To investigate their importance in non-Hodgkin’s lymphoma (NHL), I enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 newly diagnosed patients CD25+FoxP3+CD127<sup>low</sup>CD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13:<i> p</i><0.001, rank sum test) and correlated with serum lactate dehydrogenase (n=14; R<sub>s</sub>=0.79, <i>p</i><0.001) and disease stage. I documented poor proliferation of T cells with mitogen ConA and almost none with recall antigens PPD and DPT in both PBMC and involved tissue samples (n=9). T cell hyporesponsiveness was reversed by depleting CD25+ cells (n=4), or by adding anti-CDLA-4 (n=3), supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. As a high percentage of Treg cells were also present in involved tissues (patients’ involved tissues median=38.8% of CD4 T cells (n=15) vs. reactive nodes median=11.6% of CD4 T cells (n=2); <i>p</i>=0.02, rank sum test), I determined if tumour cells could induce a T regulatory phenotype. I incubated CD25+ depleted PBMC with tumour cells <i>in vitro</i> for five days. A dose and time dependent T regulatory phenotype induction from CD25+ depleted PBMC fractions were seen (n=6, maximum induction of 86.7%). Partial induction was seen when these fractions were separated with transwells. These ‘induced Treg cells’ were FACS sorted and suppressed effector T cells proliferation. I conclude that NHL cells are powerful inducers of Treg cells. These cells circulate systemically and induce active immune tolerance both systematically and within tumour microenvironment, thus representing a new therapeutic target in NHL.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:499958 |
| Date | January 2009 |
| Creators | Mittal, Sajjan |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=26200 |
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