Association of immune mediators at diagnosis of Type 1 diabetes with later clinical remission

Schloot, Nanette C.; Hanifi-Moghaddam, Pejman; Aabenhus-Andersen, N.; Alizadeh, Behrooz Z.; Saha, Marja‐Terttu; Knip, Mikael; Devendra, Devasenan; Wilkin, Terry; Bonifacio, Ezio; Roep, Bart O.; Kolb, Hubert; Mandrup-Poulsen, Thomas

doi:10.1111/j.1464-5491.2007.02096.x

Cited by 66 publications

(51 citation statements)

References 49 publications

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“…In contrast, CCL3 remained stable during follow up suggestive of differential regulation of CCR5 ligands early after diagnosis of type 1 diabetes without general up regulation of systemic immune mediators confirming a previous study [17]. Although these observations suggest a change of cytokines overtime, it is unclear whether this is of clinical or biological meaning.…”

Section: Discussionsupporting

confidence: 83%

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Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

Pfleger

Kaas

Hansen

et al. 2008

Clinical Immunology

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Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with β-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the β-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased β-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes.

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Section: Discussionsupporting

confidence: 83%

“…First, a more classical definition of partial remission was applied with HbA1c b 7.5% and daily insulin b0.4U/kg (remission 7.5) [17]. However, partial remission discriminated by HbA1c b 7.5% is not always indicative for a euglycemic status.…”

Section: Metabolic Parametersmentioning

confidence: 99%

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

Pfleger

Kaas

Hansen

et al. 2008

Clinical Immunology

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“…This could not be documented so far in patients with T1D (50). In an experimental approach, such as the one used in the IDDM rat in the present and in previous studies for mono-and combination therapies (25,36), pancreatic tissue could be directly accessed for b-cell analyses by biopsies.…”

Section: Cytokine Profile Changes As Biomarkers For Success Of Combinmentioning

confidence: 98%

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

et al. 2015

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Anti–tumor necrosis factor-α (TNF-α) therapy (5 mg/kg body weight), alone or combined with the T-cell–specific antibody anti–T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased β-cell proliferation and reduced apoptosis led to a restoration of β-cell mass along with an immune cell infiltration–free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti–T-cell therapy, and anti–TNF-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.

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“…The techniques for measuring immune mediators in the circulation have improved over the last decade, enabling more detailed and comprehensive investigations than in previous years. Recent studies performed in childhood or adolescent type 1 diabetes have found associations of certain cytokines such as IL-1 receptor antagonist (IL-1 ra), IL-6 and TNF alpha with the presence of type 1 diabetes [7,8] and IL-1 ra, IL-10 and IFN gamma with progression [9,10] of type 1 diabetes; however results are partly discordant. One reason for discrepancies may be unaccounted differences in insulin sensitivity.…”

Section: Introductionmentioning

confidence: 94%

Circulating immune mediators are closely linked in adult-onset type 1 diabetes as well as in non-diabetic subjects

et al. 2014

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Relationships between circulating immune mediators (cytokines, chemokines and growth factors) and a beta cell destructive autoimmune process in adult-onset type 1 diabetes are poorly elucidated. We measured serum levels of immune mediators in type 1 diabetic patients in the context of ongoing deterioration of endogenous insulin secretion. Levels of 27 immune mediators were measured in 34 GADA (glutamic acid decarboxylase antibodies) positive type 1 diabetic patients, aged 27.4 ± 1.2 years at a mean of 7 weeks after diagnosis (designated 0 month) and 6 months later. Endogenous insulin secretion was assessed by C-peptide glucagon stimulation tests during 12 months. Additional data (for baseline analysis) was obtained in 9 GADA positive type 1 diabetic subjects and in 43 non-diabetic age- and sex-matched subjects. In general, the levels of immune mediators displayed large inter- but small intra-individual differences with only minor changes observed between measurements at 0 month and at 6 months. Levels of the majority of immune mediators were strongly and positively correlated to each other not only in the diabetic, but also in the non-diabetic subjects. Body weight (BMI) was positively associated with levels of IL-1 ra, IL-2, IL-4, IL-6, IL-17, Basic FGF, GCSF, IFN gamma and MIP-1 alpha. Adjustment for BMI removed most associations to C-peptide. When adjusted for BMI, levels at 0 month for Basic FGF and MIP-1 alpha were inversely associated with the percentage decline in stimulated C-peptide from 0 to 12 months (nominally p < 0.05). We conclude that associations between different immune mediators are strikingly but not exclusively tied in autoimmune diabetes. BMI is a major confounder in the analysis of associations to autoimmunity. Associations of beta cell decline to individual immune mediators need confirmation in further studies.

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Association of immune mediators at diagnosis of Type 1 diabetes with later clinical remission

Abstract: We conclude that the systemic immunoregulatory state at diagnosis of T1D is predictive of clinical improvement during the remission phase. There was no general change in systemic immune reactivity in the months after diagnosis and initiation of insulin therapy.

Cited by 66 publications

References 49 publications

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

Circulating immune mediators are closely linked in adult-onset type 1 diabetes as well as in non-diabetic subjects

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