Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes

Abstract

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4+ T cells, CD8+ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.

Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes

“…In addition to ATG+G-CSF, combinatorial agents promoting β-cell regeneration or islet transplant may be necessary to provide recovery of functional β-cell mass in subjects with established disease. Indeed, we previously reported a four-drug combination treatment that was able to reverse not only new-onset diabetes but even established disease in the NOD model (24) using low-dose ATG+G-CSF plus dipeptidyl peptidase 4 inhibitor and proton pump inhibitor. These two additional agents have together afforded efficacy in preclinical type 1 diabetes studies (25), are already approved by the U.S. Food and Drug Administration for use in treating type 2 diabetes and gastroesophageal reflux disease, and are commonly prescribed in the clinic with low associated risks.…”

Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

“…The tested approaches to reverse T1D have largely focused on adaptive immunity. However, one approach that was highly successful in reversing T1D in NOD included granulocyte-colony stimulating factor (G-CSF) along with an anti-T-cell agent 76. We suspect, but do not know, that this approach may mobilize similar suppressive APCs as our TLR4-Ab.…”

Combinatorial drug delivery approaches for immunomodulation

“…Approaches utilizing immunoablating techniques have also generated interest in autoimmune disease to deplete autoreactive cells in order to reprogram homeostatic immunity. Combination therapy with anti-thymocyte globulin and GM-CSF has been shown to increase Treg frequency, alter DC pheno-types, and improve survival in mouse models of type 1 diabetes [124,125]. This combinatorial approach was validated when explored in clinical trials of type 1 diabetics, improving Treg frequency and preserving β-cell function compared to placebo controls [126,127].…”