Identifying novel biomaterials that re-direct T cell function in vivo
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
The PhD project will utilise self-assembling peptide hydrogels modified with glycosaminoglycans to identify specific 3D environments that are able to induce plasticity in the phenotype of T cell populations with the ultimate aim of diverting immune cell function in vivo. Our established systems use isolated T cells directed to different phenotypes with antibodies and cytokines. What is now needed is a defined, non-toxic materials platform to advance this work to a stage where these can be used in vivo. We will use human and mouse T-cells populations (e.g. regulatory T-cells (Treg)), characterised with phenotype / function assays (Flow cytometry, ELISA, PCR) after culturing in these novel 3D hydrogels to assess the induction of plasticity. Experiments will be initially undertaken on planar surfaces with isolated cells, and ultimately adapted to in vivo studies measuring the induction of T cell plasticity in mouse models. The outcome will be novel classes of materials that selective redirect T-cell differentiation and alter their function in vivo. The characterisation of novel "materials switches" for immune instruction is an important milestone for our future understanding of materials-cellular communication (i.e. instructive devices, implants, regenerative medicine). This has significant potential to impact on human and animal health (e.g. cancer, autoimmunity).
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N50970X/1 | 01/10/2016 | 30/09/2021 | |||
| 1974836 | Studentship | EP/N50970X/1 | 01/10/2017 | 27/10/2021 | Ilona Sica |
| Description | Human T cells were isolated from healthy donors and encapsulated in self-assembling peptide gel, making a 3D T cell culture. There is no similar research conducted (or not published yet) by looking at human T cells and peptide gel. The gel could be adjusted to have a stiffness of soft or hard tissue (e.g. cancer, normal tissue) and include biological components to resemble a specific tissue area. In this research, peptide gel supported T cell viability and promoted other T cell-related functions. This 3D cell culture could improve current in vitro T cell studies and replace animal models. Different peptide gel density (stiffness) supported T cell viability. In this experiment, T cells were stimulated or rested before encapsulation. This is to indicate whatever both forms of T cells (activated/non-activated) could stay viable in peptide gels. The results have shown T cell ability to adapt to the changing gel's density. Another achievement was done with T cell stimulation by antibody-coated beads within the gel structure. Antibody-coated beads are classed as 'artificial' antigen presenting cells (APC) as they imitate the actual cells found in the body, which stimulate T cells to induce an immune response. Antibody-coated beads were able to stimulate T cells within the peptide gel, which resulted in T cell proliferation and pro-inflammatory cytokine secretion (INFy). This shows material's ability to support T cell stimulation and also retain the biological function of antibodies. Moving from artificial-APC, T cells were encapsulated in peptide gel with dendritic cells, which are also known as 'professional' APC. These cells constantly sample the environment to detect any possible danger for the host's system. Upon activation they migrate to the lymph node to promote T cells activation and induce an immune response. In this research, dendritic cells were activated with viral derivatives and encapsulated together with T cells in the peptide gel. Peptide gel supported co-culture of cells, as T cells responded to the activated dendritic cells by proliferation and secretion of cytokines. Peptide gel supported different cell interactions and allowed classic T cell activation. As the gel's purpose is to support T cell-based 3D culture, it is important to test whatever T cells could be activated by the material itself. Peptide gel is composed from short amino acid chains, which form a fibrous network upon temperature and pH change. T cells could only be activated by APC and in this case dendritic cells were tested against peptide gel. Dendritic cells were encapsulated or incubated with peptide gel fragments. Cells activation depends on the dynamic change of surface markers (e.g. HLA-DR, CD86) and IL-12 cytokine secretion. However, peptide gel does not activate dendritic cells as all key markers were absent. This proves the material's inability to induce an immune system, which guarantees the absence of non-specific T cell response. |
| Exploitation Route | 3D T cell culture model with peptide gel could benefit various academic and non-academic sectors. Current results show peptide gel's ability to accommodate human T cells and support their function outside of a human's body. Several impacts from this research could be delivered: - Improve current T cells studies with 3D models replicating healthy and disease microenvironments - Provide human T cells with a realistic culture environment (tissue architecture, biological molecule compositions) as found in human tissues - Represent realistic T cell behaviour, which could allow studying disease development, drug efficiency, cell to cell interactions - Provide knowledge on biomaterial requirements to act as a clinical implant delivering T cells - Conduct animal-free studies, reduce animal sacrifice for human related studies |
| Sectors | Education,Environment,Healthcare,Government, Democracy and Justice,Pharmaceuticals and Medical Biotechnology |