, IFNγ, GM-CSF and MIP1β) and proliferation compared to treated individuals without DR3DQ2. Stratification of samples from GAD-alum treated patients according to C-peptide preservation at 15 months revealed that “good responder” individuals with better preservation of C-peptide secretion, independently of the HLA haplotype, had increased GAD65-induced proliferation and IL13 secretion at 3 months, and a 2,5-fold increase of IL5 and IL10 as compared to “poor responders”. The second dose of GAD-alum also induced a more pronounced cytokine secretion in “good responders” with DR3DQ2, compared to few “good responders” without DR3DQ2 haplotype.ConclusionPatients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD65-induced IL13 secretion and proliferation that seems to be associated with a better clinical outcome. If confirmed in the ongoing larger randomized double-blind placebo-controlled clinical trial (DIAGNODE-3), including only patients carrying DR3DQ2 haplotype, these results might be used as early surrogate markers for clinical efficacy. |
| first_indexed | 2024-04-10T18:02:05Z |
| format | Article |
| id | doaj.art-d963aa7ed1834bd6b443394cf237d62d |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T18:02:05Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-d963aa7ed1834bd6b443394cf237d62d2023-02-02T15:13:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.11125701112570Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotypeSara Puente-Marin0Fabrícia Dietrich1Peter Achenbach2Peter Achenbach3Hugo Barcenilla4Johnny Ludvigsson5Johnny Ludvigsson6Rosaura Casas7Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, SwedenDivision of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, SwedenInstitute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Munich, GermanyTechnical University Munich, School of Medicine, Forschergruppe Diabetes at Klinikum rechts der Isar, Munich, GermanyDivision of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, SwedenDivision of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, SwedenCrown Princess Victoria Children´s Hospital, Linköping University, Linköping, SwedenDivision of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, SwedenGAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype.MethodsGAD autoantibodies, GADA subclasses, GAD65-induced cytokine secretion (Luminex panel) and proliferation of peripheral mononuclear cells were analyzed in T1D patients (n=109) who received either three intra-lymphatic injections (one month apart) with 4 µg GAD-alum and oral vitamin D supplementation (2000 IE daily for 120 days), or placebo.ResultsHigher GADA, GADA subclasses, GAD65-induced proliferation and cytokine secretion was observed in actively treated patients after the second injection of GAD-alum compared to the placebo group. Following the second injection of GAD-alum, actively treated subjects with DR3DQ2 haplotype had higher GAD65-induced secretion of several cytokine (IL4, IL5, IL7, IL10, IL13, IFNγ, GM-CSF and MIP1β) and proliferation compared to treated individuals without DR3DQ2. Stratification of samples from GAD-alum treated patients according to C-peptide preservation at 15 months revealed that “good responder” individuals with better preservation of C-peptide secretion, independently of the HLA haplotype, had increased GAD65-induced proliferation and IL13 secretion at 3 months, and a 2,5-fold increase of IL5 and IL10 as compared to “poor responders”. The second dose of GAD-alum also induced a more pronounced cytokine secretion in “good responders” with DR3DQ2, compared to few “good responders” without DR3DQ2 haplotype.ConclusionPatients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD65-induced IL13 secretion and proliferation that seems to be associated with a better clinical outcome. If confirmed in the ongoing larger randomized double-blind placebo-controlled clinical trial (DIAGNODE-3), including only patients carrying DR3DQ2 haplotype, these results might be used as early surrogate markers for clinical efficacy.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1112570/fullimmunotherapyautoantigenGAD-alumtype 1 diabetesDR3DQ2 haplotypeintra-lymphatic treatment |
| spellingShingle | Sara Puente-Marin Fabrícia Dietrich Peter Achenbach Peter Achenbach Hugo Barcenilla Johnny Ludvigsson Johnny Ludvigsson Rosaura Casas Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype Frontiers in Immunology immunotherapy autoantigen GAD-alum type 1 diabetes DR3DQ2 haplotype intra-lymphatic treatment |
| title | Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype |
| title_full | Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype |
| title_fullStr | Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype |
| title_full_unstemmed | Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype |
| title_short | Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype |
| title_sort | intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with dr3dq2 haplotype |
| topic | immunotherapy autoantigen GAD-alum type 1 diabetes DR3DQ2 haplotype intra-lymphatic treatment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1112570/full |
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