Regulatory T Cells in Type 1 Diabetes Patients Treated With IL-2 (DILT1D)

University of Cambridge, Juvenile Diabetes Research Foundation, National Institute for Health Research, United Kingdom, Wellcome Trust

Type 1 diabetes is the most common severe chronic autoimmune disease worldwide and is caused by the autoimmune (loss of self tolerance) mediated destruction of the insulin producing pancreatic beta cells thus leading to insulin deficiency and development of hyperglycaemia. Currently, medical management of type 1 diabetes focuses on intensive insulin replacement therapy to limit complications (retinopathy, nephropathy, neuropathy); nevertheless clinical outcomes remain sub optimal. There are intensive efforts to design novel immunotherapies that can arrest the autoimmune process and thereby preserve residual insulin production leading to fewer complications and better clinical outcomes. The vast majority of genes that contribute to susceptibility to type 1 diabetes have been found to encode proteins involved in immune regulation and function. In particular, several susceptibility proteins are involved in the interleukin 2 (IL-2) pathway that regulates T cell activation and tolerance to self antigens. Aldesleukin is a human recombinant IL-2 product produced by recombinant DNA technology using genetically engineered E. coli stain containing an analog of the human interleukin-2 gene. There is substantial nonclinical, preclinical and clinical data that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by induction of functional T regulatory cells. However, prior to embarking on large proof of concept trials in type 1 diabetes it is essential that the optimum dose of IL-2 (aldesleukin) is determined. The objective of this study is to establish in patients with type 1 diabetes the optimal dose of IL-2 (aldesleukin) to administer in order to increase T regulatory cell response.

A single, subcutaneous dose will be given administered with the maximum dose allowed 1.5 X 106 IU/M2.

The primary endpoint is based upon the percentage of CD4+T regulatory (defined as CD3+CD4+CD25highCD127low) cells within the CD3+CD4+T cell gate following treatment with IL-2.

Inclusion Criteria: Written informed consent Type 1 diabetes 18-50 years Duration of diabetes less than 24 months from diagnosis One positive autoantibody (anti-islet cell, anti-GAD, anti-IA2, anti-ZnT8) Exclusion Criteria: Hypersensitivity to aldesleukin or any of the excipients History of severe cardiac disease History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ) History or concurrent use of immunosuppressive agents or steroids History of unstable diabetes with recurrent hypoglycaemia Active autoimmune, hyper or hypothyroidism Active clinical infection Major pre-existing organ dysfunction or previous organ allograft Females who are pregnant, lactating or intend to get pregnant during the study - Males who intend to father a pregnancy during the study Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration Abnormal ECG Abnormal full blood count, chronic renal failure (Stage 3,4,5) and/or evidence impaired liver function Positive Hepatitis B surface Antigen (HBsAg) or Hepatitis C serology or Human Immunodeficiency Virus (HIV) test Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern

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