Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation

Abstract

SUMMARY The objective of this study was to determine the effects of Methotrexate (MTX) on the development and the course of experimental murine SLE, as well as on the cytokine profile involved in the disease. SLE was induced in naive BALB/c female mice by injection of the human anti‐DNA MoAb bearing a common idiotype (16/6 Id). Six weeks following immunization, when high levels of autoantibodies were demonstrated, the mice were treated with MTX (2 mg/kg once a week) for a period of 10 months. MTX treatment had no effect on 16/6 Id‐induced autoantibody production. However, MTX treatment had beneficial effects on the clinical manifestations of the experimental disease (i.e. leucocyte counts, levels of protein in the urine and immune complex deposits in the kidneys). Thus, only 20% of 16/6 Id‐immunized BALB/c mice that were treated with MTX had immune complex deposits in their kidneys compared with 100% of SLE‐afflicted BALB/c mice that were not treated. We have observed a significant elevation in IL‐1, tumour necrosis factor (TNF) and IL‐10 secretion in BALB/c mice afflicted with experimental SLE. IL‐2, IL‐4, IL‐6 and interferon‐gamma (INF‐γ) levels were decreased in these mice compared with the levels detected in healthy controls. Treatment with MTX reversed the levels of all the above cytokines to normal levels observed in control mice. These studies demonstrate therapeutic effects of MTX on murine experimental SLE. The normal cytokine profile observed following treatment with MTX is suggested to play a role in the amelioration of the clinical manifestations of experimental SLE.

Immunomodulatory Effect of Agave tequilana Evaluated on an Autoimmunity Like-SLE Model Induced in Balb/c Mice with Pristane

“…In the model used, proteinuria development was not observed four months after TMPD was administered as reported by [ 25 ]; although, after seven months an increment of albumin elimination in urine was registered. Mtx was capable of controlling the inflammatory process as observed in Figure 1 ; it also provoked an increment of protein elimination in urine; this represents one of the collateral effects previously reported for the strain of mice used in this model [ 26 ] and this is what determines the deleterious capacity of Mtx on the nephron. The anti-inflammatory effect of Pdn also protected the nephrons from damage since proteinuria was not provoked, as has previously been reported in laboratory tests and clinical studies [ 27 , 28 ], where it has been suggested that Pdn has the capacity to improve the nephron function.…”

677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis

“…S-adenosylmethionine is the main donor of methyl group in numerous biochemical pathways and reactions of DNA methylation. The limited availability of S-adenosylmethionine may affect expression of many genes, being a postulated mechanism of immunosuppressive properties of MTX [21]. The increased availability of 5-methylene-THF, which is a MTHFR substrate, might be another mechanism of higher response rate to MTX treatment in carriers of alleles associated with lower MTHFR expression.…”

Insulin‐like growth factor‐1 in psoriatic plaques treated with PUVA and methotrexate

“…Methotrexate (Mtx) decreases the activation state of antigen‐stimulated cells and may alter the expression of adhesion molecules 25 . Treatment with Mtx was associated with a decrease in elevated TNF‐α in murine model of SLE 26 and inhibition of fibroblast proliferation in culture; 27 these two actions may consequently reduce the IGF‐1 and explain its decrease in our patients treated with Mtx.…”