Elsevier

Journal of Autoimmunity

Volume 39, Issue 3, September 2012, Pages 130-142
Journal of Autoimmunity

Review
Role of TWEAK in lupus nephritis: A bench-to-bedside review

https://doi.org/10.1016/j.jaut.2012.05.003Get rights and content

Abstract

There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK – namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis – are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients.

Highlights

► TWEAK (TNFSF12) can contribute to several mechanisms important in lupus nephritis. ► TWEAK promotes inflammation, cell activation/proliferation/apoptosis, and fibrosis. ► Inhibiting TWEAK signaling is beneficial in multiple animal models of nephritis. ► Kidney expression of TWEAK and Fn14 is increased in human lupus nephritis. ► Anti-TWEAK therapy is being developed as a novel approach in human lupus nephritis.

Introduction

Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematous (SLE), and a major cause of morbidity and mortality. Up to 50% of unselected adult patients with SLE have signs of renal involvement early in the course of their disease, and up to 60% of adults may eventually develop overt kidney disease [1], [2]. The clinical course of LN varies from mild subclinical disease to an aggressive course that may progress to end-stage renal disease (ESRD).

The introduction of currently available therapies for LN including the use of broadly immunosuppressive therapies, namely glucocorticoids, cyclophosphamide, azathioprine and mycophenolate mofetil (MMF), has improved outcomes of the disease. However, response to therapy is slow and incomplete, with less than 10% of patients achieving complete remission by 6 months and around 60% by 3 years [3]. Complete normalization of renal function cannot always be achieved, in particular when renal scarring has already occurred despite therapeutic intervention. Also, the majority of subjects experience a relapse within 5 years despite continued immunosuppressive therapy [4]. Furthermore, although the survival rates for patients with LN treated with the currently available immunosuppressive agents has improved to 88% at 10 years, around 10–20% of these individuals will develop ESRD [5].

Patients with active LN who do achieve a complete renal response after induction therapy have excellent overall and renal survival compared with those patients with no renal response [6], [7]. Achieving partial renal response has also been demonstrated to have a beneficial effect on patient and renal survival compared to non-responders. A study of 86 subjects with diffuse proliferative LN showed after 10 years of follow up that patient survival was 95% for patients achieving complete remission, 76% for patients achieving partial remission and 46% for non-remission subjects, and that renal survival (as defined by lack of development of ESRD) was 94% for patients achieving complete remission, 45% for patients achieving a partial remission and 13% for non-remission [8]. Therefore, the treatment of LN should aim to increase the number of patients with a complete response, as well as to reduce the number of non-responders by converting them into partial or complete responders.

Several clinical trials conducted over the last 10 years assessing induction therapy for LN [9], [10], [11] have demonstrated improved safety and tolerability of newer therapeutic protocols, but failed to show a substantial improvement in renal response rates compared to established regimens of high dose cyclophosphamide and corticosteroids. In addition, the number of patients achieving a complete renal response within a short time frame remains relatively small. Importantly, current treatments for LN and some of the therapies investigated in clinical trials are broadly immunosuppressive and do not target specific pathways responsible for the development of renal disease. Moreover, these regimens are associated with poor treatment adherence, and may result in significant side effects and, occasionally, death [12], [13], [14]. It is therefore reasonable to speculate that we may have reached the ceiling of therapeutic response using broadly immunosuppressive agents in LN, and that a therapy that is more targeted to impact the pathogenic processes driving the progression of ESRD may enable achievement of greater renal response.

The pathogenesis of LN is complex, involving autoantibody deposition in the glomerulus, activation of complement and macrophages, cell proliferation, production of extracellular matrix proteins, proinflammatory cytokines, chemokines and MMPs, which then link through multiple mechanisms to tubular damage, tubulointerstitial inflammation and fibrosis [15], [16]. In order to improve patient outcome, targeted therapies for LN should ideally impact the common pathological features of LN that are responsible for progression of ESRD including glomerulosclerosis and tubulointerstitial fibrosis [17], [18], [19]. The development of more specific therapeutic approaches should result in increased efficacy, without paying the price in safety, tolerability, and side effects.

The cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the TNF superfamily that is prominently featured in normal and pathological remodeling of tissues. TWEAK, expressed primarily as a soluble cytokine by infiltrating leukocytes, mediates multiple activities through its receptor FGF-inducible molecule 14 (Fn14, TNFRSF12) which is upregulated locally on epithelial and mesenchymal cell types in injured and diseased target tissues including the kidney. TWEAK is involved in proinflammatory responses, vascular activation and angiogenesis, cell growth, cell death, fibrogenic responses, and progenitor responses.

In this paper, we will review the evidence supporting a role for the TWEAK/Fn14 pathway in driving the development and progression of LN, including the elevated expression of both TWEAK and Fn14 locally in the kidneys in human LN, and the ability of TWEAK acting through Fn14 on various kidney-resident cell types to promote many of the key pathogenic processes underlying LN. In addition, data from multiple animal models of LN and kidney injury in which TWEAK/Fn14 pathway deficiency or pathway blockade by anti-TWEAK monoclonal antibodies (mAbs) has proven efficacious will be presented. Finally, the relevance of TWEAK-driven mechanisms of pathogenesis will be related to human LN. Taken together, targeting the TWEAK/Fn14 pathway may represent an attractive therapeutic option to increase renal response and achieve remission in a greater number of patients due to its tissue protective effect, without an anticipated increase in toxicity and patient morbidity.

Section snippets

Introduction to the TWEAK/Fn14 pathway

TWEAK was cloned and identified as a member of the TNF superfamily in 1997 [20]. Since then, the basic biology of this pathway has been largely elucidated, and considerable evidence has been gathered linking the TWEAK pathway to a variety of inflammatory and autoimmune diseases. In particular, there is a growing appreciation for the pathological role of this pathway in affected tissues in disease, such as the kidney in LN.

A type II transmembrane receptor, TWEAK can be cleaved to generate a

Pathological mechanisms of TWEAK in LN

The function of TWEAK, as described above, in promoting an inflammatory response, renal cell proliferation and apoptosis, vascular changes, and fibrosis, together with an increasing appreciation for the locally elevated levels of TWEAK in LN patients, suggests that TWEAK may play an active role in the kidney in the context of LN.

Multiple experimental models have been employed to assess the potential contribution of the TWEAK/Fn14 pathway to LN. These include several models in which renal injury

Relevance of TWEAK mechanisms to human LN

In the previous sections, we discussed how modulation of the TWEAK/Fn14 pathway in the context of animal models of lupus and kidney injury can ameliorate renal disease parameters and kidney histopathology via multiple processes underlying this pathology. In this section, we will describe our current understanding of the relevance of these same disease parameters to human LN, with a specific focus on renal function indicators, fibrosis and other histopathological findings, and inflammatory

Opportunity for targeting the TWEAK pathway in the clinic

BIIB023 is a monoclonal antibody against TWEAK in clinical development for the treatment of lupus nephritis. To date, BIIB023 has completed a phase I double-blind, placebo-controlled, single-dose study in subjects with RA [145]. BIIB023 treatment was well tolerated across all dose groups in this study. No dose-dependent safety finding was observed in any of the dose groups. In addition, there was no increase in infection rate associated with the use of BIIB023 in this study.

Although this was

Conclusion

Renal involvement remains a challenge for clinicians as current standard of care therapies do not result in an adequate renal response for LN patients. Available therapies are largely immunosuppressive and do not typically target the complex pathologic mechanisms underlying LN or key features of disease, namely glomerulosclerosis and tubulointerstitial fibrosis. The TWEAK/Fn14 axis represents a novel pathway which has been mechanistically linked to multiple pathological processes occurring

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