T cells in rheumatoid arthritis

Zhang X, Nakajima T, Goronzy JJ, Weyand CM. Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis. Arthritis Rheum 2005 ... 

Steiner, G., Tohidast-Akrad, M., Witzmann, G., Vesely, M., Studnicka-Benke, A., Gal, A., Kunaver, M., Zenz, P., and Smolen, J. S. (1999). Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology 38, 202-213. 

Steiner G, Tohidast-Akrad M, Witzmann G, Vesely M, Studnicka-Benke A, Gal A, Kunaver M, Zenz P, Smolen JS Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) 1999 38 202-213. 

Shadidi, K., Thompson, K., Henriksen, J., Natvig, J., and Aarvak, T. (2002). Association of antigen specificity and migratory capacity of memory T cells in rheumatoid arthritis. Scand. J. Immunol. 55, 274-283. 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

Fournier C. Where do T cells stand in rheumatoid arthritis Joint Bone Spine 2005 72(6) 527-532. 

Robinson E, Keystone EC, Schall TJ, Gillett N, Fish EN. Chemokine expression in rheumatoid arthritis (RA) evidence of RANTES and macrophage inflammatory protein (MIP)-l beta production by synovial T cells. Clin Exp Immunol 1995 101(3) 398-107. 

Thompson SD, Luyrink LK, Graham TB, et al. Chemokine receptor CCR4 on CD4+ T cells in juvenile rheumatoid arthritis synovial fluid defines a subset of cells with increased IL-4 IFN-gamma mRNA ratios. J Immunol 2001 166(11) 6899-6906. 

Matsui T, Akahoshi T, Namai R, et al. Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis. Clin Exp Immunol 2001 125(1) 155-161. 

Nanki T, Hayashida K, El-Gabalawy HS, et al. Stromal cell-derived factor-l-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 2000 165(11) 6590-6598. 

Blaschke S, Middel P, Domer BG, et al. Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. Arthritis Rheum 2003 48(7) 1858-1872. 

Yang PT, Kasai H, Zhao LJ, Xiao WG, Tanabe F, Ito M. Increased CCR4 expression on circulating CD4(+) T cells in ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematosus. Clin Exp Immunol 2004 138(2) ... 

Rheumatoid arthritis Vitamin B is a potential agent in management of RA. It mainly acts by correcting abnormalities in RACD8-t T cells in autologous mixed lymphocyte reaction (AMLR). 

In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, whereas leukocytes localize mainly in the synovial fluid. The major eicosanoids produced by leukocytes are leukotrienes, which facilitate T-cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE2 and TXA2 and large amounts of leukotrienes. 

Fishman P (2008) Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis data from a phase II clinical trial. J Rheumatol 35(1 ) 41—48 Sizova L (2008) Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs. Br J Clin Pharmacol 66(2) 173-178 Spargo LD, Cleland LG, Cockshell MP, Mayrhofer G (2006) Recruitment and proliferation of CD4+ T cells in synovium following adoptive transfer of adjuvant-induced arthritis. Int Immunol 18(6) 897-910... 

IL-18 augments T- and NK-cell maturation, cytotoxicity and cytokine production. It stimulates TH differentiation, promotes secretion of TNF-a, IFN-y and GM-CSF and enhances NK cell cytotoxicity by increasing FasL expression. IL-8-mediated neutrophil chemotaxis is promoted by IL-18 via its effects on TNF-a and IFN-y, which are stimulatory in action. It plays an important role in maintaining synovial inflammation and inducing joint destruction in rheumatoid arthritis. In synovium of patients with rheumatoid arthritis, enhanced levels of TNF-a and IL-1 are associated with augmented expression of IL-18. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Mechanism of Action. The basis for the antiar-thritic effects of penicillamine is unknown. Reductions in serum immunoglobulin M-rheumatoid factor have been observed with penicillamine, and this drug has been shown to depress T-cell function.53 These and similar findings suggest that penicillamine works by suppressing the immune response in rheumatoid arthritis, but the exact mechanisms remain to be determined. 

Lorenz HM. T-cell-activation inhibitors in rheumatoid arthritis. BioDrugs. 2003 17 263-270. 

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease see Chapter 63 Drugs Used in the Treatment of Gastrointestinal Diseases). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression of T cell responses to concanavalin and inhibition of in vitro B cell proliferation have also been documented. It is not clear how these findings relate to the clinical efficacy of sulfasalazine in rheumatoid arthritis. 

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it increases the magnitude of delayed hypersensitivity or T cell-mediated immunity in humans. In immunodeficiency associated with Hodgkin s disease, levamisole has been noted to increase the number of T cells in vitro and to enhance skin test reactivity. Levamisole has also been widely tested in rheumatoid arthritis and found to have some efficacy. However, it has induced severe agranulocytosis (mainly in HLA-B27-positive patients), which required discontinuation of its use. The drug may also potentiate the action of fluorouracil (5-FU) in adjuvant therapy of colorectal cancer, and this combination has been approved for clinical use in the treatment of Dukes class C colorectal cancer after surgery. Its use in these cases reduces recurrences, and the mechanism... 

Panayi, G. S. (1997). T-cell-dependent pathways in rheumatoid arthritis. Curr. Opin. Rheumatol. 9, 236-240. 

CSF, M-CSF, called the autocrine loop). TNF-a and IL-1 are potent upregulators of several cell t) es including fibroblasts and T cells. TNF-a may act earlier in the hierenchy than other cytokines and has proven to be an important target for anticytokine therapy in rheumatoid arthritis and Crohn s disease (see later, anti-TNF therapy). Some small amounts of anti-inflammatory cytokines may also be present (such as IL-10 and interferon-y), but because the system is not in balance, the end result is inflammation. 

Inosine pranobex is a synthetic product, also known as isoprinosine or inosine dimepranol acedobene, with antiviral properties that are assumed to be related to its effect on T cell-mediated immunity rather than to direct antiviral activity. It has been tried in a wide range of viral diseases and also in rheumatoid arthritis (1), multiple sclerosis (2), and alopecia (3). However, clinical trials have mostly shown only modest therapeutic benefit or none at all (1,4), and no specific adverse effects, except for an increase in serum uric acid concentrations (5), reflecting the metabolic pathways of purines (6). 

Backlund, J, Carlsen, S, Hdger, T, Hohn, B, Eugger, L, Kihlberg, J, Burkhardt, H, Holmdahl, R, Predominant selection of T cells specific for the glycosylated collagen t)fpe II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis, Proc. Natl. Acad. Sci. USA, 99,9960-9965, 2002. 

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