Apoptotic cells (AC) are able to modulate the immune system, dampening inflammation and triggering anti-inflammatory responses by various immune cells as a consequence of interaction and uptake. Rituximab (RTX) is an anti-CD20 monoclonal antibody used as a treatment in several autoimmune diseases, including rheumatoid arthritis (RA). Treatment results in B cell depletion, with B cell apoptosis known to contribute to RTX-mediated B cell death. However the simple removal of B cells from the system does not seem to account for all the beneficial effects of this biologic. We propose that RTX treatment in RA results in the re-establishment of temporary tolerance to the system, through an apoptotic B cell-dependent mechanism. Initial in vitro and in vivo investigations were undertaken to explore the validity of this hypothesis. The present work sought to examine the immunomodulatory capacity of apoptotic B cells and to determine whether the potential anti-inflammatory effects of apoptotic B cells are modulated by RTX, with both in vitro methods and an in vivo model of autoimmunity utilized in these studies. The results presented in this thesis demonstrate that apoptotic B cells have comparable effects on bone marrow derived macrophage (BMDM) phenotype and function in vitro as previously described AC from other cellular sources. Surprisingly, in the in vitro assay system used, viable cells had the same immunomodulatory effects on BMDM as AC, for all criteria investigated. Preliminary studies indicate this may be a promising avenue of inquiry, however further work is needed before a conclusion can be reached as to the relative level of involvement of apoptotic B cell-mediated tolerance in the improvement seen on RTX treatment in RA.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:616446 |
| Date | January 2014 |
| Creators | Herrington, Felicity |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/5330/ |
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