T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3-rich synovium lacks response to CTLA-4ig but is successfully treated by interleukin-17 neutralization (original) (raw)
Activated T Lymphocytes of the Synovial Membrane in Rheumatoid Arthritis and Other Arthropathies
Scandinavian Journal of Immunology, 1985
Immunohistological techniques were used to identify activated T lymphocytes within the synovial membrane of patients with rheumatoid arthritis, using the monoclonal antibody (MoAb) RFT2, which identifies a 40-k dalton molecule preferentially expressed by T blasts or activated cells. Using this reagent together with a monoclonal ‘cocktail’ that stains all T cells, cell counts on consecutive sections of rheumatoid synovium revealed that up to 50% T lymphocytes were RFT2+ (range 9.3-50.2%, mean 25.4). Subsequent analysis using combination immunofluorescence demonstrated that over 90% of these activated cells were of the T4+ subset. Furthermore all these cells appeared to be Leu8-. suggesting that the activated population were exclusively ‘true helpers’ and not suppressor inducers. Studies indicated that 50% of the RFT2+ cells were positive with anti-Tac MoAb. Comparisons with tissues from other arthropathies demonstrated that this relatively high proportion of RFT2+ cells was a feature restricted to rheumatoid arthritis, although biopsies from patients with psoriatic arthritis and ankylosing spondylitis also contained activated cells. Biopsies of Reiter's syndrome, osteo-arthritis, and pigmented villonodular synovitis contained no activated cells, no were any seen in sections of normal synovium. The presence in rheumatoid synovial membrane of activated T cells which are only of the T4+, Leu8+ subset adds weight to the suggestion that local immunoregulatory dysfunction contributes to the chronic inflammation of rheumatoid arthritis.
Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis
The Journal of Immunology, 2011
CD4 + CD25 + Foxp3 + regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-a blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-a overexpression in vivo and of TNF-a inhibiting treatments. We used human TNF-a transgenic mice as a model of strictly TNF-a-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-a transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-a with either the anti-human TNF-a Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-a strategies promoted the differentiation of a CD62L 2 Treg population. In conclusion, in an in vivo model of TNF-a-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-a-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L 2 Treg population.
Development of a new humanized mouse model to study acute inflammatory arthritis
Journal of Translational Medicine, 2012
Background: Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis. Methods: One to two-day old irradiated NOD-scid IL2rγ null (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund's adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically.
Arthritis Research & Therapy, 2010
Introduction: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mainly affects synovial joints. Biologics directed against tumor-necrosis-factor (TNF)-α are efficacious in the treatment of RA. However, the role of TNF receptor-1 (TNFR1) in mediating the TNFα effects in RA has not been elucidated and conflicting data exist in experimental arthritis models. The objective is to investigate the role of TNFR1 in the synovial lining cells (SLC) and the reticuloendothelial system (RES) during experimental arthritis. Methods: Third generation of adenovirus serotype 5 were either injected locally in the knee joint cavity or systemically by intravenous injection into the retro-orbital venous sinus to specifically target SLC and RES, respectively. Transduction of organs was detected by immunohistochemistry of the eGFP transgene. An adenoviral vector containing a short hairpin (sh) RNA directed against TNFR1 (HpTNFR1) was constructed and functionally evaluated in vitro using a nuclear factor-kappaB (NF-κB) reporter assay and in vivo in streptococcal cell wall-induced arthritis (SCW) and collagen-induced arthritis (CIA). Adenoviruses were administered before onset of CIA, and the effect of TNFR1 targeting on the clinical development of arthritis, histology, quantitative polymerase chain reaction (qPCR), cytokine analyses and T-cell assays was evaluated. Results: Systemic delivery of Ad5.CMV-eGFP predominantly transduced the RES in liver and spleen. Local delivery transduced the synovium and not the RES in liver, spleen and draining lymph nodes. In vitro, HpTNFR1 reduced the TNFR1 mRNA expression by three-fold resulting in a 70% reduction of TNFα-induced NF-κB activation. Local treatment with HpTNFR1 markedly reduced mRNA and protein levels of interleukin (IL)-1β and IL-6 in SLC during SCW arthritis and ameliorated CIA. Systemic targeting of TNFR1 in RES of liver and spleen by systemic delivery of Ad5 virus encoding for a small hairpin RNA against TNFR1 markedly ameliorated CIA and simultaneously reduced the mRNA expression of IL-1β, IL-6 and Saa1 (75%), in the liver and that of Th1/2/17-specific transcription factors T-bet, GATA-3 and RORγT in the spleen. Flow cytometry confirmed that HpTNFR1 reduced the numbers of interferon (IFN)γ (Th1)-, IL-4 (Th2)-and IL-17 (Th17)-producing cells in spleen. Conclusions: TNFR1-mediated signaling in both synovial lining cells and the reticuloendothelial system independently played a major pro-inflammatory and immunoregulatory role in the development of experimental arthritis.
Arthritis & Rheumatism, 1992
Our understanding of the immunopathogenesis of rheumatoid arthritis (RA) has undergone a major revolution if we compare the concepts propounded 30 years ago with those proposed today. Synovitis is no longer conceived as an antibody-mediated process involving rheumatoid factors and immune complexes, but rather as a cell-mediated process involving T cells, antigen-presenting cells (APC), macrophages, synoviocytes, and cytokines. Recently, Firestein and Zvaifler have proposed that the pathogenesis of RA is predominantly based on macrophages (1). This hypothesis stems from their observations, and those by other groups, that the rheumatoid synovium (SM) expresses messenger RNA (mRNA) and protein products for a whole host of macrophage monokines, while it is d a c u l t to detect T cell products. These differences between the T cell and the macrophage "schools" may only be quantitative; nevertheless,
TNF blockade requires 1,25(OH)2D3 to control human Th17-mediated synovial inflammation
Annals of the Rheumatic Diseases, 2012
Objectives T helper 17 (Th17) cells from patients with early rheumatoid arthritis (RA) induce a proinfl ammatory feedback loop upon RA synovial fi broblast (RASF) interaction, including autocrine interleukin (IL)-17A production. A major challenge in medicine is how to control the pathogenic Th17 cell activity in human infl ammatory autoimmune diseases. The objective of this study was to examine whether tumour necrosis factor (TNF) blockade and/or 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) controls Th17-mediated synovial infl ammation. Methods Peripheral CD4+CD45RO+CCR6+ Th17 cells of patients with early RA, Th17-RASF cocultures and synovial biopsy specimens were cultured with or without 1,25(OH) 2 D 3 and/or TNFα blockade. Intracellular cytokine expression was detected by fl ow cytometry. Cytokine and matrix metalloprotease (MMP) production was determined by ELISA. Results The authors show that the 1,25(OH) 2 D 3 , but not TNFα blockade, signifi cantly suppressed autocrine IL-17A production in Th17-RASF and synovial biopsy cultures. Combining 1,25(OH) 2 D 3 and TNFα blockade had a signifi cant additive effect compared with single treatment in controlling synovial infl ammation, indicated by a further reduction in IL-6, IL-8, MMP-1 and MMP-3 in Th17-RASF cocultures and IL-6 and IL-8 expression in cultures of RA synovial tissue. Conclusions These data show that TNF blockade does not suppress IL-17A and IL-22, which can be overcome by 1,25(OH) 2 D 3 . The combination of neutralising TNF activity and 1,25(OH) 2 D 3 controls human Th17 activity and additively inhibits synovial infl ammation. This indicates more valuable therapeutic potential of activation of Vitamin D receptor signalling over current TNF neutralisation strategies in patients with RA and potentially other Th17-mediated infl ammatory diseases. ▶ Additional tables are published online only. To view the fi les please visit the journal online at