الفهرس 
Introduction
Histopathology of rheumatoid arthritisOnly 14 pages are availabe for public view
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Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown etiology affecting about 1% of the world population. It is characterized by chronic inflammation of the synovial tissues of multiple joints leading to joint destruction and loss of function. Several induced animal models have been developed to aid the understanding of the disease process and for the development of therapeutic tools for intervention. One such model is pristane-induced arthritis (PIA) which is notable for its delayed onset of arthritis and resembles the joint inflammation and destruction seen in human RA. Obviously, rheumatoid arthritis was thought to be T-helper1 cell-associated disease. However, this view has dramatically changed after the discovery of T-helper 17 cells; these cells have emerged as an important mediator of human immune diseases such as rheumatoid arthritis. Th1-cells produce IFN γ and are important mediators of cell immune response to infectious agents and in some autoimmune disease models. INF-γ is the predominant cytokine in synovial tissues of RA patients. TH17 cells produce IL-17A which is a proinflammatory cytokine that has a direct effect on synovial fibroblasts and can induce production of proinflammatory mediators such as metalloproteinases, prostaglandins, chemokines, nitric oxide, and IL-6.
Methotrexate (MTX), a folic acid antagonist, is one of the most important disease-modifying anti-rheumatic drugs and has become the predominant immunosuppressive agent used in the treatment of patients with RA. The use of MTX has been limited by some of its aggressive side effects such as hepatic cirrhosis, interstitial pneumonitis, myelosuppression, abdominal discomfort, alopecia and oral ulcerations. One approach to reduce dosing amounts, frequency of administration, and adverse side effects while maintaining the drug efficiency, is the development of new drug delivery systems with inflammatory site targeting and long circulating time. The use of nanoscaled carriers in drug delivery is expected to increase specificity of drugs and thus reduce side effects decreasing the dose of administered drugs. So, the present investigation has been a trial to assess: the functional role of T-helper17 and T-helper1 cells in pristane-induced arthritis by measuring IL-17A and INF-γ which represents hallmarks for Th17 and Th1 cells respectively and compare between them to determine whether RA is a Th17 cell mediated or a Th1 cell mediated disease; design and synthesize novel hydrophilic/biodegradable nano-particles for the formulation of developed drug delivery systems and investigate their physicochemical characteristics; examine the effect of nano-particle carriers as targeted drug delivery for conventional antirheumatic drug methotrexate on these immunological parameters reflecting the outcome of disease improvement and compare between MTX treated pristane-induced arthritis and MTX loaded onto nano-carrier as regards immunological parameters. This is in addition to the study of the possible side effects of methotrexate on different organs by histological examination of spleen, joint, liver and testes. A total of 72 adult male albino rats were used. RA was induced to groups of the experimental rats by intradermal injection of 150 l of pristane at the base of the tail. Animals were then put under the following different experimental regiments for a total duration of 10 weeks:- Group I: Normal Control group (C).
Group II: Methotrexate high dose group receiving i.p. injection of 0.5 mg of MTX/ kg b.wt./week (MTX/HD).
Group III: Methotrexate low dose group receiving i.p. injection of 0.25 mg of MTX/ kg b.wt./week (MTX/LD).
Group IV: Rheumatoid arthritis group (RA).
Group V: RA Group treated with i.p. injection of 0.5 mg of MTX/ kg b.wt./week (RA+ MTX/HD).
Group VI: RA Group treated with i.p. injection of 0.25 mg of MTX/ kg b.wt./week (RA+ MTX/LD).
Group VII: RA group treated with i.p. injection of 0.5 mg of MTX loaded onto nanocrystalline lignin / kg b.wt./week (RA+ MTX/L/HD).
Group VIII: RA group treated with i.p. injection of 0.25 mg of MTX loaded onto nanocrystalline lignin / kg b.wt./week (RA+ MTX/L/LD).
Group IX: RA group treated with i.p. injection of 0.5 mg of MTX loaded onto mesostructured silica nanocrystals / kg b.wt./week (RA+ MTX/ MSNCr/ HD).
Group X: RA group treated with i.p. injection of 0.25 mg of MTX loaded onto mesostructured silica nanocrystals / kg b.wt./week (RA+ MTX/ MSNCr/ LD).
Group XI: RA group treated with i.p. injection of 0.5 mg of MTX loaded onto nano iron oxide/micro-sized mesoporous silica / kg b.wt./week (RA+ MTX/ Fe-MSNPs /HD).
Group XII: RA group treated with i.p. injection of 0.25 mg of MTX loaded onto nano iron oxide/micro-sized mesoporous silica / kg b.wt./week (RA+ MTX/ Fe-MSNPs /HD). The results of investigation revealed alterations in different immunological parameters. There was a highly significant increase of both IL-17A and INF-γ levels in rheumatoid arthritis group as compared to normal controls which indicates that T helper17 and T helper1 cells have an important pathogenic role in rheumatoid arthritis. This increase was accompanied by diminished activity; loss of appetite, rapid development of arthritic signs that appeared first in metatarsal joints of the paws and progressed to include larger joint areas and very slight increase in their body weight. It was worth mentioning that, IL-17A mRNA gene expression showed highly significant elevation than INF-γ mRNA gene expression in rheumatoid arthritis group. In addition, IL-17A mRNA gene expression was more decreased than INF-γ mRNA expression in almost all treated groups (6 from 7 treated groups) which provides that TH17 has a more predominant role than TH1 in the pathogenesis of the disease. In addition, both IL-17A and INF-γ mRNA gene expressions in the spleen showed highly significant decreased levels in MTX treated groups comparison to rheumatoid arthritis group providing the beneficial effect of MTX in the treatment of rheumatoid arthritis. Also, Methotrexate loaded onto nanoparticles treated groups showed highly significant decreased in both IL-17A and INF-γ mRNA gene expressions in comparison to rheumatoid arthritis group with very limited side effects on spleen, liver and testis than groups treated with MTX only.Moreover, groups treated with low doses of MTX loaded onto nanoparticles showed enhanced results in comparison to those treated with high doses providing that the use of nanoscaled carriers in drug delivery is expected to increase specificity of drugs and thus reduce side effects by decreasing the dose of administered drugs. In conclusion, the present study emphasizes on the pathogenic role of Thelper-17 and Thelper-1 cells in rheumatoid arthritis. In addition, the more valuable role could be that of Thelper-17 cells. Methotrexate stimulates serious side effects to different tissue rendering it more harmful than beneficiary. Initiation of new drug delivery systems may attribute in delivery of the drug to the site of action and overcoming such therapeutic drawback. Further studies may also be presently recommended.