Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis

Recently, divergent reports on the role of mast cells (MC) in different glomerular diseases have brought our attention to their role in an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Genetically MC-deficient Kit(W)/Kit(W-v) mice, MC-reconstituted Kit(W)/Kit(W-v) mice and Kit+/+ control mice were subjected to anti-GBM GN. Kit(+/+) mice developed moderate proteinuria and glomerular damage following the induction of anti-GBM nephritis. In contrast, proteinuria and glomerular damage were dramatically increased in MC-deficient Kit(W)/Kit(W-v) mice. MC-reconstituted Kit(W)/Kit(W-v) mice showed proteinuria and glomerular damage comparable to Kit+/+ mice. A significant increase in infiltrating T cells and macrophages was detected in MC-deficient Kit(W)/Kit(W-v) mice as compared to Kit+/+ control mice and MC-reconstituted Kit(W)/Kit(W-v) mice. Accordingly, we observed an increase of TGF-beta1 mRNA in kidneys from Kit(W)/Kit(W-v) mice. Interestingly, we did not detect MC in the kidney using either Giemsa staining or RT-real-time PCR, but MC were found in the regional lymph nodes. Finally, mortality of Kit(W)/Kit(W-v) mice was significantly increased after the induction of anti-GBM GN due to uremia. Our report provides the first direct evidence that MC are protective in anti-GBM GN, possibly by modulating the influx of effector T cells and macrophages to inflammatory sites in the kidney.     

Canine necrotizing encephalitis associated with anti-glomerular basement membrane glomerulonephritis

A 2-year-old male West Highland white terrier with a 4-month history of seizures was referred for investigation. Depressed mentation, proprioceptive deficit and decreased menace response were noted at neurological examination. Post-mortem examination of the brain revealed multifocal lesions located principally in the left side of the diencephalon and mesencephalon. The lesions consisted of non-suppurative inflammation and large areas of cavitation. The clinical evaluation and histopathological findings were consistent with a diagnosis of necrotizing meningoencephalitis (NME). Immunofluorescence performed on frozen sections of kidney revealed strong smooth linear labelling of the glomerular basement membrane with anti-IgG serum as well as weaker linear labelling with anti-IgM serum. This histomorphological pattern was consistent with anti-glomerular basement membrane glomerulonephritis. The association of this type of glomerulonephritis with a necrotizing encephalitis would support the hypothesis of an immune-mediated aetiology for NME.     

Endogenous glucocorticoids modulate neutrophil migration and synovial P-selectin but not neutrophil phagocytic or oxidative function in experimental arthritis

Pharmacologic glucocorticoids are powerful inhibitors of the inflammatory response at many levels, including leucocyte trafficking and function. The adhesion molecule P-selectin is a key participant in polymorphonuclear neutrophil (PMN) migration to sites of inflammation. The extent to which endogenous glucocorticoids influence PMN migration and activation is not clear. We used the glucocorticoid receptor antagonist RU486 to examine the effect of endogenous glucocorticoid blockade on PMN migration and function in carrageenan monoarthritis in the rat. Arthritis was induced by intra-articular injection of carrageenan and disease severity measured by PMN count in synovial lavage fluid. Decalcified frozen sections of injected joints were analysed for expression of P-selectin by immunohistochemistry. Adrenal glucocorticoid action was blocked in vivo with RU486 20 mg/kg. PMN phagocytosis and reactive oxygen species synthesis were measured by flow cytometry. Carrageenan injection was associated with severe arthritis (synovial lavage PMN 5.9 ± 0.7 × 10⁶, P < 0.01 versus control) which was dose-dependent. P-selectin was not detected in normal joints but was abundant in joints injected with 500 μg carrageenan. RU486 resulted in exacerbation of carrageenan arthritis (9.7 ± 0.8 × 10⁶, P < 0.05). RU486 also altered the threshold for disease induction, in that most RU486-treated animals were susceptible to arthritis at a dose of carrageenan (2.5 μg) which did not induce arthritis in most control-treated animals (P < 0.05), denoting an altered threshold for arthritis induction. RU486 treatment was associated with increased synovial P-selectin expression. Activation status as measured by PMN phagocytic and oxidative function were not influenced by endogenous glucocorticoid blockade. These findings suggest that endogenous glucocorticoids selectively influence PMN migration to inflamed joints via P-selectin expression, but have no effect on PMN activation status.     

Strain differences and the genetic basis of experimental autoimmune anti-glomerular basement membrane glomerulonephritis

Goodpasture's, or anti-glomerular basement membrane (GBM), disease presents with rapidly progressive glomerulonephritis, caused by autoimmunity to a component of the GBM, the non-collagenous domain of the α3 chain of type IV collagen [α3(IV)NC1]. To investigate the mechanisms of inflammation in glomerulonephritis and to test new approaches to treatment, animal models of glomerulonephritis, termed experimental autoimmune glomerulonephritis (EAG), have been developed in susceptible strains of rats and mice. This review article describes how these models of EAG have been developed over the past three decades, discusses the evidence for the involvement of both humoral and cell-mediated immunity in the induction and pathogenesis of glomerulonephritis in these models and highlights recent, emerging data that have identified potential candidate genes that may control the genetic susceptibility in these different strains of rats and mice. The identification of these susceptibility genes has lead to a better understanding of the genetic basis of this model of anti-GBM disease, which may be relevant to the immunopathogenesis of Goodpasture's disease, and more generally to the progression from autoimmunity to target-organ damage.     

Thrombotic microangiopathy in anti-glomerular basement membrane glomerulonephritis

A review was made of the clinical histories, treatment, and renal histologic features of 12 patients with anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM disease). Two patients had milder histopathologic changes in their kidney biopsy specimens and achieved clinical remission. The other ten patients with severe lesions in their biopsy specimens progressed to renal failure. In addition, vascular lesions of thrombotic microangiopathy were present in six of 12 patients. Six patients had clinical laboratory evidence of microangiopathic hemolytic anemia. There are two important points to be noted from this study. First, the kidney biopsy specimen may be a useful indicator of disease severity and prognosis. Second, clinical laboratory or histologic evidence of thrombotic microangiopathy may occur in 75% of patients with anti-GBM disease.     

Implication of the complement system in the induction of anti-glomerular basement membrane glomerulonephritis in WKY rats

In WKY rats, administration of a small dose of anti-glomerular basement membrane antibody induces severe crescentic glomerulonephritis, which is characterized by infiltration of CD8-positive lymphocytes and monocytes/macrophages into the glomeruli with crescent formation. In this study, the involvement of the complement system was examined in the induction of this model. To deplete complement, cobra venom factor (CVF) was used. By a single injection with CVF at 24 h prior to the induction of this model, plasma C3 level from days 0-2 was less than 10% compared with pre-injection of CVF. Complement was almost depleted in the early phase of this model. No significant differences were observed in proteinuria and the frequency of glomeruli associated with the extracapillary crescentic lesions between the CVF-treated group and the control group. In addition, the number of monocytes/macrophages and CD8-positive lymphocyte infiltration into the glomeruli showed no significant differences between both groups. These results indicate that the possibility of complement system involvement is considered low in the induction of this model.     

Therapeutic effect of sulphated hyaluronic acid,a potential selectin-blocking agent,on experimental progressive mesangial proliferative glomerulonephritis

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 micro g/ml and 100 micro g/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis.     

Local macrophage proliferation in the pathogenesis of glomerular crescent formation in rat anti-glomerular basement membrane (GBM) glomerulonephritis

Glomerular crescent formation is a feature of aggressive forms of glomerulonephritis. The conventional view of crescent formation within Bowman's space involves proliferation of parietal epithelial cells and the recruitment of blood monocytes. However, the potential role of local macrophage proliferation in this process has not been investigated. The current study examines macrophage proliferation within Bowman's space on the basis of expression of the proliferating cell nuclear antigen (PCNA) in a rat model of crescentic glomerulonephritis (accelerated anti-GBM disease). ED1⁺ macrophages accounted for 42% of cells within early cellular crescents, and 38% of these crescent macrophages were proliferating on the basis of PCNA expression. Macrophages became the dominant cell population in advanced cellular and fibrocellular crescents (64–71%), and there was a significant increase in the level of macrophage proliferation, with 62% and 67% of ED1⁺ macrophages expressing the PCNA, respectively. This high level of macrophage proliferation was confirmed by incorporation of bromo-deoxyuridine and the presence of mitotic figures within crescents. Indeed, macrophages accounted for 73% of all proliferating cells within advanced and fibrocellular crescents. Macrophage proliferation within Bowman's space was a local event, as shown by a lack of proliferating monocytes in the circulation, the presence of mitotic figures within crescents and a reciprocal relationship between the numbers of ED1⁺PCNA⁺ cells within Bowman's space compared with that in the capillary tuft during the progression from early to advanced and fibrocellular crescents. In conclusion, this study has changed the conventional view of the pathogenesis of crescent formation in glomerulonephritis with the demonstration of substantial local macrophage proliferation within Bowman's space. It is proposed that local proliferation is a major mechanism of macrophage accumulation within crescents and plays an important role in the progression of epithelial-dominated early cellular crescents to macrophage-dominated advanced and fibrocellular cellular crescents.     

Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice

Several recent studies have demonstrated the central role of Fc receptors (FcR) rather than the complement system in triggering hypersensitivity reactions. We investigated the role of FcR for IgG (FcgammaR) using a murine model of accelerated anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis as a representative of type II hypersensitivity diseases. Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice. Light microscopic findings revealed marked tissue damage in the glomeruli of wild-type C57BL/6 and CD40(+/-) mice. However, no tissue damage except polymorphonuclear cell infiltration was observed in the glomeruli of FcRgamma(-/-) mice. The glomeruli of CD40(-/-) mice were almost normal. Immunohistochemistry revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM antibody. However, depositions of mouse IgG and complement to the glomeruli were not observed in CD40(-/-) mice, and deposition of fibrin was not observed in FcRgamma(-/-) or CD40(-/-) mice. These findings suggest that FcgammaR may initiate anti-GBM antibody-mediated renal disease. We conclude that FcgammaR rather than the complement system is critically involved in the development of type II hypersensitivity diseases.     

Cyclosporin A and anti-glomerular basement membrane antibody glomerulonephritis in rats

In a telescoped model of antiglomerular basement membrane (GBM) antibody induced nephritis, Lewis strain rats were injected in the footpad with rabbit IgG on day 0 and then given a single intravenous injection of rabbit anti-rat GBM antibody on day 5. Proteinuria developed within 24 h and renal histology 7 days later showed a focal or diffuse proliferative glomerulonephritis. In this study rats treated as above were given Cyclosporin A (CyA) 20 mg/kg daily by intraperitoneal injection from day 0 or from day 5. Rats given CyA plus anti-GBM antibody developed extensive glomerular infiltration with polymorphs and glomerular thrombosis, lesions not seen with unmodified anti-GBM nephritis or in rats who received CyA alone. The mechanism by which CyA given prior to or at the onset of immunological insult in this model worsens glomerular injury is unclear.     

Transfer of anti-glomerular basement membrane antibody-induced glomerulonephritis in inbred rats with isologous antibodies from the urine of nephritic rats

Anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM nephritis) was transferred from nephritic rats to normal recipient rats with isologous antibodies obtained from the urine of the nephritic rats. The original actively-immunized anti-GBM nephritis was induced in inbred WKY/NCrj rats by injecting the nephritogenic antigen from bovine renal basement membranes. Excreted urinary antibodies were collected, purified, and then injected into recipient rats of the same strain. Haematuria and proteinuria appeared on day 2 and day 3, respectively; both became heavier and reached a plateau by day 5. Endocapillary hypercellularity of mononuclear cells in glomeruli was the first histological change, which was observed from day 2, and later extracapillary changes such as fibrin deposition, capsular adhesion, and crescent formation were observed. These histological changes were the same as those seen in the actively-immunized nephritis. The results demonstrate that anti-GBM nephritis is clearly induced by autoantibodies. This new passively-immunized model of anti-GBM nephritis makes it possible and easier to analyse further the mechanism of anti-GBM nephritis because only isologous antibodies are used. This study also indicates that the urine of the nephritic rat is a good source of autoantibodies.     

Recurrence of anti-glomerular basement membrane antibody mediated glomerulonephritis in an isograft

A renal isograft was performed without immunosuppression in a patient with Goodpasture's syndrome, whose anti-glomerular basement membrane (GBM) antibody titer by radioimmunoassay had been undetectable for more than 1 year. Within 2 weeks of the transplant hematuria and proteinuria were noted, and 5 months post-transplant renal biopsy showed linear IgG deposits in glomerular basement membrane and the anti-GBM antibody titer rose. Treatment with steroids, azathioprine, and plasmapheresis was instituted. The glomerular filtration rate has remained normal, and the anti-GBM antibody titer fell and has remained undetectable. Follow-up is now more than 3 years. The data suggest that reintroduction of renal tissue stimulated reappearance of anti-GBM antibody.     

Cyclosporin A and anti-glomerular basement membrane antibody glomerulonephritis in rats.

In a telescoped model of antiglomerular basement membrane (GBM) antibody induced nephritis, Lewis strain rats were injected in the footpad with rabbit IgG on day 0 and then given a single intravenous injection of rabbit anti-rat GBM antibody on day 5. Proteinuria developed within 24 h and renal histology 7 days later showed a focal or diffuse proliferative glomerulonephritis. In this study rats treated as above were given Cyclosporin A (CyA) 20 mg/kg daily by intraperitoneal injection from day 0 or from day 5. Rats given CyA plus anti-GBM antibody developed extensive glomerular infiltration with polymorphs and glomerular thrombosis, lesions not seen with unmodified anti-GBM nephritis or in rats who received CyA alone. The mechanism by which CyA given prior to or at the onset of immunological insult in this model worsens glomerular injury is unclear.     

Endogenous glucocorticoids modulate neutrophil function in a murine model of haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is caused by Shiga-toxin-producing Escherichia coli (STEC). Although, Shiga toxin type 2 (Stx2) is responsible for the renal pathogenesis observed in patients, the inflammatory response, including cytokines and polymorphonuclear neutrophils (PMN), plays a key role in the development of HUS. Previously, we demonstrated that Stx2 injection generates an anti-inflammatory reaction characterized by endogenous glucocorticoid (GC) secretion, which attenuates HUS severity in mice. Here, we analysed the effects of Stx2 on the pathogenic function of PMN and the potential role of endogenous GC to limit PMN activation during HUS development in a murine model. For this purpose we assessed the functional activity of isolated PMN after in vivo treatment with Stx2 alone or in simultaneous treatment with Ru486 (GC receptor antagonist). We found that Stx2 increased the generation of reactive oxygen intermediates (ROI) under phobol-myristate-acetate (PMA) stimulation and that the simultaneous treatment with Ru486 strengthened this effect. Conversely, both treatments significantly inhibited in vitro phagocytosis. Furthermore, Stx2 augmented in vitro PMN adhesion to fibrinogen (FGN) and bovine serum albumin (BSA) but not to collagen type I (CTI). Stx2 + Ru486 caused enhanced adhesion to BSA and CTI compared to Stx2. Whereas Stx2 significantly increased migration towards N-formyl-methionyl-leucyl-phenylalanine (fMLP), Stx2 + Ru486 treatment enhanced and accelerated this process. The percentage of apoptotic PMN from Stx2-treated mice was higher compared with controls, but equal to Stx2 + Ru486 treated mice. We conclude that Stx2 activates PMN and that the absence of endogenous GC enhances this activation suggesting that endogenous GC can, at least partially, counteract PMN inflammatory functions.     

Simultaneous anti-glomerular basement membrane and membranous glomerulonephritis: case report and literature review

A 20-year-old male experienced a sore throat, fever, and lumbar pain. Examination revealed haematuria, proteinuria, and transiently impaired renal function. Renal biopsy revealed minor mesangial widening and small cellular crescents in 20% of the glomeruli under the light microscope, whereas immunofluorescence showed bright, linear staining of IgG along the glomerular basement membrane (GBM). Ultrastructural analysis showed minute subepithelial deposits analogous to early membranous glomerulonephritis (MGN). Anti-GBM antibodies were detected in the patient's serum. These findings were suggestive of simultaneous anti-GBM and immune complex glomerulonephritis in a patient with a mild, reversible renal illness.     

Effect of CTLA-4 chimeric protein on rat autoimmune anti-glomerular basement membrane glomerulonephritis

The interaction of the T cell receptor with the antigen/major histocompatibility class II complex is insufficient to induce optimal T cell activation. Co-stimulatory signals, including those provided by CD28/CTLA-4 on T cells and B7 molecules (B7-1, ?2 and ?3) on antigen-presenting cells, are also required. CD28-B7 interactions can be blocked by a soluble human CTLA-4 chimeric protein (CTLA4Ig). We tested the effect of administration of CTLA4Ig on experimental anti-glomerular basement membrane (GBM) autoimmune glomerulonephritis in Wistar-Kyoto rats induced by immunization with bovine GBM. The disease is characterized by development of antibody to the α3 chain of type IV collagen (Goodpasture's antigen), deposition of rat IgG in GBM, infiltration of the kidney by T cells and macrophages, severe crescent formation and renal failure leading to death in 5–6 weeks. Animals injected with human CTLA4Ig from day 0 to day 14 or to day 35 had reduced disease severity. Beneficial effects were observed even when injections were begun after the onset of glomerulonephritis on day 14. However, the rats developed antibody to the human CTLA4Ig, associated with reduction in levels of circulating CTLA4Ig. The results provide evidence for CD28/CTLA-4 signaling in rat autoimmune glomerulonephritis, and suggest that more effective inhibition of B7-dependent T cell activation, such as might be achieved with homologous CTLA4Ig, could be useful in the treatment of autoimmune diseases.     

Lack of endothelial nitric oxide synthase aggravates murine accelerated anti-glomerular basement membrane glomerulonephritis

Nitric oxide (NO) radicals generated by endothelial nitric oxide synthase (eNOS) are involved in the regulation of vascular tone. In addition, NO radicals derived from eNOS inhibit platelet aggregation and leukocyte adhesion to the endothelium and, thus, may have anti-inflammatory effects. To study the role of eNOS in renal inflammation, the development of accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was examined in mice lacking a functional gene for eNOS and compared with wild-type (WT) C57BL/B6j mice. WT C57BL/6j mice (n = 12) and eNOS knockout (-/-) mice (n = 12) were immunized intraperitoneally with sheep IgG (0.2 mg in complete Freund's adjuvant). At day 6.5 after immunization, mice received a single i.v. injection of sheep anti-mouse GBM (1 mg in 200 microl PBS). Mice were sacrificed at day 1 and 10 after induction of the disease. All WT mice survived until day 10, whereas 1 eNOS-/- mouse died and 2 more became moribund, requiring sacrifice. At day 10, eNOS-/- mice had higher levels of blood urea nitrogen than WT mice (P < 0.02), although proteinuria was comparable. Immunofluorescence microscopy documented similar IgG deposition in both WT and eNOS-/- mice, but eNOS-/- mice had more extensive glomerular staining for fibrin at day 10 (P < 0.007). At day 10, light microscopy demonstrated that eNOS-/- mice had more severe glomerular thrombosis (P < 0.003) and influx of neutrophils (P < 0. 006), but similar degrees of overall glomerular endocapillary hypercellularity and crescent formation. In conclusion, accelerated anti-GBM glomerulonephritis is severely aggravated in eNOS-/- mice, especially with respect to glomerular capillary thrombosis and neutrophil infiltration. These results indicate that NO radicals generated by eNOS play a protective role during renal inflammation.     

Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats

Anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats is characterized by glomerular accumulation of CD8(+) T cells and monocytes/macrophages, followed by crescent formation. The mechanism of leukocyte accumulation after antibody binding to GBM is still unclear. To unveil an involvement of Fcgamma receptors (FcgammaR) in leukocytes recruitment we examined the expression of FcgammaR in glomeruli and the effects of the administration of F(ab')(2) fragment of anti-GBM antibody or FcgammaR blocking on the initiation and progression of this model. A gradual increase of FcgammaR mRNA expression in glomeruli during the time course of disease suggested their significance in the development of glomerulonephritis. Glomerular lesions and proteinuria were induced only in rats injected with intact IgG of anti-GBM antibody, but not with the F(ab')(2) fragment. In vivo blocking of FcgammaR by administering heat-aggregated IgG led to the decrease of mRNA expression for all types of FcgammaR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcgammaR2-expressing cells in glomeruli were identified as macrophages, but not CD8(+) T cells. The expression of FcgammaR1 and 3 was significantly decreased, and that of FcgammaR2 became undetectable in CD8(+) T cell-depleted rats. Thus, CD8(+) T cells may stimulate FcgammaR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc-FcgammaR interaction in glomerular recruitment of macrophages and following induction of anti-GBM glomerulonephritis in WKY rats.     

WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease

Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands are medications used to treat hyperlipidaemia and atherosclerosis. Increasing evidence suggests that these agents are immunosuppressive. In the following studies we demonstrate that WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease (AGBMD). C57BL/6 mice were fed 0.05% WY14,643 or control food and immunized with the non-collagenous domain of the alpha3 chain of Type IV collagen [alpha3(IV) NC1] in complete Freund's adjuvant (CFA). WY14,643 reduced proteinuria and greatly improved glomerular and tubulo-interstitial lesions. However, the PPARalpha ligand did not alter the extent of IgG-binding to the GBM. Immunohistochemical studies revealed that the prominent tubulo-interstitial infiltrates in the control-fed mice consisted predominately of F4/80(+) macrophages and WY14,643-feeding decreased significantly the number of renal macrophages. The synthetic PPARalpha ligand also reduced significantly expression of the chemokine, monocyte chemoattractant protein (MCP)-1/CCL2. Sera from mice immunized with AGBMD were also evaluated for antigen-specific IgGs. There was a significant increase in the IgG1 : IgG2c ratio and a decline in the intrarenal and splenocyte interferon (IFN)-gamma mRNA expression in the WY14,643-fed mice, suggesting that the PPARalpha ligand could skew the immune response to a less inflammatory T helper 2-type of response. These studies suggest that PPARalpha ligands may be a novel treatment for inflammatory renal disease.