Su Metcalfe is available for consultancy.
The application of nanotechnology to healthcare - nano-medicine - is now recognised worldwide as a new era in clinical medicine. Based on our work focussed on regulatory transplantation tolerance in vivo, we have identified a novel regulatory hub in CD4+ T cell differentiation wherein leukaemia inhibitory factor (LIF) not only promotes Treg, but also suppresses IL-6-driven Th17 lineage progression. Moreover, by incorporating the complexity of environmental factors when looking for specific features that characterize transplantation tolerance, versus aggression, unexpected patterns of gene activity in tolerance were discovered: most notably that a novel E-3 ligase, MARCH-7 (previously termed axotrophin), regulates T lymphocyte responsiveness both in terms of proliferation and in release of LIF, probably by providing rheostat-type control of the LIF-receptor, gp190.
Given LIF's central role in stem cells, tissue regeneration and repair, and - now - in adaptive immune tolerance, LIF provides a highly attractive therapeutic: BUT soluble LIF is rapidly degraded and excreted. Therefore, working together with Tarek Fahmy at Yale, we have invented "nano-LIF" - comprising LIF within biodegradable, biocompatible PLGA particles. Potential therapeutic applications being developed include (i) targeting to CD4+ T cells to guide the Treg lineage and oppose Th17; (ii) supporting cell transplants, eg for regenerative medicine, where LIF not only promotes survival but also supports tissue integration; and (iii) promoting endogenous stem and precursor cells in situ. Our current clinical focus is for (a) treatment of multiple sclerosis, both to oppose the Th17-driven pathogenesis and to promote remyelination at lesioned sites; and (b) for cell therapies in treatment of Parkinson's Disease.
Please see http://www.neuroscience.cam.ac.uk/directory/profile.php?smm1001 for further information
FOXP3 ; LIF ; CNS ; T lymphocyte ; IL-6 ; regulatory T cells ; Th17 ; lymphocytes, ; allotolerance ; nano-therapy
Dong H, Fahmy TM, Metcalfe SM, Morton SL, Dong X, Inverardi L, Adams DB, Gao W, Wang H. Immuno-isolation of pancreatic islet allografts using pegylated nanotherapy leads to long-term normoglycemia in full MHC mismatch recipient mice. PLoS One 2012. 2012;7(12)
Metcalfe SM, Fahmy TM.Targeted nanotherapy for induction of therapeutic immune responses. Trends Mol Med. 2012 Feb;18(2):72-80.
Metcalfe SM, Multiple sclerosis: One protein, two healing properties. Nature 2011 477(7364):287-8
Thompson HL, Whiston RA, Rakhimov Y, Taccioli C, Liu C-G, Croce C and Metcalfe SM A LIF/Nanog Axis is Revealed in T lymphocytes that lack MARCH-7, a RINGv E3 Ligase that Regulates the LIF-Receptor. Cell Cycle 2010 9:20, 4213-4221
Gao W, Thompson L, Zhou Q, Putheti P, Fahmy TM, Strom TB and Metcalfe SM Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6. Cell Cycle 2009 8:9, 1444-145
Metcalfe SM Axotrophin and leukaemia inhibitory factor (LIF) in transplantation tolerance. Philos Trans R Soc Lond B Biol Sci 2005 360(1461):1687-94