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

Abstract

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.

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…In the studies that use drugs to reverse diabetes, success is often only seen in the early stages of the disease with blood glucose concentrations only mildly hyperglycaemic [60][61][62][63]. Pancreas and islet transplantation is effective in reversing hyperglycaemia in BB rats and NOD mice if immune suppression or costimulatory blockade is administered [64][65][66][67] or if an encapsulation device is used [68].…”

Animal models of human type 1 diabetes for evaluating combination therapies and successful translation to the patient with type 1 diabetes

“…In particular, this model fulfils the crucial prerequisite that it shows no major deviations from the pathophysiology of human T1DM, namely no sex bias as exists in the NOD mouse model and no severe lymphopenia, as is characteristic for the BB rat (Table ). One of the major effective therapeutic antibodies in preventive combination therapy is anti‐CD3 . However, this antibody causes a reduction of peripheral lymphocyte counts, which is significant at high doses .…”

“…A reliable model must clearly mirror the different stages of the disease process. This must correlate with the initial blood glucose concentration at the start of therapy, the C‐peptide values, and a residual beta cell volume . This is not the case in the NOD mouse model …”

“…A particular advantage of drug combinations is that they grant therapy success even with reduced doses of the single compounds, thereby minimizing the risk of serious side effects and at the same time maximizing therapy success, ie, lasting restitution of normoglycaemia through restoration of a normal beta cell mass in an immune cell infiltration free pancreas . Therapy success to be achieved should be a full restoration of beta cell mass in the pancreas, which can be documented by regain of a normal plasma C‐peptide concentration, which is the ideal biomarker for this purpose …”

“…Otherwise, the earliest starting point for therapy will be immediately after diabetes manifestation and diagnosis, as it is typically the case in the majority of patients, because they do not have a close relative with T1DM and therefore do not have the chance to be identified before disease manifestation as being at risk by antibody biomarker screening. That is the moment, when there is still much beta cell mass left, maximizing the chance of therapy success …”