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PLoS One. 2011;6(9):e24590. doi: 10.1371/journal.pone.0024590. Epub 2011 Sep 13.
All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.
Lu L, Ma J, Li Z, Lan Q, Chen M, Liu Y, Xia Z, Wang J, Han Y, Shi W, Quesniaux V, Ryffel B, Brand D, Li B, Liu Z, Zheng SG.
Source
Division of Rheumatology, Department of Medicine, Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Abstract
BACKGROUND:
It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4(+)Foxp3(+) regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.
METHODOLOGY/PRINCIPAL FINDINGS:
Addition of atRA to naïve CD4(+)CD25(-) cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+) iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+) cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+) cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+) cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+) cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.
CONCLUSIONS/SIGNIFICANCE:
We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.

All-trans-retinoic acid (atRA), a Vitamin A derivative

In the immune system, atRA plays important roles in regulating the functions of many different cell types [3]. Vitamin A and its derivatives are capable of ameliorating several models of autoimmunity, including inflammatory bowel disease, rheumatoid arthritis, type I diabetes, and experimental encephalomyelitis [4]–[5].

All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation

Toxicity has been shown to be mitigated through vitamin E (tocopherol), cholesterol, zinc, taurine, and calcium.
Cholesterol has been shown to prevent retinol induced golgi fragmentation.[9]
In rats, the toxic effects of vitamin A were significantly reduced when diets were supplemented with taurine or Cholestin

Scott1 wrote:... taking Vitamin A as a supplement as it can accumulate in the system and become toxic (you turn yellow). ...

Signs of acute toxicity include nausea and vomiting, headache, dizziness, blurred vision, and loss of muscular coordination.

Scott1 wrote:Please try a big glass of Carrot juice each day in preference to a Vitamin A tablet.

gibbledygook wrote:I have observed a change since starting the vitamin A in that my night spasms are better or milder and the walking somewhat stiffer about 5 hours after taking the vitamin a but not substantially more difficult

Mult Scler. 2013 Apr;19(4):451-7. doi: 10.1177/1352458512457843. Epub 2012 Aug 20.
Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis.
Løken-Amsrud KI, Myhr KM, Bakke SJ, Beiske AG, Bjerve KS, Bjørnarå BT, Hovdal H, Lilleås F, Midgard R, Pedersen T, Benth JS, Torkildsen Ø, Wergeland S, Holmøy T.
Source
Department of Neurology, Innlandet Hospital Trust, Lillehammer, Norway.
Abstract
BACKGROUND:
Vitamin A has immunomodulatory properties and may regulate the transcription of genes involved in remyelination.
OBJECTIVE:
To investigate the association between retinol and disease activity in multiple sclerosis (MS).
METHODS:
Cohort study of 88 relapsing-remitting MS patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS study), followed prospectively for 24 months with repeated assessments of serum-retinol and magnetic resonance imaging (MRI). All patients were initiated on interferon β-1a after month 6.
RESULTS:
Each 1 µmol/L increase in serum-retinol reduced the odds (95% confidence interval) for new T1 gadolinium enhanced (Gd(+)) lesions by 49 (8-70)%, new T2 lesions by 42 (2-66)%, and combined unique activity (CUA) by 46 (3-68)% in simultaneous MRI scans, and 63 (25-82)% for new T1Gd(+) lesions, 49 (3-73)% for new T2 lesions and 43 (12-71)% for CUA the subsequent month. Serum-retinol also predicted new T1Gd(+) and T2 lesions six months ahead. The associations were not affected by HLA-DRB1*15, or serum levels of 25-hydroxyvitamin D, eicosapentaenoic acid or docosahexaenoic acid.
CONCLUSION:
Serum retinol is inversely associated with simultaneous and subsequent MRI outcomes in RRMS.
Comment in
Vitamin A: yet another player in multiple sclerosis pathogenesis? [Expert Rev Clin Immunol. 2013]
PMID: 22907941 [PubMed - indexed for MEDLINE]

Arch Neurol. 1998 Mar;55(3):315-21.
All-trans retinoic acid potentiates the ability of interferon beta-1b to augment suppressor cell function in multiple sclerosis.
Qu ZX, Dayal A, Jensen MA, Arnason BG.
Source
Department of Neurology and the Brain Research Institute, University of Chicago, Ill 60637, USA.
Abstract
OBJECTIVE:
To determine the effects of combination all-trans retinoic acid (RA) and interferon beta-1b therapy on immune system functions potentially relevant to multiple sclerosis (MS).
DESIGN:
Interferon gamma-secreting cells, T suppressor cell function, and lymphocyte proliferative responses were assayed using peripheral blood mononuclear cells from patients with MS and control subjects under control conditions and in the presence of interferon beta-1b, RA, and the 2 combined.
SETTING:
A university hospital MS clinic.
PARTICIPANTS:
Seventeen patients with secondarily progressive MS and 25 control subjects.
RESULTS:
Interferon beta-1b use increased interferon gamma-secreting cell counts, augmented T suppressor cell function, and inhibited T-cell proliferation. Therapy with RA decreased interferon gamma-secreting cell counts, had a minimal positive effect on T suppressor cell function, and had no effect on T-cell proliferation. When RA and interferon beta-1b were combined, the inhibitory effect of RA on interferon gamma-secreting cells predominated, T suppressor cell function increased synergistically over the increment observed with interferon beta-1b use alone, and the inhibitory effect of interferon beta-1b alone on T-cell proliferation remained unchanged.
CONCLUSIONS:
Treatment with interferon beta-1b partially restores defective T suppressor cell function in patients with MS. This potentially beneficial action is synergistically potentiated by RA. Interferon beta-1b increases the number of interferon gamma-secreting cells in the circulation when treatment is initiated. A similar increment in interferon gamma-secreting cells is observed when interferon beta-1b is added to cultural peripheral blood mononuclear cells in vitro. This potentially deleterious action of interferon beta-1b is reversed by RA. Interferon beta-1b inhibits lymphocyte proliferation modestly but reproducibly. This action of interferon beta-1b is unaltered by RA. These data provide a rationale for a trial of combination treatment with interferon beta-1b and RA in patients with MS.
PMID: 9520005 [PubMed - indexed for MEDLINE]

gibbledygook wrote:Interferon beta-1b use increased interferon gamma-secreting cell counts