PhD Studentship: Targeting The Thymus To Improve Immune Recovery Following Stem Cell Transplantatio

Background
The treatment of cancer frequently requires the transplantation of bone marrow to regenerate the immune system that is damaged following ablative therapy. For example, haemopoietic stem cell transplantation (SCT) is used in the treatment of haematological malignancies including leukemias and lymphomas. Following transplant, the restoration of a naive T-cell pool critically depends upon host thymus function to support the recruitment and development of donor-derived progenitors. However, T-cells represent the last blood cell lineage to recover post-transplant, a process that can take years. This leaves patients at risk from increased infection and mortality rates. Our laboratory has a long-standing interest in how T-cells are produced in the thymus (see website http://www.birmingham.ac.uk/staff/profiles/iandi/anderson-graham.aspx).

This project will develop this area of research by developing a new theme to therapeutically target the thymus to improve T-cell mediated immunity following SCT.

Aims
Our recent work has identified the TNF Receptor superfamily member Lymphotoxin Receptor (LTR) as a key regulator of T-cell progenitor entry to the thymus. The overall aim of this project is to investigate whether targeting of LTR will provide a new approach to improve T-cell reconstitution after bone marrow transplantation, and so offer a new immunotherapy for the rapid and effective recovery of the immune system in the treatment of cancer.

Methods
1. Using well-established models of bone marrow transplantation in normal mice, we will determine whether administration of agonistic anti-LTR antibodies enhances the entry of donor-derived T-cell progenitors into the thymus. This will involve detailed flow cytometric/qPCR analysis of lymphoid progenitors in the bone marrow and thymus as part of an analysis of intrathymic T-cell development. Established collaborations with Dr. Carl Ware (Sanford Burnham USA) will provide agonistic antibodies to the mouse LTR that have been used effectively in vivo.
2. To determine whether LTR stimulation improves recovery of the peripheral T-cell compartment, we will transplant host mice with Rag2GFP/Foxp3RFP ‘dual reporter’ bone marrow. Using this approach we can monitor how LTR impacts the re-generation of the peripheral T-cell compartment, including analysis of conventional and regulatory Recent Thymus Emigrants.
3. To investigate the mechanism by which LTR triggering enhances immune recovery, we will isolate defined thymic stromal cell subsets (epithelium, mesenchyme, endothelium) from anti-LTR and control treated mice, and perform RNA-seq analysis to identify downstream targets of LTR.

This work will provide in-depth training and access to cellular and molecular techniques including novel mouse strains for immunological research, flow cytometry, qPCR, genome wide gene analysis, confocal microscopy and in vivo manipulation of the immune system. It will also allow us to develop links with our clinical stem cell transplantation colleagues in Birmingham, the largest transplant centre in Europe, to enable our long term goal of improving immune reconstitution in cancer patients.

Person Specification
Applicants should have a strong background in Biomedical Science, and ideally a background in Immunology/Haemopoiesis. They should have a commitment to research in Immunology and Haemopoiesis and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biomedical Sciences related subjects.

Apply below.

Funding Notes

Applications are invited from self-funding applicants only.

References

1) Anderson-G; Takahama-Y (2012). Thymic epithelial cells: working class heroes for T-cell development and repertoire selection. Trends in Immunol. 33:256-263.

2) Cowan-JE, Parnell-SM, Nakamura-K, Caamano-JH, Lane-P, Jenkinson-EJ, Jenkinson-W, Anderson-G (2013). The thymus medulla is required for foxp3+ regulatory, but not conventional CD4+ thymocyte development. J. Exp. Med. 210:675-681.

3) Baik-S, Sekai-M, Hamazaki-Y, Jenkinson-WE, Anderson-G (2016). Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. Eur. J. Immunol. 46:857-862.

4) Cowan-JE, McCarthy-NI, Anderson-G (2016). CCR7 controls thymus recirculation, but not production and emigration, of Foxp3+ T-cells. Cell Reports 14:1041-1048.