thymosin and Arthritis--Rheumatoid

Topics: Adolescent; Adult; Aged; Animals; Arthritis, Rheumatoid; Child; Clinical Trials as Topic; Double-Blind Method; Humans; Immunologic Deficiency Syndromes; Middle Aged; Neoplasms; Rats; T-Lymphocytes; Thymosin; Thymus Hormones

The aim of this study was to evaluate whether thymosin β4 (Tβ4) levels are increased in the serum of rheumatoid arthritis (RA) patients, and if this increase is associated with RA disease activity and resistance to treatment. Blood samples from 40 patients with RA were collected at baseline and 6 months after starting treatment with disease-modifying antirheumatic drugs (DMARD) and/or tumor necrosis factor (TNF)-α blocker. Serum levels of Tβ4 were measured by ELISA. Tβ4 levels (mean ± standard deviation) in RA patients were significantly (approximately tenfold) higher than in healthy controls (577.4 ± 67.92 vs. 56.61 ± 5.72 ng/mL). Serum Tβ4 levels in patients with severe disease activity before therapy were slightly higher than in patients with moderate disease activity (662.4 ± 491.5 vs. 462.5 ± 305.3 ng/ml, P > 0.05). Tβ4 levels were significantly associated with disease activity according to the 28-joint Disease Activity Score. The mean Tβ4 level at baseline in the DMARD treatment group was significantly lower than in the DMARD + TNF-α blocker treatment group. Tβ4 levels were increased in the serum of patients with RA and were positively associated with disease activity. Levels of Tβ4 may also be relevant in determining or predicting resistance to RA treatment. Further studies are necessary to determine if Tβ4 is an appropriate therapeutic target for controlling inflammation associated with RA.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Resistance; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Severity of Illness Index; Thymosin; Tumor Necrosis Factor-alpha

Thymosin (Tβ4) may have various biological effects that are relevant to the pathogenesis of rheumatoid arthritis (RA). This study was performed to gain insight into the relevance of Tβ4 in the pathogenesis of inflammatory arthritis.. The level of Tβ4 in synovial fluid from patients with osteoarthritis (OA) or RA was measured by enzyme-linked immunosorbent assay. An association between Tβ4 and matrix metalloproteinase (MMP)-1 and MMP-13 (collagenases), MMP-2 and MMP-9 (gelatinases), MMP-7, adiponectin, lactoferrin, vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), interleukin (IL)-6, IL-8 and prostaglandin E2 (PGE(2) ) in synovial joint fluids from OA and RA patients were investigated.. The level of Tβ4 in the synovial joint fluid of patients with OA and RA was (mean ± SD) 145 ± 88 and 1359 ± 1685 ng/mL, respectively. The level of Tβ4 in the synovial joint fluid of RA patients was significantly associated with the levels of MMP-9, MMP-13, VEGF, uPA, IL-6 and IL-8, but not with MMP-1, MMP-2, MMP-7, adiponectin and lactoferrin. In contrast, the level of Tβ4 in the synovial joint fluid of patients with OA was not associated with any of these molecules.. The results suggest that Tβ4 may play an important role in bone degradation and inflammation in RA but not OA, although nothing is known about the molecular mechanisms mediating Tβ4 in arthritic joints. The role of Tβ4 in arthritis should be studied to understand its relevance to the pathogenic processes in arthritis.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Female; Humans; Inflammation; Joints; Male; Middle Aged; Osteoarthritis; Synovial Fluid; Thymosin

Prothymosin alpha (ProT) is regulated by c-Myc, an oncoprotein overexpressed in synovium of rheumatoid arthritis, and is associated with cell proliferation. However, ProT also exerts immunomodulatory activities. The growth-promoting activity of ProT can be abolished by deleting its nuclear localization signal (NLS). In this study, we showed that AdProTDeltaNLS, an adenoviral vector encoding ProT lacking the NLS, did not enhance the proliferation of synovial fibroblasts. AdProTDeltaNLS treatment abolished the up-regulation of the MIP-1alpha promoter activity induced by TNF-alpha in synovial fibroblasts. AdProTDeltaNLS suppressed macrophage chemotaxis and reduced macrophage infiltration into the ankle joints in rats with collagen-induced arthritis (CIA). Neutralization test confirmed the involvement of MIP-1alpha in macrophage chemotaxis. Administration of AdProTDeltaNLS reduced the severity of CIA in the clinical, radiographic, and histological aspects. The levels of TNF-alpha (mean +/- SEM, 1261.9 +/- 107.9 vs 2880.1 +/- 561.4 pg/mg total protein; p < 0.05), IL-1beta (56.8 +/- 8.0 vs 109.2 +/- 4.9 pg/mg total protein; p < 0.01), and MIP-1alpha (41.7 +/- 3.6 vs 55.2 +/- 1.1 pg/mg total protein; p < 0.05) in the ankle joints were lower in the AdProTDeltaNLS-treated rats with CIA than those in their control counterparts. In the AdProTDeltaNLS-treated ankle joints, matrix metalloproteinase-9 expression was decreased by 40% and infiltrating macrophages reduced by 50%. Our results demonstrate that intra-articular delivery of AdProTDeltaNLS significantly ameliorated the clinical course of CIA in rats. This study is the first to suggest that ProT lacking the NLS may have therapeutic potential for the management of rheumatoid arthritis.

Topics: Adenoviridae; Animals; Ankle Joint; Arthritis, Rheumatoid; Cell Proliferation; Chemokine CCL3; Chemokine CCL4; Chemotaxis; Collagen; Fibroblasts; Genetic Therapy; Genetic Vectors; Humans; Interleukin-1beta; Macrophage Inflammatory Proteins; Macrophages; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nuclear Localization Signals; Protein Precursors; Rats; Sequence Deletion; Synovial Fluid; Thymosin; Tumor Necrosis Factor-alpha; Up-Regulation

Interleukin-2 (IL-2) production and effects of thymosin fraction 5 (F5) on IL-2 production by peripheral blood mononuclear cells from patients with active rheumatoid arthritis (RA) were studied. Three patients with RA had elevated IL-2 production which was which was suppressed by F5. IL-2 production by peripheral blood mononuclear cells from 17 other patients with RA was similar to controls and was not affected by F5. Our results are consistent with hyperproduction of IL-2 by some patients with RA which is suppressed by F5.

Topics: Arthritis, Rheumatoid; Aurothioglucose; Cells, Cultured; Humans; Immunity, Cellular; Interleukin-2; Monocytes; T-Lymphocytes; Thymosin

Topics: Amino Acid Sequence; Arthritis, Rheumatoid; Humans; In Vitro Techniques; Rosette Formation; Thymosin

Peripheral blood lymphocytes (PBL) from patients with rheumatoid arthritis (RA) and age and sex-matched normal controls were compared in a Concanavalin A (Con A)-induced suppressor cell assay. Suppression induced by pre-incubation with Con A was significantly greater in PBL from RA patients than in PBL from normal controls. Preincubation with thymosin fraction 5, in the absence of Con A, also induced greater suppressor cell activity in PBL from normal controls. Preincubation with Con A and thymosin, simultaneously, induced suppression similar to that seen with Con A alone. These results suggest the presence of an immunoregulatory defect in RA, characterized by an excess of both Con A and thymosin-inducible suppressor cells, that may play a role in disease pathogenesis. The implications of these observations for immunotherapy of rheumatoid arthritis with thymosin are discussed.

Topics: Adult; Aged; Arthritis, Rheumatoid; Concanavalin A; Female; Humans; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Rosette Formation; T-Lymphocytes, Regulatory; Thymosin

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Cytotoxicity, Immunologic; Humans; Lupus Erythematosus, Systemic; Lymphocyte Culture Test, Mixed; Lymphocytes; Myasthenia Gravis; Thymalfasin; Thymosin; Thymus Gland; Thymus Hormones

Five patients with autoimmune disorders were given thymosin, fraction 5, parenterally for periods ranging from 2 to 35 mth. Four patients had systemic lupus erythematosus and the 5th had rheumatoid arthritis and Sjögren's syndrome. Treatment with thymosin was based on the hypothesis of a T-suppressor defect in these autoimmune disorders. Circulating T lymphocytes increased and remained above pretreatment levels in all patients. Assays for cytotoxicity, using mouse thymocytes and patients' sera, were positive initially and declined during the course of the treatment. In all patients, serum cytotoxicity levels were reduced to zero. There has been clinical improvement in 3 patients, and in 1, the disease has become stable. The evaluation of the 5th patient has been inconclusive. No ill effects related to the administration of thymosin were observed.

Topics: Adult; Arthritis, Rheumatoid; Autoimmune Diseases; B-Lymphocytes; Complement C3; Complement C4; Female; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Middle Aged; Rosette Formation; Sjogren's Syndrome; T-Lymphocytes; Thymosin; Thymus Hormones

The in vitro effect of calf thymosin fraction 5 on T-rosette forming cells (E-RFC) was studied in Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The baseline percent E-RFC in sixteen normal controls was67-2 +/- 6-9. E-RFC was significantly decreased in SLE (42-6 +/- 17-0, P less than 0-0001) and SS (51-8 +/- 16-9, P less than 0-002) but not in RA (59-7 +/- 14-1). Ten of twenty-five SS patients and two of eleven RA patients had less than 50% E-RFC, and all showed a significant increase after incubation with thymosin (+ 16-5 +/- 6-5%, P less than 0-0001, and + 11 +/- 4-9%, P less than 0-001, respectively). Eleven of sixteen SLE patients had less than 50% E-RFC. Their response to thymosin was less dramatic but still statistically significant (+ 5-3 +/- 6-0%, P = 0-03). There was no response to thymosin in control subjects or in patients with baseline E-RFC greater than 50%. No increase in E-RFC was seen after incubation with calf spleen fraction 5 or known stimulators of cyclic-AMP. Sera from four active SLE patients, as well as the supernatant obtained from overnight culture of the lymphocytes from one SLE patients, were able to block T-rosette formation by normal lymphocytes, even after exposure to thymosin. Two 'blocking' sera were fractionated by sucrose density gradient ultracentrifucation. In one, the blocking capacity was found to reside in the 19S region containing IgM. In the second, the blocking capacity was in the 7S region containing IgG. Four 'blocking' lupus sera were depleted of IgG or IgM by immunoabsorption with goat anti-human IgG or goat anti-human IgM sepharose 4B. The blocking ability in three sera was partially decreased by depletion of either IgG or IgM, and in a fourth, only by removing IgG. The percent of lymphocytes staining with fluorescein labelled goat anti-human immunoglobulin antisera was increased in SLE patients (35-9 +/- 20-2 vs 21-7 +/- 5-9 in controls, P = 0-02). After overnight culture, the percent of staining cells decreased to normal values. These results suggest that thymosin can stimulate the differentiation of T-lymphocytes in patients with SS, SLE, and RA when the baseline E-RFC is decreased. Furthermore, the decreased percent E-RFC in SLE is probably due to cell-bound anti-lymphocyte antibodies that block sheep erythrocyte receptors on the T-cell and, possibly, thymosin receptors on undifferentiated lymphocytes.

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Binding, Competitive; Female; Humans; Immunoglobulin G; Immunoglobulin M; Immunologic Techniques; Lupus Erythematosus, Systemic; Lymphocytes; Male; Middle Aged; Receptors, Antigen, B-Cell; Sjogren's Syndrome; T-Lymphocytes; Thymosin; Thymus Hormones