Improving drug therapies for immune diseases
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Immunology | .(JavaScript must be enabled to view this email address) |
Dr Susanne Heinzel (Co-supervisor) |
Immunology | .(JavaScript must be enabled to view this email address) |
Details of project
In clinical settings such as transplantation and autoimmune disease immunosuppressive drugs are used to prevent the unwanted activation of immune cells. These drugs operate on different pathways of lymphocyte activation in a complex and usually poorly understood manner. In our laboratory we have developed new models of lymphocyte biology that allows us to run simulations of the immune response for the first time.
In this project we will investigate the effect of known, and experimental, immunosuppressive drugs on activation, survival, division and differentiation of T cells in vitro. The data collected will be analysed using modeling software we have developed. Our aim is to show that we can use these models to calculate immune outcomes for drugs used alone, and, more importantly, to be able to predict those that will work in synergy.
The models will predict and improve inhibition of immune activation in response to antigenic stimulation with immunosuppressive drugs and we will test these predictions in disease models in vivo. The successful student will improve our understanding of the regulation of the immune system and become skilled in cell manipulation (flow cytometry, microscopic imagining), molecular techniques (PCR, western blotting), IT biology (curve prediction, cell simulation).
Project references
- Gett AV and Hodgkin PD. A cellular calculus for signal integration by T cells. Nat Immunol. 2000 Sep;1(3):239-44. PMID: 10973282.
- Hawkins ED, Turner ML, Dowling MR, van Gend C and Hodgkin, PD. A model of immune regulation as a consequence of randomized lymphocyte division and death times. Proc Natl Acad Sci USA 2007 104:5032-5037.
- Hawkins ED, Hommel M, Turner ML, Battye FL, Markham JF, Hodgkin PD. Measuring lymphocyte proliferation, survival and differentiation using CFSE time-series data. Nat Protoc. 2007;2(9):2057-67. PMID: 17853861.
- Hawkins ED, Markham JF, McGuinness LP, Hodgkin PD. A single-cell pedigree analysis of alternative stochastic lymphocyte fates. Proc Natl Acad Sci USA. 2009 Aug 11;106(32):13457-62. PMID: 19633185;
Research interests
The immune system has fascinated scientists for decades. On the one hand it appears immensely complex, involving the coordinated contribution of many cell types. However, when cells are studied in isolation they follow clear simple rules suggesting a comprehensive theory is within reach of science - especially given the powerful array of present day tools for cell exploration and data gathering.
Our laboratory is interested in the regulation of the many directions the immune response can take, both in responding to infection, and when ‘getting it wrong’ during autoimmunity or allergy. To explore this question the Hodgkin laboratory combines experiment with theory and quantitative mathematical modeling. We have developed new techniques for studying the ongoing immune response and the changing patterns of response mediated by combinations of different signals. We are also attempting to develop powerful new tools for direct imaging of cellular responses.
Over the last decade we have developed an understanding of lymphocytes as following fundamentally simple behaviour but with the complication that an extraordinary degree of randomness arises from their ‘construction’, effectively making every cell different. Models that capture this random element using probability distributions are capable of powerful predictions of the immune response. We will apply this framework to address the specific research projects outlines below.
Selected publications
- Markham JF, Wellard CJ, Hawkins ED, Duffy KR, Hodgkin PD. A minimum of two distinct heritable factors are required to explain correlation structures in proliferating lymphocytes. J R Soc Interface. 2010 Jul 6;7(48):1049-59. PMID: 20053654.
- Turner ML, Corcoran LM, Brink R, Hodgkin PD. High-affinity B cell receptor ligation by cognate antigen induces cytokine-independent isotype switching. J Immunol. 2010 Jun 15;184(12):6592-9. PMID:20483733
- Dowling MR, Hodgkin PD. Modelling naive T-cell homeostasis: consequences of heritable cellular lifespan during ageing. Immunol Cell Biol. 2009 Aug-Sep;87(6):445-56. PMID: 19290017.
- Subramanian VG, Duffy KR, Turner ML, Hodgkin PD. Determining the expected variability of immune responses using the cyton model. J Math Biol. 2008 Jun;56(6):861-92. PMID: 17982747.
Research theme
Chronic inflammatory diseases
Scientific discipline
- Autoimmunity
- Cell Biology
- Immunology
- Mathematics
- Systems Biology
Keywords
Immune regulation, T cells