tretinoin and Autoimmune-Diseases

A leaky gut has been observed in a number of autoimmune diseases including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Previous studies from our laboratory have shown that lupus mice also bear a leaky gut and that the intestinal barrier function can be enhanced by gut colonization of probiotics such as

Topics: Animals; Autoimmune Diseases; Autoimmunity; Bacteria; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Immunologic Factors; Intestines; Permeability; Treatment Outcome; Tretinoin

This review is in two sections. The first section summarises 35 conditions, both common and infrequent, causing cicatrising conjunctivitis. Guidelines for making a diagnosis are given together with the use of diagnostic tests, including direct and indirect immunofluorescence, and their interpretation. The second section evaluates our knowledge of ocular mucous membrane pemphigoid, which is the commonest cause of cicatrizing conjunctivitis in most developed countries. The clinical characteristics, demographics, and clinical signs of the disease are described. This is followed by a review and re-evaluation of the pathogenesis of conjunctival inflammation in mucous membrane pemphigoid (MMP), resulting in a revised hypothesis of the autoimmune mechanisms causing inflammation in ocular MMP. The relationship between inflammation and scarring in MMP conjunctiva is described. Recent research, describing the role of aldehyde dehydrogenase (ALDH) and retinoic acid (RA) in both the initiation and perpetuation of profibrotic activity in MMP conjunctival fibroblasts is summarised and the potential for antifibrotic therapy, using ALDH inhibition, is discussed. The importance of the management of the ocular surface in MMP is briefly summarised. This is followed with the rationale for the use of systemic immunomodulatory therapy, currently the standard of care for patients with active ocular MMP. The evidence for the use of these drugs is summarised and guidelines given for their use. Finally, the areas for research and innovation in the next decade are reviewed including the need for better diagnostics, markers of disease activity, and the potential for biological and topical therapies for both inflammation and scarring.

Topics: Aldehyde Dehydrogenase 1 Family; Autoantibodies; Autoimmune Diseases; Cicatrix; Conjunctivitis; Fibroblasts; Fluorescent Antibody Technique, Indirect; Humans; Immunosuppressive Agents; Inflammation; Isoenzymes; Pemphigoid, Benign Mucous Membrane; Retinal Dehydrogenase; Tretinoin

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

Naturally arising regulatory T cells (Tregs) originate from the thymus and are characterised by the expression of Foxp3 as a key control gene for their development and function. Their pivotal role is maintaining immunological self tolerance. Recently, Tregs have been shown to express Toll-like receptors (TLRs), which are essential components of the innate immune system for the detection of microbial infections and the activation of dendritic cells (DC) maturation programs to induce adaptive immune responses. TLRs are type 1 transmembrane receptors characterised by a highly variable extracellular region containing a leucine rich repeat domain (LRR) involved in ligand binding and an intracellular tail containing a highly conserved region, the TIR homology domain, which mediates interaction between TLRs and downstream signalling molecules. Recent data suggest that the activation of TLRs on Tregs can increase or decrease their suppressive activity, thus providing an important link between innate and adaptive immune responses. Treg modulation by TLRs might influence such processes as the response to infections, immune surveillance to cancer, transplant rejection, and the induction of autoimmunity. Understanding the link between Tregs and TLR could be beneficial to the discovery of new therapeutic targets and strategies.

Topics: Animals; Autoimmune Diseases; Cytokines; Dendritic Cells; Forkhead Transcription Factors; Graft Rejection; Humans; Immunity, Innate; Immunologic Surveillance; Immunosuppression Therapy; Self Tolerance; T-Lymphocytes, Regulatory; Toll-Like Receptors; Tretinoin

Regulatory T (Treg) cells are emerging as key players in the regulation of different immune responses, thereby representing potential candidates for therapeutic interventions in a broad variety of immunological disorders. While the reduction or loss in function would be of benefit during the treatment of cancer, induction and/or expansion of Treg cell function might be helpful to interfere with unwanted immune responses in transplantation medicine, during autoimmunity, allergy and inflammation. However, a better understanding of Treg cell biology is a prerequisite to specifically modulate its function during immune responses in vivo. In the present review we will discuss current concepts on different cell types, components and some novel surface receptors expressed by Treg cells, namely Neuropilin-1, CD83 and G protein-coupled receptor 83 which might represent promising targets for the modulation of Treg cell function in human disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Antigens, CD; Autoimmune Diseases; CD83 Antigen; Humans; Immunoglobulins; Immunotherapy; Inflammation; Membrane Glycoproteins; Neuropilin-1; Receptors, G-Protein-Coupled; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

Retinoid is a collective term for compounds which bind to and activate retinoic acid receptors (RARalpha, beta, gamma and RXRalpha, beta, gamma), members of nuclear hormone receptor superfamily. The most important endogeneous retinoid is all-trans-retinoic acid (ATRA) which is an RARalpha, beta and gamma ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and some skin diseases. Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, tamibarotene (Am80) is an RARalpha- and RARbeta-specific (but RARgamma- and RXRs-nonbinding) synthetic retinoid that is effective in the treatment of psoriasis patients and relapsed APL. Experimentally, this compound is also active in animal models of rheumatoid arthritis and experimental autoimmune encephalomyelitis. On this background, possible application of retinoids for the treatment of autoimmune diseases was discussed. In particular, Th1 dominant autoimmune diseases may be the targets of the retinoids.

Topics: Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Benzoates; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoids; Skin Diseases; T-Lymphocytes; Tetrahydronaphthalenes; Tretinoin

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T

Topics: Animals; Antirheumatic Agents; Arthritis; Autoimmune Diseases; Inflammation; Mice; T-Lymphocytes, Regulatory; Tretinoin

We determined the mechanism by which all-trans retinoic acid (ATRA) inhibits experimental autoimmune uveitis (EAU) and determined the role of γδ T cells in this autoimmune disease.. C57BL/6 (B6) mice were immunized with the uveitogenic, interphotoreceptor retinoid-binding protein1-20 peptide (IRBP1-20) in complete Freund's adjuvant (CFA), with or without a preceding ATRA treatment. Responses and pathogenic activity of Th1- and Th17-autoreactive T cells were compared, and the effects of ATRA on γδ T cells and CD25(+) dendritic cell (DC) subset were determined. Interactions among uveitogenic T cells, DC subsets, and γδ T cells were investigated.. Administration of ATRA to B6 mice in which EAU was induced suppressed the response of Th17 autoreactive T cells, which was associated with decreased generation of the CD25(+) DC subset and suppressed activation of γδ T cells. Adoptively transferred γδ T cells isolated from ATRA-treated mice showed a diminished ability to promote the activation of Th17 autoreactive T cells in vitro and in vivo compared to γδ T cells from untreated donors.. ATRA inhibits the expansion of CD25(+) DCs and γδ T-cell activation, thereby restraining the Th17 autoreactive T-cell response.

Topics: Animals; Antineoplastic Agents; Autoimmune Diseases; Cell Differentiation; Dendritic Cells; Disease Models, Animal; Interleukin-17; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, gamma-delta; Th17 Cells; Tretinoin; Uveitis

Primary cultured retinal pigment epithelial (RPE) cells can convert T cells into T regulatory cells (Tregs) through inhibitory factor(s) including transforming growth factor β (TGFβ) in vitro. Retinoic acid (RA) enhances induction of CD4(+) Tregs in the presence of TGFβ. We investigated whether RA produced by RPE cells can promote generation of Tregs. We found that in vitro, RA-treated T cells expressed high levels of Foxp3 in the presence of recombinant TGFβ. In GeneChip analysis, cultured RPE cells constitutively expressed RA-associated molecules such as RA-binding proteins, enzymes, and receptors. RPE from normal mice, but not vitamin A-deficient mice, contained significant levels of TGFβ. RPE-induced Tregs from vitamin A-deficient mice failed to suppress activation of target T cells. Only a few Foxp3(+) T cells were found in intraocular cells from vitamin A-deficient experimental autoimmune uveitis (EAU) mice, whereas expression was higher in cells from normal EAU mice. RA receptor antagonist-pretreated or RA-binding protein-siRNA-transfected RPE cells failed to convert CD4(+) T cells into Tregs. Our data support the hypothesis that RPE cells produce RA, thereby enabling bystander T cells to be converted into Tregs through TGFβ promotion, which can then participate in the establishment of immune tolerance in the eye.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Coculture Techniques; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Forkhead Transcription Factors; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Pregnancy; Real-Time Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinal Pigment Epithelium; RNA, Messenger; RNA, Small Interfering; T-Lymphocytes, Regulatory; Transfection; Transforming Growth Factor beta; Tretinoin; Uveitis; Vitamin A; Vitamin A Deficiency

To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins.. We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293.. The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups.. Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.

Topics: Adolescent; Antineoplastic Agents; Autoimmune Diseases; Cell Differentiation; Cell Line, Tumor; Child; Child, Preschool; Chorea; Female; Flow Cytometry; Humans; Immunoglobulin G; Male; Neuroblastoma; Neurons; Obsessive-Compulsive Disorder; Statistics, Nonparametric; Streptococcal Infections; Tourette Syndrome; Tretinoin

Mild but efficient treatments of autoimmune diseases are urgently required. One such therapy, long-term maintenance of chronic delayed type hypersensitivity, has been described for alopecia areata (AA), a hair follicle-affecting autoimmune disease. The molecular mechanisms underlying the therapeutic efficacy are unknown, but may involve myeloid-derived suppressor cells (MDSCs). AA-affected mice were treated with squaric acid dibutyl ester (SADBE). The immunoreactivity of SADBE-treated AA lymphocytes and of AA lymphocytes co-cultured with SADBE-induced MDSCs was analyzed. The curative effect of SADBE was abolished by all-transretinoic acid, which drives MDSCs into differentiation, confirming a central role for MDSCs in therapeutic SADBE treatment. SADBE and SADBE-induced MDSCs strongly interfered with sustained autoreactive T-cell proliferation in response to AA skin lysate (autoantigen), which was accompanied by weak ζ-chain down-regulation and strongly impaired Lck activation. In contrast, activation of the mitochondrial apoptosis pathway and blockade of the anti-apoptotic PI3K/Akt pathway by SADBE-induced MDSCs did not require T-cell receptor engagement. Apoptosis induction correlated with high TNF-α expression in SADBE-induced MDSCs and elevated TNFRI levels in AA lymphocytes. SADBE-induced MDSCs interfere with persisting autoreactive T-cell proliferation and promote apoptosis of these T cells, which qualifies MDSCs induced and maintained by chronic delayed type hypersensitivity reactions as promising therapeutics in organ-related autoimmune diseases.

Topics: Adaptor Proteins, Signal Transducing; Alopecia Areata; Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; CD4-CD8 Ratio; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclobutanes; Hypersensitivity, Delayed; Lymphocyte Activation; Mice; Mice, Inbred C3H; Mitochondria; Myeloid Cells; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Antigen, T-Cell; Receptors, Tumor Necrosis Factor; Signal Transduction; T-Lymphocytes; Tretinoin; Tumor Necrosis Factor-alpha

To determine whether an active metabolite of vitamin A, all-trans retinoic acid (ATRA), reduces inflammation in experimental autoimmune uveoretinitis (EAU).. Naive CD4(+) T cells were activated with anti-CD3, anti-CD28 and transforming growth factor (TGF)-beta, in the presence or absence of ATRA. Intracellular expression of transcription factor forkhead box P3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. C57BL/6 mice were immunised with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP(1-20)). ATRA was administered intraperitoneally every other day (0.2 mg/mouse per day) from day 0 to day 21. In vivo-primed draining lymph node cells from vehicle-treated or ATRA-treated mice were stimulated with IRBP(1-20) and the culture supernatant fraction was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA.. ATRA synergised with TGF-beta to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-beta and IL-6. ATRA treatment reduced the severity of EAU clinically, and IFN-gamma and IL-17 production were significantly reduced in ATRA-treated mice.. These findings demonstrate that ATRA treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. ATRA may represent a new therapeutic modality for human refractory uveitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Differentiation; Cells, Cultured; Drug Evaluation, Preclinical; Female; Forkhead Transcription Factors; Interferon-gamma; Interleukin-17; Lymph Nodes; Mice; Mice, Inbred C57BL; Receptors, Interleukin-6; Retinitis; T-Lymphocytes, Regulatory; Tretinoin; Uveitis

Recent studies have demonstrated that plasticity of naturally occurring CD4(+)Foxp3(+) regulatory T cells (nTregs) may account for their inability to control chronic inflammation in established autoimmune diseases. All-trans retinoic acid (atRA), the active derivative of vitamin A, has been demonstrated to promote Foxp3(+) Treg differentiation and suppress Th17 development. In this study, we report a vital role of atRA in sustaining the stability and functionality of nTregs in the presence of IL-6. We found that nTregs treated with atRA were resistant to Th17 and other Th cell conversion and maintained Foxp3 expression and suppressive activity in the presence of IL-6 in vitro. atRA decreased IL-6R expression and signaling by nTregs. Of interest, adoptive transfer of nTregs even from arthritic mice treated with atRA suppressed progression of established collagen-induced arthritis. We suggest that nTregs treated with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.

Topics: Animals; Arthritis, Experimental; Autoimmune Diseases; Cells, Cultured; Female; Forkhead Transcription Factors; Gene Knock-In Techniques; Immunity, Innate; Immunophenotyping; Inflammation Mediators; Interleukin-17; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Tretinoin

The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-beta, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation. The major vitamin A metabolite all-trans retinoic acid (RA) not only enforces the generation of Treg cells but also inhibits the differentiation of Th17 cells. Herein we show that RA enhances TGF-beta signaling by increasing the expression and phosphorylation of Smad3, and this results in increased Foxp3 expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6Ralpha, IRF-4, and IL-23R and thus inhibits Th17 development. In vitro, RA significantly promotes Treg cell conversion, but in vivo during the development of experimental autoimmune encephalomyelitis it does not increase the frequency of Treg cells in the face of an ongoing inflammation. However, RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses. These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Cells, Cultured; Female; Forkhead Transcription Factors; Interleukin-17; Interleukin-6; Interleukins; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptor-CD3 Complex, Antigen, T-Cell; Receptors, Interleukin; Receptors, Interleukin-6; Signal Transduction; Smad3 Protein; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; Tretinoin

Topics: Autoimmune Diseases; Clinical Trials as Topic; Humans; Skin Diseases; Tretinoin

Mercuric chloride (HgCl2) induces an autoimmune nephritis in the Brown Norway (BN) rats characterized by anti-glomerular basement membrane antibodies (anti-GBM Ab) deposition, proteinuria and a severe interstitial nephritis, all evident at day 13 of the disease. We assessed the effects of all-trans retinoic acid (at-RA) in this experimental model. At-RA is a vitamin A metabolite which has shown beneficial effects on several nephropathies, even though no clear targets for at-RA were provided.. We separated animals in four different experimental groups (HgCl2, HgCl2+at-RA, at-RA and vehicle). From each animal we collected, at days 0 and 13, numerous biological samples: urine, to measure proteinuria by colorimetry; blood to determine VLA-4 expression by flow citometry; renal tissue to study the expression of VCAM-1 by Western blot, the presence of cellular infiltrates by immunohistochemistry, the IgG deposition by immunofluorescence, and the cytokines expression by RT-PCR. Additionally, adhesion assays to VCAM-1 were performed using K562 alpha4 transfectant cells. ANOVA tests were used for statistical significance estimation.. We found that at-RA significantly decreased the serum levels of anti-GBM and consequently its deposition along the glomerular membrane. At-RA markedly reduced proteinuria as well as the number of cellular infiltrates in the renal interstitium, the levels of TNF-alpha and IL-1beta cytokines and VCAM-1 expression in renal tissue. Moreover, we reported here for the first time in an in vivo model that at-RA reduced, to basal levels, the expression of VLA-4 (alpha4beta1) integrin induced by mercury on peripheral blood leukocytes (PBLs). In addition, using K562 alpha4 stable transfectant cells, we found that at-RA inhibited VLA-4 dependent cell adhesion to VCAM-1.. Here we demonstrate a therapeutic effect of at-RA on an autoimmune experimental nephritis model in rats. We report a significant reduction of the VLA-4 integrin expression on PBLs as well as the inhibition of the VLA4/VCAM1-dependent leukocyte adhesion by at-RA treatment. Thereby we point out the VLA-4 integrin as a target for at-RA in vivo.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Immunity, Innate; Immunosuppressive Agents; Integrin alpha4beta1; Male; Mercuric Chloride; Nephritis; Rats; Treatment Outcome; Tretinoin

Topics: Antineoplastic Agents; Autoantibodies; Autoimmune Diseases; Humans; Hypothyroidism; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Peroxidase; Tretinoin

Acute promyelocytic leukemia (APL) is specifically associated to a t(15; 17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RARalpha, to a previously unknown gene PML. The PML protein is localized in the nucleus on a specific domain of unknown function (PML nuclear bodies, NB) previously detected with autoimmune sera from patients with primary biliary cirrhosis (PBC). These bodies are nuclear matrix-associated and all of their identified components (PML, Sp100, and NDP52) are sharply upregulated by interferons. We show that autoantibodies against both PML and Sp100 are usually associated in sera with multiple nuclear dot anti-nuclear antibodies and demonstrate that PML is an autoantigen, not only in PBC, but also in other autoimmune diseases. In APL, the PML/RARalpha fusion interferes with both the retinoic acid (RA) response and PML localization on nuclear bodies, but the respective contribution of each defect to leukemogenesis is unclear. RA induces the terminal differentiation of APL blasts, yielding to complete remissions, and corrects the localization of NB antigens. Arsenic trioxide (As2O3) also induces remissions in APL, seemingly through induction of apoptosis. We show that in APL, As2O3 leads to the rapid reformation of PML bodies. Thus, both agents correct the defect in NB antigen localization, stressing the role of nuclear bodies in the pathogenesis of APL.

Topics: Animals; Antibodies, Antinuclear; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Autoantigens; Autoimmune Diseases; Cell Differentiation; CHO Cells; Cricetinae; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Oxides; Promyelocytic Leukemia Protein; Transcription Factors; Transfection; Tretinoin; Tumor Suppressor Proteins