More on Intralymphatic Injection of Autoantigen in Type 1 Diabetes

Abstract

To the Editor: Residual insulin secretion de-creases complications and improves quality of life in patients with type 1 diabetes. However, effective interventions to preserve residual beta-cell function are lacking. Antigen-based therapy requires adequate presentation to T cells. Treat-ment with antigen-based therapy with the use of glutamic acid decarboxylase (GAD65) has been encouraging but not sufficiently effective. 1 To render the presentation of GAD65 antigen to T cells in the lymph nodes more efficient than has previously been described, 2,3 we now report the administration of GAD65 autoantigen directly into an inguinal lymph node rather than subcu-taneously. We also added oral vitamin D therapy as a potential immune modulator, although one trial showed that beta-cell function was not pre-served in patients who received vitamin D alone. 4 DIAGNODE-1 (GAD-Alum [Diamyd] Admin-istered into Lymph Nodes in Combination with Vitamin D in Type 1 Diabetes; ClinicalTrials.gov number, NCT02352974), a pilot open-label clinical trial, involved six adult patients who were 20 to 22 years of age and had had incident diabetes for less than 6 months. All the patients were GAD65 antibody–positive and had fasting C-peptide levels greater than 0.12 nmol per liter (0.36 ng per milli-liter). They received an injection of 4 μg of alum-formulated GAD65 (GAD-alum) into an inguinal lymph gland under direct ultrasonographic guid-ance, followed by two intranodal booster injec-tions at 1-month intervals. Each patient also re-ceived vitamin D (calciferol) in an oral solution (2000 U per day) over 4 months, starting 1 month before the first GAD-alum injection. All patients provided written informed consent. The trial was approved by the research ethics committee at Linköping University, Linköping, Sweden, and by the Medical Products Agency, Uppsala, Sweden. Beta-cell function was estimated with mixed-meal tolerance tests. Immune function was as-sessed by means of cell-proliferation assays, flow cytometry, and measurement of cytokine levels through advanced techniques (Bio-Rad and Lumi-nex) and GAD65 autoantibodies, including sub-classes. There were no apparent treatment-related ad-verse events, except for mild transient injection-site reactions. The fasting and maximum stimu-lated C-peptide levels from baseline to 6 months did not decrease in six patients. After 15 months, the mean area under the curve of the serum C-peptide level remained stable in four patients, with an increase of 34% in the fasting C-peptide level (Fig. 1A). The glycated hemoglobin level (Fig. 1B) and insulin dose (Fig. 1C) decreased in each patient. Immunologic markers showed type 2 helper T-cell (Th2) up-regulation, with a stepwise increase of Th2 markers (e.g., interleukin-13 and interleukin-5) after each GAD-alum injection and a decrease of type 1 helper T cell (Th1) markers (e.g., interferon-γ and tumor necrosis factor α) along with signs of T-cell up-regulation (e.g., an increase in interleukin-2 and interleukin-10 levels) after 15 months. Direct injection of GAD-alum into the lymph