Related Experiment Video
Updated: Jul 20, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing
Carl K Edwards1, Alison M Bendele, Leonid I Reznikov
1Amgen, Inc., Thousand Oaks, California, USA. Carl.Edwards@UCHSC.edu
Objective:
The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha.
Methods:
A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha-/- mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis.
Results:
The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively).
Conclusion:
These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha.
Insights
Transmembrane tumor necrosis factor alpha (TNFalpha) drives arthritis development in mice. Inhibiting TNFalpha with soluble TNF receptors (sTNFR) effectively reduced inflammation and joint damage, offering insights into rheumatoid arthritis treatments.
Area of Science:
- Immunology
- Rheumatology
- Genetics
Background:
- The distinct roles of transmembrane (tmTNFalpha) and secreted tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) pathogenesis are not fully understood.
- Varied efficacy of anti-TNFalpha therapies suggests differing mechanisms of action, potentially targeting either tmTNFalpha or secreted TNFalpha.
Purpose of the Study:
- To investigate the specific roles of transmembrane TNFalpha in initiating and maintaining arthritis.
- To evaluate the therapeutic potential of soluble TNF receptors (sTNFR) in neutralizing tmTNFalpha-mediated arthritis.
Main Methods:
- Generation of three mouse strains: tmTNFalpha-transgenic, TNFalpha-knockout (KO), and tmTNFalpha-transgenic/TNFalpha-KO.
- Induction and assessment of arthritis through clinical and histopathological analysis.
- Treatment with vehicle, dexamethasone, or recombinant human sTNFR p55/p75.
Main Results:
- tmTNFalpha-transgenic/TNFalpha-KO mice exhibited severe inflammatory arthritis with spinal deformities, mimicking ankylosing spondylitis.
- Both tmTNFalpha-transgenic and tmTNFalpha-transgenic/TNFalpha-KO mice developed arthritis, with the latter showing earlier onset.
- Dexamethasone and sTNFR treatments significantly reduced arthritis severity and joint destruction in tmTNFalpha-transgenic/TNFalpha-KO mice.
Conclusions:
- Transmembrane TNFalpha is sufficient for initiating and sustaining arthritis in the studied mouse model.
- Recombinant human sTNFR p55 and p75 effectively neutralize tmTNFalpha, ameliorating arthritis development and its destructive consequences.
