Anti-cytokine therapies in T1D: Concepts and strategies

Nepom, Gerald T.; Ehlers, Mario R.; Mandrup-Poulsen, Thomas

doi:10.1016/j.clim.2013.02.003

Cited by 60 publications

(45 citation statements)

References 59 publications

(61 reference statements)

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“…The proinflammatory cytokine TNF-a, expressed in the infiltrating immune cells, is known to be a key player in the pathology of many autoimmune diseases, including T1D (9,12,13). However, although a monotherapy with anti-TNF-a is an established successful therapy in a number of autoimmune diseases (15)(16)(17), anti-TNF-a is not effective in T1D treatment (18)(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

“…Cumulative evidence from studies in a variety of other autoimmune diseases supports the contention that the inflammatory process in the affected organs always goes along with a high TNF-a expression (9)(10)(11)(12)(13). Anti-TNF-a therapy is therefore an established therapeutic principle (14)(15)(16) in rheumatoid arthritis, inflammatory bowel diseases, lupus erythematosus, Sjögren syndrome, psoriasis, and Hashimoto thyroiditis (10,15,17).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…At the onset of T1D, the inflammatory response is thought to be directed toward pancreatic islets (2), a process that seems to play a crucial role in maintaining the autoimmune response as well as representing a key feature of its pathology (3). Consequently, control of the inflammatory response is a strategic and somewhat underexplored action for influencing the disease (4)(5)(6)(7).…”

mentioning

confidence: 99%

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

et al. 2014

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Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2+ myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual β-cells holds the potential to make a significant change in the approach to management of human T1D.

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“…Administration of ponesimod to diabetic NOD mice followed by anti-CD3 mAb treatment, started a few days before discontinuation of ponesimod, induced long-lasting disease remission in all treated mice [130]. IL-1β is an interesting therapeutical target in T1D as it has been shown to inhibit insulin secretion and synthesis and to affect β-cell viability [131]. Ablamunits et al found synergistic reversal of autoimmune diabetes and enhanced immune regulation in NOD mice treated with anti-CD3 mAb together with IL-1 receptor antagonist [132].…”

Section: Review Kuhn and Weinermentioning

confidence: 98%

Therapeutic Anti-Cd3 Monoclonal Antibodies: From Bench to Bedside

2016

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The induction of tolerance is a major goal of immunotherapy. Investigations over the last 20 years have shown that anti-CD3 monoclonal antibodies (mAbs) effectively treat autoimmune disease in animal models and have also shown promise in clinical trials. Tolerance induction by anti-CD3 mAbs is related to the induction of Tregs that control pathogenic autoimmune responses. Here, we review preclinical and clinical studies in which intravenous or mucosal administration of anti-CD3 mAbs has been employed and provide an outlook on future developments to enhance the efficacy of this promising therapeutic approach.

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Anti-cytokine therapies in T1D: Concepts and strategies

Cited by 60 publications

References 59 publications

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

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

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

Therapeutic Anti-Cd3 Monoclonal Antibodies: From Bench to Bedside

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