tretinoin and Lupus-Nephritis

Lupus nephritis is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). In these patients, treatment with immunosuppressive agents can significantly improve the outcome of lupus nephritis. However, these agents have severe adverse reactions and some patients are refractory to those therapies. Retinoids, a group of natural and synthetic derivatives of vitamin A, play important regulatory roles of cellular proliferation, differentiation and apoptosis. They have been used for the treatment of acute promyelocytic leukemia and inflammatory disorders such as psoriasis and acne. It has also been shown that retinoids have therapeutic effects in various animal models of kidney disease, including lupus nephritis. Based on these findings, retinoids are a promising agent for the treatment of lupus nephritis. We studied the clinical effects of retinoid therapy in patients with lupus nephritis. In open clinical trial, 7 patients with active lupus nephritis that was refractory to steroid therapy were studied. In all these patients, retinoid was added to the immunosuppressive therapy and its therapeutic effects were evaluated. As a result, 4 out of 7 patients showed improvement of the clinical symptoms and laboratory findings, including urinary protein and anti-dsDNA antibody levels. No important adverse effects of ATRA therapy were observed in all patients. Thus, retinoids might be indicated in cases of lupus nephritis that are refractory to conventional immunosuppressive therapy.

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Humans; Immunosuppressive Agents; Lupus Nephritis; Tretinoin

We previously showed that all-

Topics: Animals; Bacterial Translocation; Contraindications, Drug; Dendritic Cells; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Drug Synergism; Dysbiosis; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Glomerulonephritis; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; RNA; RNA-Seq; Specific Pathogen-Free Organisms; Spleen; Terpenes; Tretinoin; Vitamin A

Lupus nephritis is a major manifestation of systemic lupus erythematosus. Treatment with such immunosuppressive agents as corticosteroids or cyclophosphamide can decrease the progression of lupus nephritis; however, these agents have potentially severe adverse reactions. Therefore, the development of new drugs with fewer side effects is needed. Here, we report 2 patients with lupus that were treated successfully with retinoids. Initially, both patients were treated with 60 mg/d of prednisolone. However, nephrotic syndrome was not improved. Subsequently, treatment with 10 mg/d of all-trans-retinoic acid was started orally and elicited a good response, showing a decrease in proteinuria. Although additional controlled clinical studies are needed to confirm these findings, we suggest that therapy using retinoids may represent a novel approach to the treatment of patients with lupus nephritis.

Topics: Adult; Female; Humans; Lupus Nephritis; Middle Aged; Remission Induction; Tretinoin

Corticosteroids are highly effective anti-inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All-trans-retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti-inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid-sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti-DNA antibody production were determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P <0.05). A single administration of ATRA reduced the Th1 [interleukin (IL)-2, interferon (IFN)-gamma and IL-12], and a Th2 (IL-4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)-specific anti-DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid-sparing drug against lupus nephritis.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Antinuclear; Body Weight; Chemokine CCL2; Cytokines; DNA; Drug Therapy, Combination; Female; Glucocorticoids; Immunoglobulin G; Immunohistochemistry; Keratolytic Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prednisolone; Proteinuria; RNA, Messenger; Spleen; Tretinoin

Retinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice.. MRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control.. tRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model.. tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.

Topics: Adoptive Transfer; Animals; Antineoplastic Agents; Body Weight; Chemokines; Cytokines; Immunoglobulin G; Kidney Glomerulus; Lupus Nephritis; Macrophages; Mice; Mice, Inbred MRL lpr; Organ Size; RNA, Messenger; T-Lymphocytes; Tretinoin

Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F(1) (NZB/W F(1)) mice. Three-month-old NZB/W F(1) mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-gamma, IL-2, and IL-10 in splenic CD4(+) T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F(1) mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.

Topics: Animals; Antibodies, Antinuclear; CD4-Positive T-Lymphocytes; Crosses, Genetic; Cytokines; Glomerulonephritis; Immunoglobulins; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred NZB; Proteinuria; RNA, Messenger; Splenomegaly; Survival Rate; Tretinoin