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 antagonisttransfected 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-␥ 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.
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-weekold 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.
Autoantibody production and lymphadenopathy are common features of systemic autoimmune disease. Targeted or spontaneous mutations in the mouse germline have generated many autoimmune models with these features. Importantly, the models have provided evidence for the gene function in prevention of autoimmunity, suggesting an indispensable role for the gene in normal immune response and homeostasis. We describe here pathological and genetic characterizations of a new mutant strain of mice, the mutation of which spontaneously occurred in the Fas-deficient strain, MRL/Mp.Faslpr (MRL/lpr). MRL/lpr is known to stably exhibit systemic lupus erythematosus-like diseases. However, the mutant mice barely displayed autoimmune phenotypes, though the original defect in Fas expression was unchanged. Linkage analysis using (mutant MRL/lpr × C3H/lpr)F2 mice demonstrated a nucleotide insertion that caused loss of expression of small adaptor protein, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). SAP is known to be a downstream molecule of SLAM family receptors and to mediate the activation signal for tyrosine kinase Fyn. Recent studies have shown pleiotropic roles of SAP in T, B, and NK cell activations and NKT cell development. The present study will provide evidence for an essential role for SAP in the development of autoimmune diseases, autoantibodies, and lymphadenopathy in MRL/lpr lupus mice.
Chronic pancreatitis is characterized by the presence of an inflammatory infiltrate and progressive destruction of acinar cells and their replacement by fibrous tissue. The dominant feature of the inflammation is infiltration of CD4 + and CD8 + lymphocytes and macrophages [1]. Up-regulation of major histocompatibility complex (MHC) class I and aberrant expression of MHC class II have been described in chronic pancreatitis [2]. In addition, the inflammatory cytokines, TNF-a, IL-6, IL-8, IL-1 and IL-10 have been implicated in the disease process [3][4][5][6][7]. These findings suggest that autoimmunity plays an important role in the development of chronic pancreatitis. Although much attention has focused on its pathogenesis, the cellular and molecular mechanisms, and their genetic bases, involved in chronic inflammation of the pancreas are not clearly understood, due partly to the lack of suitable animal models of autoimmune pancreatitis. Commonly used models, such as alcohol administration [8], duct ligation [9] or injection of a toxic compound [10] have produced inconsistent results and their relevance to human disease has been questioned recently [11]. Thus, a suitable animal model would be very useful for elucidating the pathogenesis of chronic pancreatitis and developing new therapeutic approaches.An MRL/MpJ strain of mice bearing the lymphoproliferation gene, lpr (MRL/lpr), which was established by backcrosses and intercrosses between LG/J, AKR/J, C3H/Di and C57BL/6 J strains of mice, develops severe autoimmunue diseases such as glomerulonephritis, arteritis, sialoadenitis and arthritis spontaneously, associated with autoantibody production and T cell dysfunction early in life [12][13][14]. MRL/Mp mice not bearing the lpr gene (MRL/+) also develop these diseases, but at a much later stage in life, and with reduced incidence and severity [13,14], suggesting that the MRL strains have an autoimmune disease-prone genetic background [15]. Moreover, our recent studies in genetic analyses revealed that each lupus lesion in MRL/lpr mice is under a control of polygenic inheritance [16][17][18].We showed previously that 34-38-week-old MRL/+ female mice develop chronic pancreatitis spontaneously with an incidence of 71%, whereas the male mice develop pancreatitis with similar histopathological manifestations much later in life, 45-50 weeks, and with an incidence of less than 40% [19] SUMMARYIn this study we established a new animal model for exploring the pathogenesis of autoimmune pancreatitis. We have found previously that MRL/Mp-+/+(MRL/+) mice develop pancreatitis spontaneously by an autoimmune mechanism but only when they are more than 34 weeks old. Because this disease might be a model of multi-factorial diseases controlled by genetic and environmental factors, beginning at 6 weeks old, we injected polyinosinic:polycytidylic acid (poly I:C) into MRL/+ mice and in addtion, into MRL/Mp mice bearing the Fas deletion mutant gene, lpr (MRL/lpr). Poly I:C induced chronic severe pancreatitis in all the MRL/+ mice and t...
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