Modulation of intra-pulmonary TGF-beta expression by mycophenolate mofetil in lupus prone MRL/lpr mice

We investigated the expression profile of inflammatory cytokines in the lung of lupus-prone MRL/lpr mice and evaluated the therapeutic potential of mycophenolate mofetil (MMF) in reducing pulmonary cytokines in active lupus. Eight-week old female MRL/lpr mice (n = 20) were treated with MMF in vehicle by oral gavage. Disease control MRL/lpr mice (n = 30) or normal control MRL mice (n = 20) received vehicle alone. The mice were sacrificed after eight or 12 weeks of treatment. Gene expression and protein synthesis of IL-1beta, MCP-1 and TGF-beta1 in lung tissues were determined. We found an increase in the gene expression of IL-1beta, MCP-1 and TGF-beta1 in lung tissues of untreated MRL/lpr mice compared with MRL mice at either 16 weeks or 20 weeks of age. MMF treatment significantly prolonged the survival of MRL/lpr mice, down-regulated the gene expression of IL-1beta, MCP-1 and TGF-beta1 in lung tissues at the end of eight or 12 weeks of treatment. Protein synthesis of TGF-beta1 was decreased following eight weeks of MMF treatment. We conclude that MMF treatment can reduce the TGF-beta1 gene expression and protein synthesis in lung tissues of lupus-prone mice. Our findings provide experimental data suggesting a beneficial potential of MMF therapy in pulmonary involvement of lupus.     

Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice

OBJECTIVE: To examine whether chemokine antagonists inhibit the initiation and progression of lupus nephritis in MRL/lpr mice. METHODS: NH(2)-terminal-truncated monocyte chemoattractant protein 1 (MCP-1)/CCL2 or thymus and activation-regulated chemokine (TARC)/CCL17 analogs were inserted into the pCXN2 expression vector and transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, established from an MRL/gld mouse. RESULTS: MCP-1 antagonist- or TARC antagonist-transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice ages 7 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease). After 8 weeks, mice bearing the MCP-1 antagonist showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis compared with control mice. This seemed to be due to decreased production of interferon-gamma and interleukin-2 in the kidney. In contrast, there was no significant difference in renal damage between mice bearing TARC antagonist and control mice. CONCLUSION: We established a new system using MRL/N-1 cells that allows long-term observation of the effects of chemokine antagonists on lupus nephritis in MRL/lpr mice. We also showed that the MCP-1 antagonist ameliorated the initiation and progression of lupus nephritis and of renal vasculitis, which might provide a new approach to the treatment of the disease.     

Prevention of autoimmune hearing loss in MRL/lpr mice by bone marrow transplantation

We examined the effects of bone marrow transplantation (BMT) on immune-mediated inner ear diseases in MRL/Mp-lpr/lpr (MRL/lpr) mice, which manifest not only lupus nephritis but also sensorineural hearing loss (SNHL) at the age of 20 weeks. These mice were treated with cyclophosphamide (CY) and irradiation (5 Gy x 2), followed by the transplantation of bones plus bone marrow cells from allogeneic normal C57BL/6 mice at the age of 12 weeks. Hematolymphoid cells were reconstituted with donor-derived cells 3 months after BMT. Thus-treated MRL/lpr mice showed neither lupus nephritis nor SNHL even 24 weeks after BMT. No pathological findings were observed in either glomeruli or cochleae. These findings suggest that BMT can be used to prevent the development of autoimmune SNHL in MRL/lpr mice.     

Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice

OBJECTIVE: To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis. METHODS: MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/lpr mice intraperitoneally with either poly(I-C) (50 or 100 microg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters. RESULTS: In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti-double-stranded DNA (anti-dsDNA) and production of cytokines, including interferon-alpha (IFNalpha), interleukin-12 (IL-12), IL-6, and IFNgamma, in splenocytes were significantly reduced in MyD88-KO MRL/lpr mice. Interestingly, MyD88-KO MRL/lpr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes. CONCLUSION: The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.     

Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is up-regulated and recruits and activates inflammatory cells in human diffuse proliferative lupus nephritis (DPLN) and in nephritis of lupus model MRL/lpr mice. The aim of this study was to examine whether anti-MCP-1 gene therapy inhibits the progression of nephritis in MRL/lpr mice. METHOD: An NH(2)-terminal deletion mutant of the MCP-1 gene, 7ND, was injected into skeletal muscles of MRL/lpr mice with advanced stage nephritis to blockade MCP-1 and its receptor (CCR2) signalling pathway. RESULT: Histological findings of kidneys in treated mice, which received more than four injections of 7ND, showed that protection against renal injury resulted from reduced infiltration of leucocytes. Therefore, this therapy has been shown to prolong the life span of MRL/lpr mice. CONCLUSION: Anti-MCP-1 gene therapy is specifically effective in the localized inflammatory region. The data presented here indicate that this anti-MCP-1 gene therapy may be effective adjunct in the management of DPLN.     

Monocyte chemoattractant protein-1 activates a regional Th1 immunoresponse in nephritis of MRL/lpr mice

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is upregulated and recruits and activates inflammatory cells in nephritis of MRL lpr mice. It has been shown that anti-MCP-1 gene therapy is specifically effective in nephritis, while it was apparent that an imbalance towards Th1 predominance accelerates nephritis in MRL/lpr mice. The aim of this study was to clarify whether blockade of the MCP-1 signal by anti-MCP-1 gene therapy influences the Th1/Th2 balance in MRL/lpr mice. METHOD: An NH2-terminal deletion mutant of the MCP-1 gene (7ND) was injected into the skeletal muscles of MRL/Ipr mice with advanced stage nephritis to suppress MCP-1 and its receptor (CCR2) signaling pathway. We evaluated the local tissue production of cytokines in splenocytes and microdissected infiltrating cells within the glomeruli or interstitium. RESULT: Although the production of cytokines in splenocytes was not influenced by anti-MCP-1 gene therapy, kidney glomeruli IL-12 mRNA production and interstitium-infiltrating cell production of IL-12 and IFN-gamma mRNA were significantly reduced. CONCLUSION: The blockade of MCP-1 gene therapy does not influence helper T cell polarization, but acts directly on the regional Th1 immunoreaction in MRL/lpr mice.     

Increased expression of insulin-like growth factors in progressive glomerulonephritis of the MRL/lpr mouse

Glomerulonephritis is an important complication of systemic lupus erythematosus (SLE). The tissue distribution and exact role of the insulin-like growth factors (IGFs) in the development of lupus nephritis in the MRL/lpr mouse model have not been established. The present study was undertaken to evaluate the changes over time in mRNA and peptide expression of IGF-I and IGFBP-2 in the MRL/lpr mouse. Using in situ hybridization and immunocytochemistry techniques, the expression of IGF-I and IGFBP-2 in MRL/lpr mouse was examined and compared to their congenic normal MRL-++ mouse counterparts from nine to 24 weeks of age. In the MRL-++ and MRL/lpr mouse kidneys, IGF-I and IGFBP-2 mRNA expression was limited to the cortical and medullary collecting ducts, while their immunoreactivity (IR) was localized to the cortical and medullary collecting ducts, loop of Henle, glomeruli and proximal tubules. Over time, and with progression of disease, the MRL/lpr mice displayed a significant increase in IGF-I IR and a modest increase in IGFBP-2 IR within the outer cortical glomeruli, which was associated with a significant increase in glomerulosclerosis and glomerular cell proliferation and with a significant decrease in renal function. In conclusion, this overexpression of IGF-I and IGFBP-2 within the glomeruli of the MRL/lpr mouse kidney supports their potential role in the alterations in renal function and morphology that accompany lupus nephritis.     

Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice

OBJECTIVE: Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration into the renal glomeruli. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. Fractalkine (Fkn)/CX3CL1 and its receptor, CX3CR1, form one such chemokine system. We therefore undertook this study to investigate whether Fkn antagonist inhibits the initiation and progression of lupus nephritis in MRL/lpr mice. METHODS: NH(2)-terminally truncated Fkn/CX3CL1 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice. RESULTS: Fkn analogs truncated by >/=4 amino acid residues from the N-terminus failed to induce chemotaxis and calcium influx by CX3CR1-expressing cells. Of these, the most potent antagonist (Fkn-AT) lacked the 4 N-terminal amino acid residues. Fkn expression in the glomerulus was significantly increased in 12-week-old MRL/lpr mice. Expression was localized predominantly in the glomerular endothelial cells, but was occasionally observed in the mesangial cells and, to a lesser extent, in the interstitial microvasculature. Inoculation of MRL/lpr mice with Fkn-AT before the onset or during the early stages of lupus nephritis significantly reduced glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis compared with control mice. This seemed to be due to a marked reduction in macrophage accumulation. In contrast, Fkn antagonist did not affect pneumonitis, sialadenitis, lymphadenopathy, or splenomegaly. CONCLUSION: We prepared a novel potent Fkn antagonist and demonstrated its ability to delay the initiation and ameliorate the progression of lupus nephritis. This agent may therefore provide a new therapeutic approach to lupus nephritis.     

IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner

BACKGROUND: In murine models of inflammatory bowel disease, colonic inflammation is considered to be caused by an aberrant Th1-type immune response. AIM: To investigate if systemic administration of interleukin (IL)-12 and IL-18 to wild-type BALB/c mice induces liver injury and intestinal inflammation, and if pathological changes are observed, what cytokines are involved. METHODS: Mice (BALB/c-wild-type (wt), MRL-lpr/lpr, BALB/c-interferon gamma knock out (IFN-gamma KO), C57BL/6-inducible nitric oxide synthase (iNOS) KO, and BALB/c tumour necrosis factor alpha (TNF-alpha) KO) were injected intraperitoneally each day with IL-12 (20 ng/g/mouse) and/or IL-18 (200 ng/g/mouse). RESULTS: Administration of IL-12 and IL-18 to BALB/c-wt mice induced prominent intestinal mucosal inflammation and fatty liver, leading to piloerection, bloody diarrhoea, and weight loss. IL-12 and IL-18 induced striking elevations in serum levels of IFN-gamma that caused NO production, although increased NO had no exacerbating effect on mice. Moreover, iNOS KO mice, or MRL lpr/lpr mice lacking functional Fas were equally susceptible to IL-12 and IL-18. Administration of IL-12 and IL-18 did not induce TNF-alpha production in wild-type mice, and the same treatment to TNF-alpha KO mice induced intestinal mucosal inflammation. Furthermore, they had diffuse and dense infiltration of small fat droplets in their hepatocytes associated with an increase in serum levels of liver enzymes. In contrast, the same treatment in IFN-gamma KO BALB/c mice and iNOS KO mice did not induce these changes. CONCLUSIONS: Our study strongly indicates that IL-18 together with IL-12 induces intestinal mucosal inflammation in an IFN-gamma dependent but TNF-alpha, NO, and Fas ligand independent manner, and fatty liver is dependent on IFN-gamma and NO.     

Rapamycin reverses the senescent phenotype and improves immuno-regulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway

We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1×10⁶ of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.     

Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice

OBJECTIVE: To examine whether the platelet-derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans. METHODS: Sixteen-week-old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed. RESULTS: In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor beta messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib-treated mice compared with that in the 10 mg/kg imatinib-treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib-treated mice, in a dose-dependent manner. Serum levels of IgG and anti-double-stranded DNA antibodies were also reduced in the imatinib-treated mice. CONCLUSION: These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.     

Intramolecular T cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151

OBJECTIVE: To analyze spontaneous T cell spreading against determinants of the U1-70K protein in young autoimmune MRL/lpr lupus mice, in comparison with the T cell spreading occurring in normal BALB/c mice immunized with peptide 131-151 of this protein. METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2. RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein. CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.     

JAK/STAT1信号转导途径在MRL/lpr狼疮鼠不同器官中的活化研究

目的探讨Janus蛋白酪氨酸激酶(JAK)/信号转导和转录激活子1(STAT1)信号转导途径在MRL/lpr狼疮鼠肾脏、肺脏、脑等不同器官中的活化和作用。方法实验组是12周龄以上已经发病的MRL/lpr雌性小鼠．对照组是未发病的同龄MRL/lpr雌性小鼠。采用免疫组织化学方法研究肾脏中磷酸化STAT1的组织分布情况。采用Western blot方法研究STAT1磷酸化蛋白表达,采用SYBR greenⅠre- M-time定量聚合酶链反应(PCR)研究SOCS-1 mRNA的表达；并与肺脏、脑相对比。结果MRL/lpr狼疮鼠STAT1磷酸化蛋白在各器官均明显活化。肾脏和肺脏的STAT1磷酸化蛋白活化较脑组织明显；肾脏、肺脏和脑组织的SOCS-1基因的表达均升高．但肾脏的SOCS-1基因表达升高程度低于肺脏和脑组织。结论JAK/STAT1信号转导途径的异常可能参与和促进了系统性红斑狼疮(SLE)各器官病理损害的发生；狼疮肾炎的病理损害还可能与SOCS-1的负反馈调节作用降低有关。     

The influence of silicone implantation on murine lupus in MRL lpr/lpr mice.

OBJECTIVE: The use of silicone breast implants has been implicated in the development of autoimmune connective tissue diseases including systemic lupus erythematosus (SLE). We examined the influence of implanted silicones in MRL lpr/lpr and MRL +/+ mice, to determine whether silicone increases autoimmunity and exacerbates experimental lupus. METHODS: Mice were implanted with either silicone gel or silicone oil (polydimethylsiloxane; PDMS), while saline injected mice were used as controls. Proteinuria levels, palpation of lymphadenopathy, serum autoantibodies, circulating cytokines, and weight change were monitored for 18 weeks, when terminal glomerulonephritis was evaluated by histopathological techniques. Proteins were extracted from the surface of recovered implants, and the composition and immune reactive status of the silicone-binding proteins (SBP) were investigated. RESULTS: No adverse influence of silicone gel or silicone oil on the clinical aspects of lupus was observed. However, anti-DNA antibodies were significantly increased in MRL mice implanted with silicone gel compared to the control animals, and rheumatoid factor titers were modestly increased in implanted MRL lpr/lpr mice. Serum cytokine levels were influenced by silicone implantation in MRL lpr/lpr mice (but not MRL +/+ mice), with interleukin 1 (IL-1) levels increased in gel implanted animals and IL-2 levels elevated in PDMS (silicone oil) implanted mice. Different SBP were detected on implants recovered from MRL lpr/lpr mice compared with MRL +/+ mice, and Western blotting revealed the presence of strong autoantibodies to SBP in sera from MRL lpr/lpr mice, but not MRL +/+ mice. CONCLUSION: These findings suggest that silicone implantation may influence immunological responses during murine lupus, including the provocation or exacerbation of autoantibodies. However, these immune modifications did not appear to influence the clinical variables of this experimental lupus model.     

Exacerbation of antigen-induced arthritis in inducible nitric oxide synthase-deficient mice.

OBJECTIVE: Inhibition of nitric oxide (NO) produced by inducible NO synthase (iNOS) is suggested to be beneficial in experimental arthritis. Although NO is important for the integrity of the microcirculation, the effects of inhibition of iNOS on the synovial microcirculation are not currently known. This study investigated the synovial microcirculation and leukocyte-endothelial cell interactions in iNOS-deficient mice with antigen-induced arthritis (AIA) and compared these findings with disease severity. METHODS: Fourteen homozygous iNOS-/- and 14 iNOS+/+ mice were used. The severity of AIA was assessed by measuring knee joint swelling and by histologic scoring. The number of rolling and adherent leukocytes was quantitatively analyzed in synovial microvessels using intravital microscopy of intraarticular synovial tissue. Nitrite/nitrate concentrations were measured, and the expression of iNOS, E- and P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 (VCAM-1) was assessed by immunohistochemistry. RESULTS: In iNOS+/+ animals with AIA, the plasma concentration of nitrite/nitrate was increased 3-fold and iNOS expression was detected in cells of the joint. Swelling of the knee joint as well as leukocyte infiltration were enhanced in the iNOS-/- arthritic animals compared with iNOS+/+ mice with AIA. AIA-associated leukocyte-endothelial cell interaction in synovial postcapillary venules was more pronounced in iNOS-/-, compared with iNOS+/+, arthritic mice. A strong expression of P-selectin and VCAM-1 was observed in the iNOS-/- arthritic mice only. CONCLUSION: These data suggest that NO production by iNOS in vivo has antiinflammatory effects in experimental arthritis, by mediating a reduction in leukocyte adhesion and infiltration.     

A novel treatment for lupus nephritis: lignan precursor derived from flax

BACKGROUND: Flaxseed has renoprotective effects in animal and human lupus nephritis. We have recently extracted the lignan precursor (secoisolariresinol diglucoside) (SDG) to determine if this more palatable derivative of flaxseed would exert renoprotection similar to the whole flaxseed in the aggressive MRL/lpr lupus mouse model. METHODS: 131 MRL/lpr mice were randomly assigned to saline gavage, 600, 1,200 and 4,800 microg lignan gavage groups. At 7 weeks, 6 animals underwent platelet aggregating factor (PAF) lethal challenge and 40 were studied with urine collection to determine the levels of secoisolariresinol, enterodiol and enterolactone in the gavaged animals. A baseline study of 10 saline gavaged animals took place at 6 weeks. 25 animals in the saline gavage, 600 and 1200 microg lignan groups were studied at 14 and 22 weeks for GFR, spleen lymphocyte S-phase and organ weight studies. RESULTS: Metabolic studies indicated that secoisolariresinol is the major metabolite absorbed and the lowest lignan dose provides a lengthening in survival for the PAF lethal challenge. Body weight, fluid and water intake studies demonstrated that the lignan was well tolerated. Changes in proteinuria, GFR and renal size showed a time- and dose-dependent protection for the lignan precursor. Cervical lymph node size and spleen lymphocyte cells in the S-phase demonstrated modest dose-dependent reductions in the lignan gavaged groups. CONCLUSION: SDG was converted in the gut to secoisolariresinol, which was absorbed and well tolerated by the MRL/lpr mice. Renoprotection was evidenced, in a dose-dependent fashion, by a significant delay in the onset of proteinuria with preservation in GFR and renal size. This study suggests that SDG may have a therapeutic role in lupus nephritis.     

Genome analysis of collagen disease in MRL/lpr mice: polygenic inheritance resulting in the complex pathological manifestations

MRL/MpJ-lpr/lpr (MRL/lpr) mice develop collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sj?gren's syndrome, respectively. In the previous studies, we observed genetic segregation of these complex pathological manifestations throughout the genome recombination with a C57Bl/6-lpr/lpr or a C3H/HeJ-lpr/lpr (C3H/lpr) strain of mice which rarely develops such lesions, indicating that development of collagen disease is dependent on an MRL host genetic background. To clarify the mode of inheritance and the gene loci affecting four types of the lesions in MRL/lpr mice; vasculitis, glomerulonephritis, arthritis and sialoadenitis, a genetic dissection of the lesions was carried out by using MRL/lpr, C3H/lpr, (MRL/lprxC3H/lpr) F1 intercross, and MRL/lprx(MRL/lprxC3H/lpr) F1 backcross mice. Definition of each lesion was performed by histopathology under light microscopy, and genomic DNA of the backcross mice were subjected to association studies by chi-square analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. We observed that gene loci recessively associated with each lesion were mapped on different chromosomal positions. We conclude that each of four types of the lesions in MRL/lpr mice is under the control of different set of genes, suggesting the complex pathological manifestations of collagen disease result from polygenic inheritance.