Selective Immunotargeting of Pathogenic CD8 T Cells of Type 1 Diabetes

Status Not yet recruiting

Clinical Trial Summary

It is well established that CD8 and CD4 T cells reactive against defined islet antigens are associated with initiation and progression of Type 1 Diabetes (T1D). In previous work, we have demonstrated that it is possible to redirect T cells against pathogenic T cells via chimeric peptide/MHC/CD3-zeta receptors in a peptide-specific manner and to prevent, or inhibit diabetes in NOD mice. In this study we intend to extend this approach to T cells of T1D patients. Working hypothesis: Beta cell-reactive CD8 T cells of human T1D patients can be immuno-targeted by their own gene-modified cytotoxic T lymphocytes (CTLs). Aims: Our major aim is to demonstrate, in a set of ex-vivo experiments, such immunotargeting with T cells derived from T1D patients at the Ziv Medical Center. To this end we will stimulate and expand autoreactive CD8 cells in blood samples of T1D patients and target them, ex-vivo, with genetically-reprogrammed CTLs which are present in the same blood samples.

Clinical Trial Description

To obtain proof-of-principle of our approach we have initiated tight collaboration between the Laboratory of Immunology at MIGAL Galilee Research Institute, Kiryat Shmona (MIGAL) and Breinin Center for Type 1 Diabetes and Endocrinology at the Ziv Medical Center in Safed (Ziv). In this study we will first identify carriers of the HLA-A0201 allele among pediatric and young adult T1D patients at Ziv. We will then screen the T cell pool in the peripheral blood samples of these patients for CD8 T cells reactive against any of 3 known HLA-A0201-binding peptides associated with autoreactivity in T1D: Insulin beta chain 10-18, IGRP 265-73 and IGRP 222-230. The influenza virus-derived peptide MP 58-66 will serve as reference. Next we will isolate polyclonal CD8 T cells from blood samples of the same patients, activate and expand them ex-vivo and transfect them via electroporation with in-vitro-transcribed mRNA encoding the respective peptide/MHC/CD3-zeta construct(s). We will then perform co-culture experiments assessing the ability of the mRNA-transfected T cells to kill the autoreactive T cells of the same patient in a peptide-selective manner. ;

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

Clinical Trial Details

NCT number	NCT02117518
Study type	Observational
Source	Migal Galilee Research Institute
Contact
Status	Not yet recruiting
Phase	N/A
Start date	May 2014
Completion date	May 2016

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Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question.

Phase 1: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase 2: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
Phase 3: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase 4: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.

Selective Immunotargeting of Pathogenic CD8 T Cells of Type 1 Diabetes Patients

Clinical Trial Summary

Clinical Trial Description

Study Design

Related Conditions & MeSH terms