The immunosuppressive function of regulatory B cells (Bregs) has now been confirmed in several murine models of chronic inflammation, including collagen induced arthritis (CIA), inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE). In particular, our group has previously been reported that IL10+ regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the Transitional-2 immature (T2) B cell pool (T2Bregs). In this thesis I first of all characterize regulatory B cells in the MRL/lpr mouse model of systemic lupus erythematosus (SLE) and report that agonistic anti-CD40 specifically targets T2 B cells and enriches T2 Bregs upon short term in vitro culture. Whilst transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40- generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, and induced the differentiation of IL-10+CD4+T cells conveying regulatory effect to CD4+T cells. In addition, in this thesis I demonstrate that freshly isolated human CD19+CD24hiCD38hi B cells contain a population with potent regulatory capacity. Immature CD19+CD24hiCD38hi Bregs suppressed the differentiation of Th1 cells via the provision of IL-10, but not TGFβ, and their suppressive capacity was abrogated by the addition of anti-CD80. In addition, although they comprise a greater percentage of the B cells in the peripheral blood of SLE patients, CD19+CD24hiCD38hi SLE Bregs were found to be refractory to further CD40 stimulation, produced less IL- 10, lacked the functional suppressive capacity of their healthy counterparts. Altered cellular function within this compartment may impact effector immune responses in SLE and other autoimmune disorders. Therapeutic strategies facilitating the enrichment, or enhancement of the suppressive activity, of human Bregs offer new treatment possibilities.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625231 |
| Date | January 2009 |
| Creators | Blair, P. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/18756/ |
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