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S. R. Morwood, L. B. Nicholson, A. D. Dick; Functional Characterisation of Macrophages and T Cells From Thrombospondin-1 Knockout Mice in Experimental Autoimmune Uveoretinitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5206.
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Thrombospondin-1 (TSP-1) is a 450KDa matricellular protein which has an important role in regulating inflammation. Of particular note are its ability to bind and activate latent TGF-beta, to down regulate T-cell proliferation and to inhibit the development of Th1 cells, by ligation of CD47. In the eye it has been implicated as a mediator of immune privilege, as supernatants from TSP-1-/- eyecups contain lower levels of active TGF-ß. TSP-1-/- mice exhibit a persistent systemic inflammatory response, with an increased number of circulating leukocytes and a propensity to develop pneumonia. In contrast to this, TSP-1-/- mice show a decreased level of disease in an accelerated model of glomerulonephritis, demonstrating that the function of TSP-1 within the immune response is diverse. We wished to investigate the role of TSP-1 in the development of autoimmune disease further.
We used the model of EAU to investigate immune response following immunisation with retinal antigens or OVA in C57BL/6 wild type (WT) and TSP-1-/- mice and also in vitro utilising IRBP1-16 lines that we derived from both WT and TSP-1-/-. As macrophages are crucial mediators of tissue destruction, we studied bone marrow derived macrophages from WT mice and TSP -1 knockout mice activated with soluble ligands.
T cell priming with foreign antigens and ocular autoantigens is unimpaired in TSP-1-/- mice. IRBP-1-16 specific T-cell lines showed an increase in the secretion of IL-4, suggesting that T cells from TSP-1-/- mice may be biased towards a Th2 lineage. Activation of WT macrophages stimulates an increase in TSP-1 mRNA which is not reduced by blocking nitrite, whilst activated TSP-1-/- macrophages generate less nitrite than WT macrophages.
Thrombospondin production by macrophages may play a role in modulating EAU.
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