About the Project
Foxp3+CD25+CD4+ regulatory T cells (Treg) have been shown to be esential for the induction of tolerance to foreign organ transplants in experimental models. In addition, human in vitro-expanded Treg prevent the rejection of human skin and vessel transplants in humanised mice and are able to suppress graft versus host disease in human bone-marrow transplant recipients. Therefore, these studies suggest that Treg that have been expanded in vitro could be re-infused back into recipients to prevent organ rejection/graft versus host disease (GVHD) and autoimmunity.
Despite the promise of Treg as a cellular therapy, we believe that genetic manipulation of such cells prior to re-introduction into patients may allow Treg to be generated that demonstrate increased immunosuppressive potency in vivo. With this in mind, the project will explore the use of retroviral delivery of genes that may aid Treg localisation, survival, stability and function. The project will make use of existing retroviral gene transduction technologies and expertise at the University of Birmingham (Bendle et al, 2010, Nat Med 16: 565-570). In addition, the immunosuppressive potency of gene manipulated Treg will be compared to sham-transduced Treg in established in vitro T cell function assays and models of skin, heart and bone-marrow (to induce GVHD) transplantation.
This project will not only identify genes that may increase Treg function but will also inform on questions such as how long injected Treg survive, which tissue Treg home to and reside in (allograft/lymphoid tissue/non-lymphoid tissue) and whether a proportion of injected Treg re-differentiate into effector cells. These are all important questions that will need to be addressed prior to the routine clinical use of such cells. Excitingly, the opening of the new Cell Therapy Facility at the University of Birmingham will enable the translation of the findings of this and other contiguous studies through to the clinical arena.
To apply, please submit your CV and a covering email/letter for consideration by the Supervisor.
References
Yang, J., M.O. Brook, M. Carvalho-Gaspar, J. Zhang, H.E. Ramon, M.H. Sayegh, K.J. Wood, L.A. Turka, and N.D. Jones. 2007. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A 104:19954-19959.
Carvalho-Gaspar, M., N.D. Jones, S. Luo, L. Martin, M.O. Brook, and K.J. Wood. 2008. Location and time-dependent control of rejection by regulatory T cells culminates in a failure to generate memory T cells. J Immunol 180:6640-6648.
Jones, N.D., M.O. Brook, M. Carvalho-Gaspar, S. Luo, and K.J. Wood. 2010. Regulatory T cells can prevent memory CD8(+) T-cell-mediated rejection following polymorphonuclear cell depletion. Eur J Immunol 40:3107-3116.
Wood, K.J., A. Bushell, and N.D. Jones. 2011. Immunologic unresponsiveness to alloantigen in vivo: a role for regulatory T cells. Immunol Rev 241:119-132.
Kinnear, G., K.J. Wood, F. Fallah-Arani, and N.D. Jones. 2013. A Diametric Role for OX40 in the Response of Effector/Memory CD4+ T Cells and Regulatory T Cells to Alloantigen. J Immunol 191:1465-1475.
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