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Title: The role of B cells in the pathogenesis of chronic graft-versus-host disease
Author: Khoder, Ahmad
ISNI:       0000 0005 0734 2342
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Chronic graft-versus-host disease (cGVHD) remains a major complication of allogeneic haematopoietic stem cell transplantation. Traditionally, GVHD has been approached as a T-cell-mediated process and current therapies reflect this understanding. The successful treatment of a proportion of refractory cGVHD patients with a CD20-depleting-agent supports a pathological role for B cells. To study the role of B cells in cGVHD, I designed a comprehensive multi-parameter panel of surface antibodies to distinguish different B cell subsets. The panel was validated on a number of healthy volunteers and applied to peripheral blood samples from cGVHD patients. I showed that patients with active chronic GVHD have an expanded population of CD21- with an 'exhausted' phenotype, based on upregulation of inhibitory receptors, altered expression of chemokine receptors and poor proliferative capacity. A similar subset of CD21- exhausted B cells was described in patients with chronic HIV viraemia. Interestingly, there was a significant correlation between frequencies of CD21- B cells and the severity of cGVHD. Further work to identify the potential antigens that drive the expansion of these cells is currently underway. I also explored the role of IL10 producing regulatory B cells (Breg); powerful regulators of immune responses. A number of B cell subsets have been described in murine models of autoimmunity and some human autoimmune diseases. I investigated the presence of IL10 producing B cells in the peripheral blood of healthy donors. Using intracellular cytokine staining for IL10 and surface phenotyping, I showed that IL10 producing B cells are enriched within the CD27+ IgMhi (IgM memory) B-cell subset. The purified populations of IgM memory B cells had regulatory properties and are capable of suppressing CD4+ T cell proliferation and IFNγ in vitro. Finally, I showed that B cells from cGVHD patients produce significantly less IL10 compared with both HC and 'no-GVHD' patients. I thereby propose that B cells play a significant role in the pathogenesis of cGVHD. Ex vivo expanded and adoptively transferred IgM memory B-cells may offer a potentially effective immunomodulatory therapy for the treatment of refractory cGVHD.
Supervisor: Rezvani, Katy ; Apperley, Jane ; MacDonald, Donald Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral