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The Journal of Immunology, 2001, 167: 2452-2455.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Amelioration of Kidney Disease in a Transgenic Mouse Model of Lupus Nephritis by Administration of the Caspase Inhibitor Carbobenzoxy-Valyl-Alanyl-Aspartyl-({beta}-o-methyl)-Fluoromethylketone1

John P. Seery*,{dagger}, Victoria Cattell{ddagger} and Fiona M. Watt2,*

* Keratinocyte Laboratory, Imperial Cancer Research Fund, London, United Kingdom; {dagger} Department of Medicine and Therapeutics, University College Dublin, Dublin, Ireland; and {ddagger} Department of Histopathology, Imperial College of Science, Technology, and Medicine, London, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is a common, potentially fatal, non-organ-specific autoimmune disorder. Immune complex-mediated kidney disease is the major cause of mortality. Apoptotic cells in the epidermis are a possible source of self Ags, and apoptosis of endothelial cells and lymphocytes is thought to contribute to end-organ damage. We have previously shown that female transgenic mice expressing IFN-{gamma} in the epidermis develop inflammatory skin disease and features of SLE that have striking parallels with the human condition. We have now tested the effects of a pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-({beta}-o-methyl)-fluoromethylketone, on disease progression. Daily s.c. administration of carbobenzoxy-valyl-alanyl-aspartyl-({beta}-o-methyl)-fluoromethylketone to female transgenic mice over a 3-wk period resulted in significant amelioration of both glomerular and interstitial renal damage, independent of the effects on autoantibody levels or skin inflammation. We propose that apoptosis inhibitors could be beneficial in the treatment of human SLE.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE)3 is characterized by the production of autoantibodies against components of the cell nucleus (antinuclear Abs, ANA) (1). A subset of ANA reactive with dsDNA (anti-dsDNA) is nephritogenic, depositing in the glomeruli and triggering a locally destructive inflammatory reaction (2). The resultant renal damage is the major cause of death in the syndrome (2). There is evidence that the ANA of SLE arise via a classical T cell-dependent immune response with nucleoprotein complexes released during apoptosis acting as self autoantigen (3). The agent (or agents) triggering this autoimmune response remain to be identified.

We have previously shown that transgenic mice expressing IFN-{gamma} in the suprabasal layers of the epidermis, under the control of the involucrin promoter, develop a lupus-like syndrome (4). As in the naturally occurring human disease, the production of pathogenic IgG ANA in this model is largely restricted to females, is T cell dependent, and is tightly correlated with the development of a proliferative glomerulonephritis (5). In addition, there is circumstantial evidence that apoptotic keratinocytes act as the source of self nuclear Ag triggering ANA production (5). IFN-{gamma} transgenics seem, therefore, to be an excellent model in which to study the effects of pharmacological apoptosis inhibition.

Carbobenzoxy-valyl-alanyl-aspartyl-({beta}-o-methyl)-fluoromethylketone (ZVAD-fmk) is a pan-caspase inhibitor that irreversibly inhibits enzymatic function and is effective in blocking apoptosis in a variety of cell types in vitro and in vivo (6, 7, 8). We have studied the effects of ZVAD-fmk administration on the lupus phenotype in IFN-{gamma}-transgenic mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

Thirty-seven female IFN-{gamma}-transgenic mice (CBA x C57/BL10 F1s) from three different founder lines (9) were assigned to receive either ZVAD-fmk (n = 19) or saline (n = 18) by daily s.c. injection for 21 days. Thirty-four animals completed the study. All animals were 6 mo of age or older at the start of the experiment (the mean age of the treatment group was 8 mo, and the mean age of the control group was 7 mo; Table IGo) and produced significant levels of IgG anti-dsDNA Abs on ELISA (OD >0.1 at a 1/100 dilution; Table IGo). Starting serum levels of anti-dsDNA Abs were comparable in the treatment and saline control groups, with mean OD on IgG anti-dsDNA ELISA of 0.360 and 0.320, respectively (Table IGo).


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  		Table I. Summary of mice that completed the study

 
The treatment group received 10 mg/kg ZVAD-fmk (Enzyme Systems Products, Livermore, CA) per day dissolved in 0.15 M saline containing 2% DMSO (8). Before use, the compound was dissolved in 100% DMSO and diluted to 1 mg/ml in 0.15 M saline. Therefore, treated animals were injected s.c. with 10 µl per gram of body weight (typically 200–300 µl/mouse). Control animals were injected with the corresponding volume of saline-DMSO diluent.

Anti-dsDNA and histone ELISA

Blood was taken from all animals for estimation of anti-dsDNA and anti-histone levels 1 wk before the onset of treatment and on days 2, 9, 16, and 21 after the start of the trial. The levels of IgG anti-dsDNA and anti-histone Abs in serum were measured as described previously (4, 5).

TUNEL staining

TUNEL staining of paraffin sections of skin was conducted as described previously (5), and sections were counterstained with propidium iodide. Sections from 15 saline-treated controls (18–20, 22–27, and 29–34 in Table IGo) and 15 ZVAD-fmk-treated animals (1–7 and 9–17 in Table IGo) were analyzed by a single observer (J. P. Seery) blinded to the treatment status of the animals. Only TUNEL-positive cells in the interfollicular epidermis that showed definite evidence of nuclear fragmentation were counted. The length of the epidermis on each section was measured, and the number of apoptotic cells per centimeter of epidermis was calculated (in total, 24.3 cm for saline-treated controls and 20.9 cm for ZVAD-fmk-treated animals).

Histological assessment of renal disease

Kidneys were fixed in formalin and were paraffin embedded, then sections were stained with H&E. The severity of renal disease in the treated and control groups was assessed as follows. The cellularity of the glomeruli was graded (0, +, ++, +++, and ++++) by an experienced renal histopathologist (V. Cattell) blinded to the treatment status of the animals. A score of 0 or + was seen in nontransgenic littermate controls and was therefore considered normal. Additional histological features of renal damage including interstitial infiltrates and glomerular sclerosis and necrosis were recorded. Immune deposits were evaluated in frozen sections of kidneys, essentially as described previously (4), using anti-mouse IgG conjugated with Alexa 488.

Statistics

The incidence of interstitial renal disease in ZVAD-fmk-treated and saline-treated animals was compared using the {chi}2 test. The degree of glomerular cellularity and percentage changes in anti-dsDNA levels in the two groups were compared using the unpaired Student t test.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 17 of the 19 IFN-{gamma}-transgenic mice assigned to receive ZVAD-fmk and 17 of the 18 assigned to receive saline injections completed the study (Table IGo). None of the ZVAD-fmk-treated animals showed an adverse response to the drug.

ZVAD-fmk treatment had no effect on the macroscopic skin disease of the animals. After treatment, the mice still had persistent skin erythema, hair hypopigmentation, and histological evidence of dermal inflammation (Fig. 1Go, A, C, and E; Ref. 9 ; and data not shown). However, the number of TUNEL-positive cells in the interfollicular epidermis and underlying dermis was lower in the ZVAD-fmk-treated animals than in saline-treated controls (1.20 vs 1.73 per centimeter of interfollicular epidermis, respectively; average of 15 animals/group; compare Fig. 1Go, B and D). One mouse was treated with ZVAD-fmk for 3 wk and was sacrificed 4 days after the final treatment; that animal had large numbers of apoptotic cells in the skin (>3 cells per centimeter of interfollicular epidermis), demonstrating that the suppressive effect of the drug was dependent on continuous application (compare Fig. 1Go, B and F). The reduction in the number of TUNEL-positive cells in the skin of ZVAD-fmk-treated mice provided evidence that the amount of drug given to the animals and frequency of application were sufficient to have an inhibitory effect on apoptosis.



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  		FIGURE 1. Effect of ZVAD-fmk on dorsal skin histology and TUNEL labeling. A, C, and E, H&E-stained sections; B, D, and F, TUNEL labeling (green) of sections counterstained with propidium iodide (red). A and B, A mouse treated with ZVAD-fmk for 3 wk before sacrifice; C and D, a control mouse treated for 3 wk with diluent alone; E and F, a mouse treated with ZVAD-fmk for 3 wk and sacrificed 4 days after the final dose. Scale bars, 50 µm (A, C, and E) and 180 µm (B, D, and F).

 
The levels of anti-dsDNA produced by individual IFN-{gamma}-transgenic mice showed a high degree of variability (Table IGo). Over the 3-wk course of treatment, average anti-dsDNA levels fell by 24% of starting value in ZVAD-fmk-treated animals, compared with a 2% fall in saline-treated controls. This difference approached, but did not reach, statistical significance (p < 0.1). Four transgenic animals showed a rapid and sustained fall in anti-dsDNA levels after starting ZVAD-fmk treatment (animals 4, 13, 15, and 16 in Table IGo; see also Fig. 2Go) to levels comparable to nontransgenic controls (the background OD in nontransgenic mice was 0.00–0.05; Ref. 4). These four animals did not produce anti-histone IgG before or after treatment (data not shown). The fall to background levels was only seen in transgenic animals producing relatively low levels of anti-dsDNA (mean pretreatment, OD 0.16; range, 0.103–0.272). Although some of the saline-treated animals showed a reduction in anti-dsDNA titer, the OD never fell below 0.1 (Table IGo).



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  		FIGURE 2. IgG anti-dsDNA levels in four animals treated daily with ZVAD-fmk for 21 days (see Table IGo for details of each animal).

 
The effect of ZVAD-fmk on autoantibody levels was not predictable. Five treated animals (3, 7, 10, 11, and 12 in Table IGo) showed sustained reciprocal changes in anti-dsDNA and anti-histone levels. One showed a fall in anti-histone accompanied by a rise in anti-dsDNA (Fig. 3GoA), and the other four showed a fall in anti-dsDNA with a rise in anti-histone (Fig. 3GoB and data not shown).



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  		FIGURE 3. Reciprocal changes in anti-dsDNA and anti-histone titers during the course of treatment with ZVAD-fmk. A, Mouse no. 12; B, mouse no. 7 (see Table IGo).

 
ZVAD-fmk-treated IFN-{gamma}-transgenic animals demonstrated a marked reduction in the severity of renal disease compared with saline-treated controls (Table IGo and Fig. 4Go). This was true for both glomerular and interstitial disease. The mean glomerular cellularity score was 1.5 in ZVAD-fmk-treated animals compared with 2.2 in the saline-treated mice (p < 0.05) (see Table IGo and compare Fig. 4Go, B and D). Interstitial infiltrates were demonstrated in 2 of 17 ZVAD-fmk-treated animals compared with 8 of 17 saline-treated controls (p < 0.03) (Table IGo). There is no increase in serum creatinine levels in this mouse model (133 ± 5.7 nmol/ml in 12-mo-old mice from founder line 1212 compared with 128 ± 5.2 nmol/ml in littermate controls; V. Cattell, unpublished observations).



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  		FIGURE 4. Kidney histology. A–D, H&E-stained sections of untreated wild-type littermate (A) and transgenic mice (B–D), untreated (B, no. 18) or treated with ZVAD-fmk for 3 wk (C and D). C, Mouse no. 3, glomerular cellularity ++++ with interstitial disease and glomerular sclerosis. D, Mouse no. 9 with no detectable kidney pathology. E and F, Direct immunofluorescence of glomeruli showing immune deposits in kidneys of control (E, no. 18)- and ZVAD-fmk-treated (F, no. 17) mice. Scale bar, 260 µm.

 
Although none of the four animals who normalized anti-dsDNA levels on treatment showed evidence of histological renal disease (Table IGo), the absence of severe kidney damage in ZVAD-fmk-treated animals could not be explained solely on the basis of changes in autoantibody levels. Some transgenic animals had no evidence of renal disease at the time of sacrifice despite persistently high levels of IgG anti-dsDNA (Table IGo, nos. 9, 12, 8, 4, 10, and 17). Of these, mouse no. 9 is a particularly striking example, because it had an OD of 0.778 after ZVAD-fmk treatment and an anti-dsDNA level invariably associated with severe kidney disease in untreated animals (4, 5), yet it had no detectable kidney disease (compare Fig. 4Go, A and D).

The kidneys of six ZVAD-fmk-treated and six saline-treated control animals were examined for glomerular deposition of autoantibodies. As reported previously (4), both capillary (Fig. 4GoE) and mesangial deposits were found in the control mice. In the ZVAD-fmk-treated mice, only mesangial deposits were observed (Fig. 4GoF), but the sample size was too small to conclude whether there had been any reduction in IgG deposition. However, it was clear that drug treatment did not abolish immune complex deposition.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Treatment with ZVAD-fmk resulted in a significant reduction in the severity of both glomerular and interstitial renal disease in the IFN-{gamma} model of SLE. This finding is of interest because the severity of renal disease is the primary determinant of prognosis in the human condition (2).

TUNEL labeling was reduced in the skin of treated transgenic mice, indicating that the ZVAD-fmk regimen was indeed inhibiting apoptosis. The residual apoptosis observed could be occurring via a caspase-independent mechanism involving PML (10). ZVAD-fmk did not prevent an anuclear stratum corneum from forming in the epidermis, in contrast to the reported effects of caspase inhibitors on keratinocytes in culture (11). The epidermal hyperproliferation and inflammation characteristic of IFN-{gamma}-transgenic animals was not affected by ZVAD-fmk, reinforcing our earlier conclusions that these aspects of the skin phenotype are independent of the kidney phenotype (4, 5).

SLE is characterized by an ill-defined dysregulation of apoptosis (12). Macromolecular complexes released during apoptosis are found in elevated levels in the serum of patients with the disease; circulating nucleosomes may trigger ANA production, and nucleosome-IgG antinucleosome complexes bind to the glomerular basement membrane (13). Subsequent in situ formation of immune complexes with anti-dsDNA results in complement activation, triggering a destructive inflammatory infiltration (13). Apoptosis plays a key role in linking glomerular injury to interstitial damage. Fas/Fas ligand (FasL)-mediated endothelial cell apoptosis in the peritubular capillaries is an early event in this process (14), and subsequent Fas-dependent apoptosis in the renal tubular epithelium may lead to tubular atrophy and progressive loss of renal function (15).

Consistent with our observations, inhibition of the Fas/FasL pathway by administration of anti-FasL Abs prevents renal disease from developing in the NZB/W F1 murine lupus model (16). In contrast, stimulation of the Fas receptor by anti-Fas mAb reduces autoantibody titers and prevents glomerulonephritis in MRL/gld mice (17). MRL mice are characterized by a genetic defect in the Fas/FasL system with consequent inhibition of immunocyte apoptosis (18), and thus it is not surprising that improvement in the lupus phenotype occurs when apoptosis is promoted. The relevance of such an effect to human disease is open to question, because the rate of immunocyte apoptosis is, if anything, increased in patients with SLE (12), and human subjects with loss of function mutations in the Fas/FasL system in general do not develop lupus (19).

ZVAD-fmk may be acting both systemically and locally to reduce renal damage in IFN-{gamma}-transgenic mice. By decreasing the overall level of apoptosis in these animals, as evidenced by reduced TUNEL staining of the skin, the agent may reduce the rate of nucleosome deposition in the glomeruli. This could result in attenuation of glomerular damage (20), even in the presence of high anti-dsDNA levels (e.g., mouse no. 9 in Table IGo) and IgG deposits in the glomeruli (Fig. 4Go, E and F).

We have previously argued that apoptotic keratinocytes provide the source of self-nuclear Ags driving ANA production in IFN-{gamma}-transgenic animals (5). Although anti-dsDNA levels normalized in four ZVAD-fmk-treated animals, it is unlikely that removing the source of Ag would switch off a mature T cell-mediated immune response within a matter of days, and indeed the autoantibody titers in other mice suggest more complex changes. The reciprocal relationship between anti-histone and anti-dsDNA levels in individual transgenics (Ref. 4 and Fig. 3Go) raises the possibility of an idiotypic/antiidiotypic relationship (21) that might be altered by ZVAD-fmk.

Apoptosis is a normal physiological process, and administration of caspase inhibitors in the long term could result in significant side effects. For this reason, experimental trials have tended to focus on acute conditions under which use of these agents is limited to a well-defined period (7, 8). SLE characteristically runs a relapsing/remitting course with acute exacerbations of both systemic and renal disease (2). Therefore, intensive treatment is pulsatile in the majority of patients, often requiring highly toxic drugs of limited efficacy (2). We propose that intermittent treatment with apoptosis inhibitors might find a role in such regimens.


   Acknowledgments
 
We thank the Imperial Cancer Research Fund Histopathology Unit, Biological Resources Unit, and Transgenic Facility for excellent technical assistance.


   Footnotes
 
1 This work was supported by the Imperial Cancer Research Fund, Bristol-Myers Squibb, and a European Union Biomed Network. Back

2 Address correspondence and reprint requests to Dr. Fiona M. Watt, Keratinocyte Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, WC2A 3PX, London, U.K. E-mail address: watt{at}icrf.icnet.uk Back

3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ANA, antinuclear Ab; ZVAD-fmk, carbobenzoxy-valyl-alanyl-aspartyl-({beta}-o-methyl)-fluoromethylketone; FasL, Fas ligand. Back

Received for publication April 27, 2001. Accepted for publication July 9, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kotzin, B. L.. 1996. Systemic lupus erythematosus. Cell 85:303.[Medline]
  2. Berden, J. H.. 1997. Lupus nephritis. Kidney Int. 52:538.[Medline]
  3. Radic, M. Z., M. Weigert. 1994. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu. Rev. Immunol. 12:487.[Medline]
  4. Seery, J. P., J. M. Carroll, V. Cattell, F. M. Watt. 1997. Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon {gamma} in the epidermis. J. Exp. Med. 186:1451.[Abstract/Free Full Text]
  5. Seery, J. P., E. C. Wang, V. Cattell, J. M. Carroll, M. J. Owen, F. M. Watt. 1999. A central role for {alpha}{beta} T cells in the pathogenesis of murine lupus. J. Immunol. 162:7241.[Abstract/Free Full Text]
  6. Slee, E. A., H. Zhu, S. C. Chow, M. MacFarlane, D. W. Nicholson, G. M. Cohen. 1996. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem. J. 315:21.
  7. Kunstle, G., M. Leist, S. Uhlig, L. Revesz, R. Feifel, A. MacKenzie, A. Wendel. 1997. ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-{alpha}. Immunol. Lett. 55:5.[Medline]
  8. Braun, J. S., R. Novak, K. H. Herzog, S. M. Bodner, J. L. Cleveland, E. I. Tuomanen. 1999. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5:298.[Medline]
  9. Carroll, J. M., T. Crompton, J. P. Seery, F. M. Watt. 1997. Transgenic mice expressing IFN-{gamma} in the epidermis have eczema, hair hypopigmentation and hair loss. J. Invest. Dermatol. 108:412.[Medline]
  10. Quignon, F., F. De Bels, M. Koken, J. Feunteun, J. C. Ameisen, H. de Thé. 1998. PML induces a novel caspase-independent death process. Nat. Genet. 20:259.[Medline]
  11. Weil, M., M. C. Raff, V. M. Braga. 1999. Caspase activation in the terminal differentiation of human epidermal keratinocytes. Curr. Biol. 9:361.[Medline]
  12. Emlen, W., J. Niebur, R. Kadera. 1994. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J. Immunol. 152:3685.[Abstract]
  13. Berden, J. H., R. Licht, M. C. van Bruggen, W. J. Tax. 1999. Role of nucleosomes for induction and glomerular binding of autoantibodies in lupus nephritis. Curr. Opin. Nephrol. Hypertens. 8:299.[Medline]
  14. Ohashi, R., H. Kitamura, N. Yamanaka. 2000. Peritubular capillary injury during the progression of experimental glomerulonephritis in rats. J. Am. Soc. Nephrol. 11:47.[Abstract/Free Full Text]
  15. Schelling, J. R., R. P. Cleveland. 1999. Involvement of Fas-dependent apoptosis in renal tubular epithelial cell depletion in chronic renal failure. Kidney Int. 56:1313.[Medline]
  16. Nakajima, A., H. Hirai, N. Kayagaki, S. Yoshino, S. Hirose, H. Yagata, K. Okumura. 2000. Treatment of lupus in NZB/W F1 mice with monoclonal antibody against Fas ligand. J. Autoimmun. 14:151.[Medline]
  17. Nishimura-Morita, Y., M. Nose, T. Inoue, S. Yonehara. 1997. Amelioration of systemic autoimmune disease by stimulation of apoptosis-promoting receptor Fas with anti-Fas mAb. Int. Immunol. 9:1793.[Abstract/Free Full Text]
  18. Takahashi, T., M. Tanaka, C. I. Brannan, N. A. Jenkins, N. G. Copeland, T. Suda, S. Nagata. 1994. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969.[Medline]
  19. Vaishnaw, A. K., E. Toubi, S. Ohsako, J. Drappa, S. Buys, J. Estrada, A. Sitarz, L. Zemel, J. L. Chu, K. B. Elkon. 1999. The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations. Arth. Rheum. 42:1833.[Medline]
  20. van Bruggen, M. C., B. Walgreen, T. P. Rijke, M. J. Corsius, K. J. Assmann, R. J. Smeenk, G. W. van Dedem, K. Kramers, J. H. Berden. 1996. Heparin and heparinoids prevent the binding of immune complexes containing nucleosomal antigens to the GBM and delay nephritis in MRL/lpr mice. Kidney Int. 50:1555.[Medline]
  21. Zhang, W., M. Reichlin. 1996. Some autoantibodies to Ro/SS-A and La/SS-B are antiidiotypes to anti-double-stranded DNA. Arthritis Rheum. 39:522.[Medline]



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