| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
*
Medicine and
Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
Short-term combination therapy with the costimulatory antagonists CTLA4Ig and anti-CD40 ligand induces prolonged suppression of disease onset in New Zealand Black/New Zealand White F1 systemic lupus erythematosus-prone mice. To determine the mechanism for this effect, 20- to 22-wk-old New Zealand Black/New Zealand White F1 mice were treated with six doses each of CTLA4Ig and anti-CD40 ligand Ab over 2 wk. Combination-treated mice, but not mice treated with either agent alone, had prolonged survival and the production of pathogenic IgG anti-dsDNA Ab was suppressed. Twenty weeks after completion of treatment the frequency of activated B cells producing anti-dsDNA Ab was decreased, and the abnormal transition of T cells from the naive to the memory compartment was blocked. Combination treatment partially suppressed class switching and decreased the frequency of somatic mutations in the VHBW-16 gene, which is expressed by pathogenic anti-DNA Abs. Treated mice were still able to respond to the hapten oxazolone when it was given 8 wk after treatment initiation, and they mounted a somatically mutated IgG anti-oxazolone response that was noncross-reactive with dsDNA. Fifty to 60% of previously treated mice, but only 14% of previously untreated mice, responded within 2–3 wk to a second course of therapy given at the onset of fixed proteinuria and remained well for a further 3–4 mo. Although this treatment had no immediate effect on serum anti-dsDNA Abs or on the abnormal T cell activation observed in sick mice, 25% of treated mice lived for >18 mo compared with 5% of untreated controls. These results suggest that the effect of costimulatory blockade in remission induction must be mediated by a different mechanism than is demonstrated in the disease prevention studies.
This article has been cited by other articles:
|
|
 |
|
  M. M. P. C. Donners, L. Beckers, D. Lievens, I. Munnix, J. Heemskerk, B. J. Janssen, E. Wijnands, J. Cleutjens, A. Zernecke, C. Weber, et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling Blood, May 1, 2008; 111(9): 4596 - 4604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ahuja, J. Shupe, R. Dunn, M. Kashgarian, M. R. Kehry, and M. J. Shlomchik Depletion of B Cells in Murine Lupus: Efficacy and Resistance J. Immunol., September 1, 2007; 179(5): 3351 - 3361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Choudhury, M. A. Maldonado, P. L. Cohen, and R. A. Eisenberg The Role of Host CD4 T Cells in the Pathogenesis of the Chronic Graft-versus-Host Model of Systemic Lupus Erythematosus J. Immunol., June 15, 2005; 174(12): 7600 - 7609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ramanujam, X. Wang, W. Huang, L. Schiffer, C. Grimaldi, A. Akkerman, B. Diamond, M. P. Madaio, and A. Davidson Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus J. Immunol., September 1, 2004; 173(5): 3524 - 3534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Daoussis, A. P. Andonopoulos, and S.-N. C. Liossis Targeting CD40L: a Promising Therapeutic Approach Clin. Vaccine Immunol., July 1, 2004; 11(4): 635 - 641. [Full Text]
|
|
|
|
 |
|
 N. Ardjomand, J. C. McAlister, N. J. Rogers, P. H. Tan, A. J. T. George, and D. F. P. Larkin Modulation of Costimulation by CD28 and CD154 Alters the Kinetics and Cellular Characteristics of Corneal Allograft Rejection Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3899 - 3905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Schiffer, J. Sinha, X. Wang, W. Huang, G. von Gonsdorff, M. Schiffer, M. P. Madaio, and A. Davidson Short Term Administration of Costimulatory Blockade and Cyclophosphamide Induces Remission of Systemic Lupus Erythematosus Nephritis in NZB/W F1 Mice by a Mechanism Downstream of Renal Immune Complex Deposition J. Immunol., July 1, 2003; 171(1): 489 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L E Schiffer, N Hussain, X Wang, W Huang, J Sinha, M Ramanujam, and A Davidson Lowering anti-dsDNA antibodies--what's new? Lupus, December 1, 2002; 11(12): 885 - 894. [Abstract] [PDF]
|
|
|
|
 |
|
 G.-C. Fan and R. R. Singh Vaccination with Minigenes Encoding VH-derived Major Histocompatibility Complex Class I-binding Epitopes Activates Cytotoxic T Cells that Ablate Autoantibody-producing B Cells and Inhibit Lupus J. Exp. Med., September 16, 2002; 196(6): 731 - 741. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
