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NDT Advance Access originally published online on December 29, 2005
Nephrology Dialysis Transplantation 2006 21(3):579-581; doi:10.1093/ndt/gfi282
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Immune therapy of lupus: what is on the horizon?

Sandra V. Navarra

Section of Rheumatology, Clinical Immunology and Osteoporosis, University of Santo Tomas, Manila, Philippines

Correspondence and offprint requests to: Sandra V. Navarra, Section of Rheumatology, Clinical Immunology and Osteoporosis, University of Santo Tomas, Manila, The Philippines. Email: snavarra{at}pacific.net.ph

Keywords: lupus nephritis; immunotherapy; anti-cytokine; treatment; monoclonal antibodies

Systemic lupus erythematosus (SLE) is a complex disease which has posed a continuing challenge to scientists and clinicians of diverse areas of specialization. It serves as a model for the study of the mechanisms of autoimmunity—providing an important basis for the development of novel targeted therapies in lupus and related conditions.

The pathophysiology of SLE stems from the abnormal clearance of apoptotic cells and/or endothelial activation. Material from dying cells such as apoptotic blebs that are not efficiently removed may act as antigenic stimuli and lead to the development of autoantibodies with consequent formation of immune complexes and an inflammatory response in a variety of organ systems [1]. This inflammatory response and resultant tissue injury is characterized and perpetuated by a disruption in the normal homeostasis of a variety of cellular factors ranging from cytokines to co-stimulatory and regulatory molecules, which have provided potential targets for therapeutic intervention [2].



   Anti-cytokines
Top
 Anti-cytokines
Targeting B cells
 Inhibiting co-stimulation
 Conclusion
 References
 
Cytokines are low molecular weight mediators of cell–cell interactions, with a wide heterogeneity of pro- and anti-inflammatory effects. Though far from complete, there is a significant body of information on the role of cytokines in lupus nephritis, increasing possibilities for anti-cytokine therapies [3]. Among the pro-inflammatory cytokines, tumour necrosis factor (TNF), which can be induced by immune complexes and antibodies to double-stranded DNA (dsDNA), has been found to be overexpressed in SLE, including lupus nephritis [4–6]. Although the place of anti-TNF blockade is less clear for SLE than for rheumatoid arthritis and related arthritides, an open-label study has shown that targeting TNF may reduce tissue damage in SLE [7].

TNF can further induce the expression of other pro-inflammatory cytokines including interleukin (IL)-18, which is overexpressed in the nephritic kidneys of MRL/lpr mice [8] and is an important inducer of the prototypical Th1 cytokine interferon-{gamma} (IFN-{gamma}). IFN-{gamma} is overexpressed in mononuclear cells of lupus kidneys and may correlate with disease activity [9,10]. Efforts are ongoing to determine the best way to inhibit the IFN-{gamma} pathway.

SLE is considered a predominantly Th-2-driven disease with documented elevations in serum IL-4, -6 and -10. IL-6 is a potent pro-inflammatory cytokine with a wide range of functions including terminal differentiation of B lymphocytes into antibody-forming cells and T cells to effector cells. IL-6 blockade inhibits the onset of autoimmune kidney disease and ameliorates disease activity in murine models of SLE [11]. An open label phase I study of a humanized monoclonal antibody against IL-6 receptor is currently underway to address its safety and efficacy in patients with moderately active SLE [12].

Alterations in IL-10 regulation may result in accelerated T-cell apoptosis and aberrant T-cell-dependent B-cell function [13]. The results of a pilot study of six patients with active SLE treated with anti-IL-10 monoclonal antibody (mAb) were promising, showing marked reduction in circulating IL-10 levels and corresponding clinical improvement which was sustained over the next 6 months [14].



   Targeting B cells
Top
 Anti-cytokines
 Targeting B cells
Inhibiting co-stimulation
 Conclusion
 References
 
B cells have been largely implicated in the pathogenesis of SLE not only as sources of autoantibody, but also as antigen-presenting cells, as well as initiators and regulators of inflammation through cytokine secretion [15–17]. Thus, targeting B cells has recently emerged as a promising therapeutic approach in SLE. Administration of rituximab, a mAb directed against the pan-B cell surface marker CD20, has shown encouraging results in SLE with major systemic involvement including nephritis [18–22]. Although not a cure, significant improvements lasting >3 years have been observed [23]. Recently, an open-label pilot study of anti-CD22 (epratuzumab) in the treatment of active SLE showed some B cell depletion but no consistent changes in autoantibody levels [24].

LJP-394 (abetimus sodium) leads to B cell tolerance by cross-linking anti-dsDNA antibodies on the surface of B cells resulting in anergy or apoptosis [25]. Preliminary studies suggest that LJP-394 may be a useful adjunct to standard therapy in SLE [26,27], though its use as induction or maintenance therapy in patients with major organ system involvement needs to be defined further.

The cytokine BLyS (B lymphocyte stimulator) or BAFF (B cell-activating factor), a member of the TNF family, has profound effects on B cell survival and stimulates plasma cell proliferation. Mice that constitutively overexpress BLyS develop autoantibodies and glomerulonephritis. The administration of soluble inhibitor of BLyS function (TACI-Ig) to NZB/W F1 mice reduced B cell numbers, anti-DNA antibody levels and proteinuria, and prolonged survival [28]. Patients with SLE have further been shown to have elevated serum BAFF levels which positively correlate with autoantibody levels [29]. A phase I trial using Lympho-Stat-B, a human mAb that neutralizes BAFF, in mild to moderate SLE has demonstrated significant reductions in peripheral blood B cells, but no change in anti-dsDNA or disease activity [30]. Phase II trials are underway, as well as the development of alternative approaches to BLyS/BAFF inhibition.



   Inhibiting co-stimulation
Top
 Anti-cytokines
 Targeting B cells
 Inhibiting co-stimulation
Conclusion
 References
 
Co-stimulatory molecules provide the necessary second signal for T-cell activation by antigen-presenting cells [31]. One of these is CD40, which is present on B cells, endothelial cells and antigen-presenting cells. It interacts with CD40 ligand (CD40L) that is upregulated on activated T-helper cells, resulting in proliferation and differentiation of B cells. Lupus-prone mice with established nephritis treated with anti-CD40L antibodies had reduced anti-DNA antibody, less renal disease and increased survival [32]. Unfortunately, anti-CD40L mAb (IDEC-131) did not prove to be clinically effective in human SLE [33], and another trial was halted because of life-threatening prothrombotic events despite improvement in serology and haematuria [34].

Another potential co-stimulatory target in patients with SLE is CTLA-4 (cytotoxic T-lymphocyte antigen-4), which inhibits T-cell activation by binding to B7 expressed on antigen-presenting cells, thus preventing the co-stimulatory signal brought about by CD28–B7 interaction. Abatacept (CTLA-4Ig) is a soluble receptor or fusion protein encoded by fusion of CTLA-4 with the Fc portion of IgG1. This has been shown to block CD28–B7 interaction and subsequent T-cell-dependent B cell function [35]. Preliminary data in mice demonstrated improvement in lupus nephritis with CTLA-4Ig [36]. Following encouraging results in rheumatoid arthritis [37], a phaseI/II study is currently underway in SLE patients.



   Conclusion
Top
 Anti-cytokines
 Targeting B cells
 Inhibiting co-stimulation
 Conclusion
References
 
Advances in our understanding of the immunopathogenesis of SLE have resulted in the development of novel immune therapies which are expected to revolutionize the management of lupus in the next decade. These targeted therapies, including those directed to molecules such as signalling pathways, specifically interfere with various processes in the immunopathogenesis of lupus, and may provide a better safety profile over the traditional immunosuppressive agents.

Conflict of interest statement. None declared.



   References
Top
 Anti-cytokines
 Targeting B cells
 Inhibiting co-stimulation
 Conclusion
 References
 

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