Evaluation of the ameliorative effects of immunosuppressants on crescentic glomerulonephritis in SCG/Kj mice
Introduction
Primary systemic vasculitides of small vessels including Wegener's granulomatosis (WG), microscopic polyangiitis and Churg–Strauss syndrome are characterized by rapidly progressive glomerulonephritis (RPGN) and also the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in a highly frequency [1]. Renal glomeruli in patients with these diseases often show crescent and/or granulomatous lesions. In the early 1970s, these vasculitides, which are potentially life-threatening, were reduced to chronic disorders by introducing a treatment regimen based on cyclophosphamide (CYC) combined with corticosteroids, and this treatment regimen has been the standard [2]. The application of CYC, however, causes hemorrhagic cystitis and increases the risk of secondary cancer, gonadotoxicity and severe infection [3].
An immunosuppressive agent, deoxyspergualin (DSG) [4] has been used in rescuing rejection crisis in renal transplant patients in Japan [5]. DSG is an analogue of spergualin [6] isolated from culture filtrate of Bacillus laterosporus, and bears a moiety of spermidine and a guanidinic group. DSG has been found to suppress humoral and cell-mediated immune responses [7], [8], [9], [10], [11], [12], [13]. Although the mechanism behind the DSG-mediated immunosuppression is still not unraveled, it is known that DSG binds to a member of the heat shock protein 70 family and may inhibit the translocation of nuclear factor NF-κB and the expression of MHC class II antigens [14], [15], [16], [17]. DSG has the ability to induce apoptosis in growing cells due to a modification of mitochondrial respiratory function and the down-regulation of Akt kinase and p70 S6 kinase [18], [19], [20]. Regarding patients with RPGN, in 1999, DSG was first administered to four patients with proliferative GN having crescents and thereafter the proteinuria in these patients improved [21]. In 2003, Birck et al. reported that DSG was also effective and well-tolerated in 20 patients with refractory Wegener's granulomatosis uncontrolled by prior treatment with CYC and other immunosuppressive drugs [22]. These findings may provide new insight into the treatment of RPGN, but there are still few therapeutic trials of DSG in these diseases.
In the present study, we evaluated the “ameliorative”, not prophylactic, effects of DSG, in comparison with those of CYC and prednisolone (PDN), on renal disorders in SCG/Kj mice [23]. Females of this strain spontaneously develop crescentic glomerulonephritis (CGN) and systemic vasculitis of small vessels, which was genetically segregated from (BXSB × MRL/lpr) F1 mice of brother × sister matings coupled with the repeated histopathological selection for the breeding of mice whose parents had severe CGN. Moreover, ANCA were detected in almost all of the mice [24]. These mice showed hematuria and proteinuria associated with the formation of crescents in glomeruli at onset, followed by a rapid deterioration of the renal function, resembling RPGN [23], [25]. We herein present the evidence that DSG can efficiently induce a remission of CGN in SCG/Kj mice when administered at the onset of hematuria.
Section snippets
Animals
Female SCG/Kj mice aged 6 to 12 weeks were used in the present study. SCG/Kj mice were bred, maintained under specific pathogen-free conditions, and had free access to food and water during this study in the laboratory of Nippon Kayaku Co., Ltd. This study was conducted according to the principles enunciated in The Guide for the Care and Use of Laboratory Animals prepared b the Laboratory Animal Committee in the Pharmaceuticals Group, Nippon Kayaku Co., Ltd.
Immunosuppressive agents
DSG (Spanidin® for injection; Nippon
Survival time
Survival time was 39% of control, 67% of 3 mg/kg of DSG, 74% of 6 mg/kg of DSG, 70% of CYC and 51% of PDN, respectively (Fig. 2). There was a significant increase in survival times in the SCG/Kj mice given DSG at 6 mg/kg and CYC, compared with the control group. Treatment with DSG at 3 mg/kg slightly (p = 0.063) prolonged survival, and PDN failed to prolong life span.
Urinalysis
At the end of the study, the percentage of SCG/Kj mice with grade ++++ severe proteinuria was 88% of control, 50% of DSG at
Discussion
A hallmark of SCG/Kj mice is extensive extraglomerular proliferation and hemorrhage in Bowman's space (Fig. 1). In a previous study of serial urinalysis and renal biopsies with SCG/Kj mice, it was found that proteinuria initially appeared, followed by hematuria at which time the mice developed prominent crescents in glomeruli [25]. In their histopathological study, neutrophils accumulated into glomeruli in the early stage of glomerular lesions of SKG mice, but not in the late phase, in which
References (31)
- et al.
Deoxyspergualin, a novel immunosuppressant, markedly inhibits human mixed lymphocyte reaction and cytotoxic T-lymphocyte activity in vitro
Int J Immunopharmacol
(1992) - et al.
Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis
Am J Kidney Dis
(1999) - et al.
SCG/Kinjoh mice: a model of ANCA-associated crescentic glomerulonephritis with immune deposits
Kidney Int
(2003) - et al.
In vivo administration of 15-deoxyspergulin inhibits antigen-presenting cell stimulation of T cells and NF-kappaB activation
Int Immunopharmacol
(2002) - et al.
Savage COS. ANCA-positive vasculitis
J Am Soc Nephrol
(2002) - et al.
A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies
N Engl J Med
(2003) - et al.
Wegener's granulomatosis: an analysis of 158 patients
Ann Intern Med
(1992) - et al.
Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety
J Antibiot
(1985) - et al.
A novel rescue drug, 15-deoxyspergualin. First clinical trials for recurrent graft rejection in renal recipients
Transplantation
(1990) - et al.
A new antitumor antibiotics, spergualin: isolation and antitumor activity
J Antibiot
(1981)
Immunosuppressive activities of 15-deoxyspergualin in animals
J Antibiot
In vitro immunosuppressive properties of spergualins to murine T cell response
J Antibiot
Mechanism of action of 15-deoxyspergualin. I. Suppressive effect on the induction of alloreactive secondary cytotoxic T lymphocytes in vivo and in vitro
Immunology
Deoxyspergualin in lethal murine graft-versus-host disease
Transplantion
The suppressive effect of deoxyspergualin on the differentiation of human B lymphocytes maturing into immunoglobulin-producing cells
Transplantation
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