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Decoy Receptor 3 Ameliorates an Autoimmune Crescentic Glomerulonephritis Model in Mice

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Decoy Receptor 3 Ameliorates an Autoimmune Crescentic Glomerulonephritis Model in Mice JASN Express. Published on August 8, 2007 as doi: 10.1681/ASN.2006111242 BASIC RESEARCH www.jasn.org Decoy Receptor 3 Ameliorates an Autoimmune Crescentic Glomerulonephritis Model in Mice ʈ Shuk-Man Ka,* Huey-Kang Sytwu,†‡ Deh-Ming Chang,§ Shie-Liang Hsieh, Pei-Yi Tsai,† and Ann Chen* *Department of Pathology, §Division of Rheumatology/Immunology & Allergy, Department of Medicine, Tri-Service General Hospital, †Graduate Institute of Medical Sciences, ‡Department of Microbiology and Immunology, National ʈ Defense Medical Center, and Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, Republic of China ABSTRACT Autoimmune crescentic glomerulonephritis (ACGN) is a variant of crescentic glomerulonephritis. The outcome of treatment of crescentic glomerulonephritis is poor. Binding of decoy receptor 3 (DCR3) to its ligand is capable of downregulating the alloresponsiveness of T cells. DCR3 has also been shown to benefit an experimental autoimmune model of diabetes. This study tested the hypothesis that a potential immune regulator, DCR3, could prevent the evolution of ACGN. With the use of an established ACGN model in mice, mice were treated with 100 ␮g/10 g body wt human DCR3 by hydrodynamics- based gene delivery at 14-d intervals. The results showed that the gene therapy resulted in (1) suppression of T and B cell activation and T cell proliferation; (2) a reduction in serum levels of proinflammatory cytokines; (3) improvement of proteinuria and renal dysfunction; (4) prevention of glomerular crescent formation, renal interstitial inflammation, and glomerulosclerosis; (5) a reduction in serum levels of autoantibodies and glomerular immune deposits; (6) inhibition of apoptosis in the spleen and kidney; (7) prevention of T cell and macrophage infiltration of the kidney; and (8) suppression of fibrosis-related gene expression in the kidney compared with empty vector–treated (disease control) ACGN mice. On the basis of these findings, it is proposed that human DCR3 exerts its preventive and protective effects on ACGN through modulation of T cell activation/proliferation, B cell activation, protection against apoptosis, and suppression of mononuclear leukocyte infiltration in the kidney. J Am Soc Nephrol 18: 2473–2485, 2007. doi: 10.1681/ASN.2006111242 Systemic lupus erythematosus (SLE) is a typical au- (ACGN) is an extremely progressive form of lupus toimmune disease involving multiple organs. Al- nephritis and is classified as a type of crescentic though its cause is not entirely clear, the basic ab- glomerulonephritis11,12 in which widespread normality seems to be a failure of mechanisms that glomerular crescents, consisting of a mixture of maintain self-tolerance, resulting in the production parietal epithelial cells, monocytes/macrophages, of diverse autoantibodies, especially antinuclear an- tibodies,1 T cell abnormalities,2,3 and apoptosis.4–6 In patients and mouse models, pathogenic T cells Received November 15, 2006. Accepted May 24, 2007. recognize self-antigens and drive B cell hyperactiv- Published online ahead of print. Publication date available at ity, confirming their central role in the pathogenesis www.jasn.org. 3,7–9 of SLE. Lupus nephritis is a major renal injury Correspondence: Dr. Ann Chen, Department of Pathology, Tri- in SLE and is characterized by immune complex Service General Hospital, National Defense Medical Center, No. deposition in the glomerular and renal tubular and 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC, Phone: ϩ886-2-8792-7008; Fax: ϩ886-2-8792-7009; E-mail: doc31717@ 10 peritubular capillary basement membranes. Clin- ndmctsgh.edu.tw ically, autoimmune crescentic glomerulonephritis Copyright © 2007 by the American Society of Nephrology J Am Soc Nephrol 18: 2473–2485, 2007 ISSN : 1046-6673/1809-2473 2473 BASIC RESEARCH www.jasn.org and lymphocytes, are formed.13,14 We have shown that a ner and significantly reduces the severity of insulitis in an au- murine chronic graft-versus-host disease, induced in toimmune diabetes model. In addition, in vivo administration C57BL/6 ϫ DBA/2J F1 hybrid mice by giving DBA/2J donor of hDCR3 ameliorates allograft rejection.17 The effects of lymphocytes, can progress to ACGN, with extensive, char- hDCR3 on immune regulation should be explored for its pos- acteristic glomerular crescent formation (up to 80% of glo- sible therapeutic use in controlling undesirable immune re- meruli examined), sclerosis, and intense interstitial inflam- sponses. Clinically, DCR3 gene expression has been detected in mation.15 Although recovery of renal functions in patients peripheral blood mononuclear leukocytes derived from pa- with crescentic glomerulonephritis can occur after early in- tients with SLE,24 although its clinical significance remains to tensive plasma exchange and/or treatment with steroids and be determined. cytotoxic agents, patients eventually require long-term di- In this study, we tested the hypothesis that in vivo over- alysis or transplantation.11 expression of hDCR3 would prevent crescentic formation of Decoy receptor 3 (DCR3) lacks the transmembrane do- an experimental ACGN. Using hydrodynamics-based gene main of the conventional TNF receptor and is a secreted delivery, we demonstrated that hDCR3 gene therapy is an protein.16,17 DCR3 can interact with Fas ligand (FasL),16 effective therapeutic approach in the ACGN model. Regu- LIGHT (homologous to lymphotoxins, shows inducible ex- lation of both T cell function and apoptosis in lymphoid pression and competes with HSV glycoprotein D for herpes organs and in the kidney seems to be the major factor re- virus entry mediator, a receptor expressed by T lympho- sponsible for its favorable effects in this autoimmune kid- cytes),18 and TNF-like molecule 1A.19 Binding of DCR3 to ney disease model. LIGHT also downregulates the alloresponsiveness of T cells.17,20 By helping tumor cells avoid immune attack through lymphocyte infiltration and FasL/LIGHT-medi- RESULTS ated apoptosis, increased DCR3 expression might benefit their growth.16,18 DCR3 exerts another regulatory function Serum Levels of hDCR3 Protein in Treated ACGN by directly modulating the differentiation and function of Mice macrophages and dendritic cells.21,22 Based on the hDCR3 expression (Figure 1, methods as de- Recently, Sung et al.23 reported that transgenic human scribed in Concise Methods), we delivered the hDCR3 plasmid DCR3 (hDCR3) protects mice from autoimmune and cyclo- to the mice at 14-d intervals. After administrations of hDCR3 phosphamide-induced diabetes in a dosage-dependent man- plasmid or empty vector, ELISA tests showed high serum levels Figure 1. Serum levels and hepatic expression of human decoy receptor 3 (hDCR3) protein. (A) Serum hDCR3 levels in normal control mice after a single injection of hDCR3 plasmid or empty vector measured by ELISA. Data are means Ϯ SEM for groups of Figure 2. Serum levels of hDCR3 in treated autoimmune crescen- 10 mice. The arrow indicates the time of gene delivery with tic glomerulonephritis (ACGN) mice. Serum levels at week 3 (A) hDCR3 or empty vector. (B) hDCR3 protein expression in the liver and week 9 (B) in ACGN mice after administration of hDCR3 or of normal control mice on day 2 after a single injection of hDCR3 empty vector. Data are means Ϯ SEM for groups of 10 mice. #Not plasmid or empty vector. Magnification, ϫ400. detectable. 2474 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 2473–2485, 2007 www.jasn.org BASIC RESEARCH of hDCR3 protein in the hDCR3-treated ACGN mice at 3 wk empty vector–treated ACGN mice at 3 wk (Figure 3, A and C) (Figure 2A) and 9 wk (Figure 2B), respectively, after ACGN or 9 wk (Figure 3, B and D) after ACGN induction, compared induction but not in the empty vector–treated ACGN mice or with normal control mice (both P Ͻ 0.005). However, this normal control mice. effect was significantly suppressed by administration of hDCR3 plasmid to ACGN mice compared with empty vec- DCR3 Suppresses T/B Cell Activities tor–treated ACGN mice (P Ͻ 0.05 at 3 wk; P Ͻ 0.005 at 9 Inhibition of T/B Cell Activation. wk). Moreover, hDCR3-treated ACGN mice showed a sig- ϩ ϩ Abnormal T and B cell cooperation can cause a graft-versus- nificantly lower percentage of CD4 CD69 cells (activated host reaction,9,25 the basic mechanism for the induction of the T helper cells) than that of empty vector–treated ACGN ACGN model. DCR3 has been reported to inhibit T cell pro- mice at week 3 (4.0 32 Ϯ 1.0 versus 8.1 Ϯ 1.5%; P Ͻ 0.05) and liferation and lymphokine secretion.17,19,21 We tested whether week 9 (9.5 Ϯ 0.5 versus 18.2 Ϯ 2.9%; P Ͻ 0.05), respec- ϩ ϩ hDCR3 could ameliorate the development of the ACGN model tively. Conversely, the percentage of CD19 CD69 cells by negatively regulating T cell and/or B cell activation by per- (activated B cells) was significantly decreased in hDCR3- forming flow cytometry of splenocytes. treated ACGN mice to the levels seen in normal control As shown in Figure 3, the percentage of CD3ϩCD69ϩ cells mice at week 9 (P Ͻ 0.005; Figure 3, B and D), although (activated T cells) in the spleen was significantly increased in there was no significant difference in the percentage of ϩ Figure 3. Flow cytometry for T and B cells in the spleen. Immunofluorescence dot-plot pattern of the CD69 activation marker on CD3 ϩ ϩ ϩ ϩ ϩ T cells or CD19 B cells. (A and C) Week 3. (B and D) Week 9. (C and D) Percentage of CD3 CD69 T cells and CD19 CD69 . Each bar represents the means Ϯ SEM for groups of 10 mice. *P Ͻ 0.05; ***P Ͻ 0.005; NS, no significant difference. J Am Soc Nephrol 18: 2473–2485, 2007 Decoy Receptor 3 Ameliorates Lupus Nephritis 2475 BASIC RESEARCH www.jasn.org CD19ϩCD69ϩ cells between empty vector–treated ACGN and hDCR3-treated ACGN mice (Figure 3, A and C) at week 3 compared with empty vector–treated ACGN mice.
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