The TNF-like trimers BAFF and APRIL are recently identified molecules essential for B cell development and survival. Levels of BAFF and APRIL are elevated in autoimmune rheumatic diseases including SLE. Blockade of BAFF and APRIL delays the onset of SLE in murine models. We have preliminary observations that short term administration of the soluble BAFF and APRIL antagonist TACI-Ig together with the T cell costimulatory blocker CTLA41g can induce remission of late stage SLE in NZB/W F1 mice. This proposal will explore the mechanism of action of BAFF/APRIL blockade, both alone and in combination with CTLA41g, using soluble BAFF receptor fusion proteins that block BAFF or both BAFF and APRIL. The studies in Aim 1 will focus on how BAFF/APRIL blockade influences the effector B cells that mediate the inflammatory and non-inflammatory manifestations of SLE. The studies described in Aim 2A will focus on the effect of BAFF/APRIL blockade on the selection of autoreactive B cell subsets and on the autoreactive immunoglobulin gene repertoire. This will allow us to determine whether the decreased B cell survival that results from BAFF/APRIL blockade is linked to alterations in B cell selection. The studies described in Aim 2B will help us determine the immunosuppressive potential of the various forms of BAFF/APRIL blockade by analyzing primary and recall B cell responses to T independent and T dependent antigens. Finally, we have a unique opportunity, through collaboration with Human Genome Sciences, to study the mechanism of action of BAFF blockade in the first clinical trial of a BAFF blocker in human SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049938-05
Application #
7618273
Study Section
Special Emphasis Panel (ZRG1-IMM-G (03))
Program Officer
Mancini, Marie
Project Start
2005-06-16
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$412,899
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Davidson, Anne (2012) The rationale for BAFF inhibition in systemic lupus erythematosus. Curr Rheumatol Rep 14:295-302
Huang, Weiqing; Moisini, Ioana; Bethunaickan, Ramalingam et al. (2011) BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus. J Immunol 187:6571-80
Liu, Zheng; Bethunaickan, Ramalingam; Huang, Weiqing et al. (2011) Interferon-? accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis Rheum 63:219-29
Bethunaickan, Ramalingam; Berthier, Celine C; Ramanujam, Meera et al. (2011) A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis. J Immunol 186:4994-5003
Liu, Zheng; Zou, Yongrui; Davidson, Anne (2011) Plasma cells in systemic lupus erythematosus: the long and short of it all. Eur J Immunol 41:588-91
Liu, Zheng; Davidson, Anne (2011) BAFF and selection of autoreactive B cells. Trends Immunol 32:388-94
Liu, Zheng; Davidson, Anne (2011) BAFF inhibition: a new class of drugs for the treatment of autoimmunity. Exp Cell Res 317:1270-7
Davidson, Anne; Aranow, Cynthia (2010) Lupus nephritis: lessons from murine models. Nat Rev Rheumatol 6:13-20
Ramanujam, Meera; Bethunaickan, Ramalingam; Huang, Weiqing et al. (2010) Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum 62:1457-68
Jacobi, Annett M; Huang, Weiqing; Wang, Tao et al. (2010) Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum 62:201-10

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