B Cell Development

B lymphocytes produce antibodies and present antigens. They are essential components of the immune response. Failure to regulate the growth, development, and response of B cells can lead to malignancy, immunodeficiency and autoimmunity. Our research efforts are directed towards a better understanding of the process of B cell commitment and the events that allow progression along the B cell pathway. Cellular, biochemical, and molecular techniques are utilized to achieve our research aims.

Understanding biochemical and cellular checkpoints during lymphoid development.
We have developed a number of in vitro assays over the years that allow for the careful examination of the stages of B lineage development from multipotent stem cells to fully functional, antibody secreting, plasma cells. We have identified a number of key features and mechanisms of action that mark transitions between stages and defined checkpoints that can result in positive and negative selection. Amongst our current interest are: The role of the peptide, HK1 (a member of the tackykinin family) in regulating early events in the B lineage pool; a potential mechanism for abrogating IL7 responsiveness based on downstream induction of SOCS proteins; and a novel role for IL21 in accelerating B cell development. Out interest in these projects is driven not only by the desire to understand the role of these molecules in normal development but also because the aberrant regulation of any of these can have direct consequences in immune regulated disease.

Immune System and Disease.
Increased understanding of the immune response and, in particular, the biochemical pathways that regulate immunity provide the basis for renewed efforts to develop cancer vaccines. We have developed a syngeneic cell-based anti-leukemia murine model focused on the expression of IL-12 derived from LV transductions. In that work we showed that syngeneic leukemia cells expressing IL-12 can induce protective, long-lasting, and specific immunity. Of interest for clinical application, we also demonstrated that as few as 0.5% of the leukemia cells have to express IL-12 to achieve immunity, as long as each cell produces IL-12 above a certain threshold. Once initiated, the immune response it is effective against all of the leukemia cells, including those that do not express IL-12. Using in vivo and in vitro culture systems we are determining the cells required both to initiate immunity and target and kill leukemia cells. This work is being extended to solid tumours as well. In addition, these techniques are now being modified using primary human leukemia cell blasts from AML, ALL, CML, and CLL in experiments which form the basis for subsequent human clinical trials.

Graduate Student(s):

• Megan Nelles

Postdoctoral Fellows

• Alexandra Berger
• Vincenzo Salerno

Selected References:

• Simard, N., Konforte, D., Tran, A.H., Esufali, J., Leonard, W.J., and  Paige, C.J. 2011. Analysis of the role of IL-21 in development of murine B cell progenitors in the bone marrow.  J. Immunol. In press

• Berger, A., P. Benveniste, S.A. Corfe, A.H. Tran, M. Barbara, A. Wakeham, T.W. Mak, N.N. Iscove, C.J. Paige.  2010.  Targeted deletion of the tachykinin 4 gene (TAC4-/-) influences the early stages of B lymphocyte development.  Blood 116(19)3792-801).

• Tran, A.H, A. Berger, G.E. Wu, B.L.Kee, C.J. Paige.  2010.    Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes.  J. Neuroimmunol. Oct. 20, 2010 [Epub]

• Berger, A., A.H. Tran, H. Dedier, M.A. Gardam, C.J. Paige.  2009.  Antimicrobial properties of hemokinin-1 against strains of Pseudomonas aeruginosa.  Life Sci. 85(19-20):700-3.

• Konforte. D., C.J. Paige.  2009.  Interleukin-21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein-Barr Virus infected B cells.  Virus Res. 144(1-2):339-43.

• Bello, A.M., D. Konforte, E. Poduch, C. Furlonger, L. Wei, Y. Liu, M. Lewis, E.F. Pai, C.J. Paige, L.P. Kotra. 2009. Structure-activity relationships of orotidine-5’-monophosphate decarboxylase inhibitors as anticancer agents. J. Med. Chem. 52(6):1648-58.

• Konforte, D., N. Simard, C.J. Paige.  2009.  IL-21: an executor of B cell fate.  J. Immunol.  182(4):1781-7.

• Tran, A.H., A. Berger, G.E. Wu, C.J. Paige.  2009.  Regulatory mechanisms in the differential expression of Hemokinin-1.  Neuropeptides.  43(1):1-12.

• Labbe, A., M. Nelles, j. Walia, L. Jia, C. Furlonger, T. Nonaka, J.A. Medin, C.J. Paige.  2008.  IL-12 Immunotherapy of murine leukemia: comparison of systemic versus gene modified cell therapy.  J. Cell Mol. Med.    Aug;13(8B):1962-76

• Janzen, V., H.E. Fleming, T. Riedt, G. Karlsson, M.J. Riese, C. Lo Celso, G. Reynolds, C.D. Milne, C.J. Paige, S. Karlsson, M. Woo, D.T. Scadden.  2008.  Hematopoietic stem cell responsiveness to exogenous signals is limited by caspase-3.  Cell Stem Cell. 2(6):585-94.
  Milne C.D., S.A. Corfe, and C.J. Paige  2008.  Heparan sulfate and heparin enhance ERK phosphorylation and mediate preBCR-dependent events during B lymphopoiesis.   J Immunol. 180 (5):2839-47.

• Konforte, D., N. Simard and C.J. Paige 2008.  Interleukin-21 regulates expression of key Epstein-Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells.  Virology. 374(1):100-13.

• Deng, S., D.J. Moore, X. Huang, M.M. Lian, M. Mohiuddin, E. Veledeoglu, M.K. Lee 4th, S, Sonawane, J. Kim, J. Wang, H. Chen, S.A. Corfe, C. Paige, M. Shlomchik, A. Caton, J.F. Markmann.  2007.  Cutting edge:  transplant tolerance induced by anti-CD45RB requires B Lymphocytes.  J. Immunol.  178(10):6028-32.

• Berger, A., A.H. Tran and C.J. Paige 2007.  Co-regulated decrease of Neurokinin-1 receptor and Hemokinin-1 gene expression in monocytes and macrophages after activation with pro-inflammatory cytokines.  J. Neuroimmunol. 187(1-2):83-93.

• Corfe, S., A.P. Gray, and C.J. Paige. 2007 Generation and characterization of Stromal cell independent IL-17 dependent cell lines. J. Immunol. Methods 325:9-19

• Konforte, D. and C.J. Paige.  2006.  Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells.  J. Immunol. 177(12)8381-92.

• Labbe, A., A. Tran and C.J. Paige 2006.  Murine model of immune-mediated rejection of the acute lymphoblastic leukemia 70Z/3.  J. Immunol.  176(9):5354-61.  

• Milne C.D. and C.J. Paige 2006.  Il-7:  a key regulator of B lymphopoiesis.  Semin. Immunol.  18(1):20-30