The long-term objective of this research is to improve treatment of rheumatoid arthritis (RA) by developing cell-based therapies that target auto reactive T cells. The hypothesis to be tested is that defined subsets of activated B cells can mediate down-regulation of inflammation by inhibiting the activity of T helper cells. This hypothesis is based on the preliminary finding that a subset of B cells from immunized mice is capable of mediating T cell death in an antigen-specific and Fas ligand (CD178)-dependent manner. These 'regulatory' B cells have been observed in other models of inflammation in mice, as well as in human diseases.
Aim 1 : Study the induction and/or down-regulation of immune regulatory molecules on B cell subsets following in vitro and in vivo stimulation.
Aim 2 : Analyze the cell-cell interactions required to induce cell death or regulation of Th cells following coculture of activated B cell subsets with arthritis antigen-specific Th cells.
Aim 3 : Study the ability of antigen-loaded, 'regulatory' B cells to maintain regulatory phenotype, skew the ThlL-17 response, and prevent or treat arthritis in mice.
Aim 4 : Determine the relative contribution of endogenous CD178+ B cells to the in vivo regulation of ThlL-17 response and joint inflammation.
These aims will be achieved using established models of arthritis in mice. B cells from these mice will be analyzed for expression of regulatory molecules after various modes of stimulation. Assays for T cell activation and death will be carried out by coculture of T cells from immunized mice and antigen-pulsed purified B cells. Cell-cell interactions between B and T cells will be blocked by neutralizing antibodies to determine which interactions are critical to T cell regulation. Expansion of murine B cells for adoptive transfer will be achieved using CD40L-transduced fibroblasts, and culture parameters will be optimized to produce large numbers of regulatory B cells. B cells will be injected into mice prior to or during established arthritis to study in vivo regulatory effects. An arthritis model involving injection of arthritogenic antigens will be tested in B cell deficient mice in order to further substantiate the importance of regulatory B cells. Relevance: Regulatory B cells have potential in treating RA because of their ability to specifically identify, interact with, and eliminate the T cells involved in arthritis progression. Elimination of disease-causing T cells, while sparing bystander T cells would be a significant improvement over current non-specific therapeutic strategies. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AR053846-01A1
Application #
7262777
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$107,015
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Klinker, Matthew W; Reed, Tamra J; Fox, David A et al. (2013) Interleukin-5 supports the expansion of fas ligand-expressing killer B cells that induce antigen-specific apoptosis of CD4(+) T cells and secrete interleukin-10. PLoS One 8:e70131
Szymczak, Wendy A; Davis, Michael J; Lundy, Steven K et al. (2013) X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection. MBio 4:
Fox, David A; Gizinski, Alison; Morgan, Rachel et al. (2010) Cell-cell interactions in rheumatoid arthritis synovium. Rheum Dis Clin North Am 36:311-23
Lundy, Steven K; Fox, David A (2009) Reduced Fas ligand-expressing splenic CD5+ B lymphocytes in severe collagen-induced arthritis. Arthritis Res Ther 11:R128
Lundy, Steven K (2009) Killer B lymphocytes: the evidence and the potential. Inflamm Res 58:345-57
Lundy, Steven K; Sarkar, Sujata; Tesmer, Laura A et al. (2007) Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther 9:202
Tran, Chinh N; Lundy, Steven K; White, Peter T et al. (2007) Molecular interactions between T cells and fibroblast-like synoviocytes: role of membrane tumor necrosis factor-alpha on cytokine-activated T cells. Am J Pathol 171:1588-98