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

Type I Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02117518
• Other study ID #: 0063-13
• Status: Not yet recruiting
• Phase: N/A
• First received: April 16, 2014
• Last updated: April 22, 2014
• Start date: May 2014
• Est. completion date: May 2016

Study information

• Verified date: April 2014
• Source: Migal Galilee Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Israeli Health Ministry Pharmaceutical Administration
• Study type: Observational

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: May 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 25 Years

Eligibility

Inclusion Criteria:

• Children and young adults, ages between 0-25 who were diagnosed with T1D no more than 3 years prior to enrollment.

Exclusion Criteria:

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Type I Diabetes

Intervention

Other:
• blood drawing

Locations

Country	Name	City	State
Israel	Ziv Medical Center	Safed

Sponsors (2)

Lead Sponsor	Collaborator
Migal Galilee Research Institute	Ziv Medical Center

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification, isolation, propagation and targeting of autoreactive T cells from T1D patients	The ability of the genetically-modified cells to target and kill target autologous autoreactive CD8 T cells will be analyzed by CFSE and HLA-I tetramer staining using flow cytometry and IFN gamma production using ELISPOT.	2 years from the final approval of study	No