Regulatory T Cells and Quality Control Parameters

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Tregs are heterogeneous cell populations with different subtypes (e.g. CD25+ Tregs and Tr1 cells) being characterised by the expression of different molecules and different epigenetic modifications. CD25+FOXP3+ Tregs from the blood of patients can be enriched using GMP compatible reagents and protocols, either by cell sorting or the use of magnetic beads. IL-10 producing Tr1 cells can be expanded/induced in an antigen-specific manner in vitro with TolDCs, or other means, using GMP compatible reagents and protocols.

Identification, validation and evaluation CTT

Main tasks that will be carried out in this WG on Regulatory T Cells and Quality Control:

1. Identification and validation of QC parameters for potency/functionality of Tregs
The aim of this Task is to identify and validate functional parameters (e.g. T cell activation markers, regulatory molecules and cytokine profiles) expressed by Tregs either ex vivo isolated (blood derived or thymus) or after in vitro expansion/induction, and to correlate their expression with the regulatory function of these cells and their MoA.

2. Identification and validation of QC parameters for safety of Tregs
As already described for the tolAPCs, in addition to functional parameters of potency, markers that will indicate the safety (e.g. stability) of the Treg products will be identified. WG1 and this WG will interact with the “ONE Study” EU consortium, in which TolDCs, Mregs and Tregs prepared by different centres in Europe will be compared for their in vivo function in the treatment of renal transplant patients.

3. Evaluate pre-clinical and clinical data in relation to different pathological conditions to determine the optimal type of CTT, including antigen-specificity of CTT.

This task will focus on the analysis of various characteristics of the different CTT products in relation to their applicability in diverse pathological conditions. Preclinical models (in vitro and in vivo in animal models) will be used. Animal models will provide information on biodistribution of the CTT products, as well as guidance on dosage and best application site (local vs systemic).

A relevant aspect of this task will be the assessment of antigen specificity of CTT and the importance hereof in relation to different diseases. Current knowledge on candidate antigens towards the tolerogenic response has to be directed, will be gathered using both literature and own experience for different diseases. The obtained information will be integrated and critically evaluated. In vitro culture assays will be developed and validated to determine the antigen specificity of the different CTT products.

The results of this task must give us insight in the type of CTT to be used and the candidate antigen(s) towards the CTT has to be directed for different diseases.

Altogether, the work carried out under WG1 & 2 aims to achieve:

• Definition of (novel) QC parameters for potency and functionality of tolDC, other tolAPCs and Treg products

• Recommendations for regulatory authorities, specifying relevant release criteria for approval of CTT

• Insight in the type of CTT to be used, dosage, application site and the putative candidate antigen(s) towards the CTT has to be directed for different pathological conditions; one step forward to personalised immunotherapy.

• Papers on novel scientific findings in relation to biomarkers (i.e. Blood, Journal of Clinical Investigation, Science Translational Medicine) or CTT release recommendations (Journal of Transl Med, Clinical Immunology, Journal of Immunother).

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