Rheumatoid arthritis (RA) is a relatively common inflammatory disease that affects roughly 1-2% of the global population. With increasing age, prevalence of the disease increases, with roughly 5% of women over the age of 55 diagnosed. Whether or not one is afflicted with the disease depends on a variety of factors, including genetics and environmental factors such as smoking, obesity, and periodontal disease. It is thought that T and B cells play an important role in the beginnings and persistence of the disease, resulting in several effective treatments including one with B-cell depleting agents (rituximab) and costimulatory blockage (abatacept).
T cells act to stimulate several cells within the immune system, including macrophages, with then release a whole array of inflammatory mediators, which give rise to joint inflammation and eventual destruction. Currently, medications to combat RA are targeted to reduce inflammation in the joints, including methotrexate, sulphasalazine, and glucocorticoids. However, there are a large number of patients that these types of therapies are not effective against the disease, thus other treatment options need to be explored. There are some recombinant immune-modulating drugs that target many different immune receptors (not just inflammatory cells) are currently under development and study, though long-term effects are not known and the treatments themselves could potentially be very expensive.
Some natural compounds with anti-inflammatory properties are just now being seriously considered as possible therapies for RA. As we’ve learned many times through this blog, resveratrol is one such compound. Known to have antimicrobial properties, as well as cardiovascular protection benefits, is has also been found that resveratrol, which is found in high levels in the skins of grapes and also red wine, possesses anti-inflammatory properties as well. In the rabbit model, researchers have shown that resveratrol can reduce lipopolysaccharide-induced joint inflammation. Also, studies have shown that alcohol itself (not just the resveratrol in the red wine) may be protective against RA.
The study presented today aimed to test the hypothesis that resveratrol could lessen experimental arthritis in the mouse model, and that it does so by modulation of autoreactive immune responses.
Male mice were experimentally induced with collagen-induced arthritis (CIA). After being inoculated with the disease, mice were either treated with resveratrol (trans-resveratrol dissolved in dimethyl sulphoxide) on day 10 (to test prevention of disease expression) or day 23 (to test treatment against established disease). Those mice being tested for treatment against the established disease were first injected at day 23, and then daily from day 23 to day 33. Doses were 20mg/kg, with or without resveratrol. Control mice received injections of dimethyl sulphoxide alone, with no resveratrol. Development of arthritis was monitored until day 38.
Standard immunological procedures were performed to measure T cell levels, as well as other various cytokines and antibodies known to be involved in CIA/RA. In addition to cellular and immunological analysis, histological analysis examining joint pathology was also performed.
Treatment Against Development of CIA and Established Disease
- Control mice developed severe CIA at day 21.
o Mice receiving 20mg/kg of resveratrol significantly reduced incidence of disease, the number of paws affected, footpad thickness, and clinical index compared with control mice.
o 15mg/kg of resveratrol had no significant effect on the development or severity of CIA.
o Resveratrol treatment significantly reduced cell infiltration into the joint, synovial hyperplasia and adjacent cartilage and bone erosion compared with control mice.
§ Results suggest resveratrol could prevent the development of collagen-induced arthritis.
- Resveratrol-treated mice significantly and rapidly reduced the clinical symptoms of CIA from the second dose on, compared with the control mice.
o Joint analysis at day 36 showed significant reduction of cell infiltration, synovial hyperplasia and bone erosion compared to control mice.
o The therapeutic effect of resveratrol lasted at least one week, without subsequent resveratrol treatments.
§ Results suggest resveratrol has a therapeutic effect on ongoing inflammatory arthritis.
- Resveratrol at the dose of 20mg/kg significantly prevented the development of IgG2a and IgG1 (collagen-specific) compared with control mice.
o This reduction was also found in mice treated with resveratrol once CIA was already established.
- Resveratrol at the dose of 20mg/kg did NOT significantly influence the levels of total IgG1 or IgG2a.
o These results suggest that resveratrol selectively controls the collagen-specific B-cell response (in CIA) rather than acting as a general B-cell depleting/suppressing factor.
- There were no significant differences in serum levels of IL-2 and IL-10 in resveratrol treated mice versus control mice, nor were there any effects on the cytokine profiles of these mice after resveratrol treatment.
- Lymph nodes from control mice had significantly higher levels of IL-17, IFNγ, TNFα, IL-1β, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1α, IL-5, and IL-13 compared to resveratrol-treated mice.
- Resveratrol treatment had no significant influence on levels of IL-4, IL-10, or IL-2 in draining lymph node cells.
- T cells from draining lymph nodes in mice treated with resveratrol showed reduced expression of IL-17 and IFNγ.
- Resveratrol treatment reduced the numbers of total cells, CD4 IL-17+ Th17 cells, and CD4 IFNγ+ Th1 cells in draining lymph nodes compared to control mice.
o These results suggest resveratrol may suppress expansion and cytokine production in Th17 and Th1 cells in mice with CIA.
o Resveratrol may also suppress Th17 cell polarization and proliferation.
This study is the first of its kind to show that resveratrol, found in grape skins and red wine, can effectively prevent and treat experimentally induced inflammatory arthritis. Resveratrol, therefore, may be a novel treatment for arthritis, other treatments of which have been dominated by synthetically manufactured drugs. This paper did not examine the actual mechanisms of why resveratrol is successful in treating inflammatory arthritis, though they do make several suggestions (of which I will not go into right now).
The results of this study seem very promising, in that both the immunological and histological analyses appeared to point to marked reductions in both the onset of disease, and also in the amelioration of the disease once established for mice treated with resveratrol at different time points. Of course, this being a murine model, it’s not to say that this result will be comparable in humans. We, of course, do not know the answer to that at the moment, thereby clinical research trials would need to be performed to be certain.
The study mentioned early on that alcohol has been shown to be effective against inflammatory arthritis, however, never do they actually test it in the experiment (though, I suppose that wasn’t the goal of the experiment). Now that we know resveratrol plays a role in ameliorating the symptoms of inflammatory arthritis in the mouse model, I’d be curious to see the next study using not only resveratrol treatments, but also red wine treatments, and perhaps red wine minus the alcohol treatments, to determine which component plays a bigger role, or if the combination of the resveratrol and alcohol has synergistic or antagonistic effects on arthritis development and treatment.
I’d love to hear what you all this about this topic! Please feel free to comment below (html tags will be deleted).
Source: Xuzhu, G., Komai-Koma, M., Leung, B.P., Howe, H.S., McSharry, C., McInnes, I.B., and Xu, D. 2012. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Annals of Rheumatic Disease 71: 129-135.
I am not a health professional, nor do I pretend to be. Please consult your doctor before altering your alcohol consumption habits. Do not consume alcohol if you are under the age of 21. Do not drink and drive. Enjoy responsibly!