TNFα depleting therapy improves fertility and animal welfare in TNFα-driven transgenic models of polyarthritis when administered in their routine breeding.

Amy J Naylor,Guillaume Desanti,Rowan S Hardy,Atif N Saghir

doi:10.1177/0023677217707985

Abstract

Transgenic tumour necrosis factor alpha (TNFα)-driven models of polyarthritis such as the TNFΔARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans. Unfortunately, the onset of joint destruction and inflammation in these models represents a significant detriment to breeding management. We examined whether TNFα depleting therapy ‘infliximab’ might represent a significant refinement in routine breeding. Clinical scores of joint inflammation were assessed in TNFΔARE males receiving either infliximab (10 mg/kg) or saline by twice-weekly intraperitoneal injection. Joint histology and bone morphology were assessed by histological analysis and micro-computed tomography (CT), respectively. Analysis of breeding was examined retrospectively in TNFΔARE males prior to, and following, regular introduction of infliximab. Clinical scores of inflammation were significantly reduced in TNFΔARE males receiving infliximab (control 6.6 arbitrary units [AU] ± 0.88 versus infliximab 4.4 AU ± 1.4; P < 0.05), while measures of pannus invasion and bone erosion by histology and micro-CT were markedly reduced. In the breeding groups, TNFΔARE males receiving infliximab injections sired more litters over their breeding lifespan (control 1.69 ± 0.22 versus infliximab 3.00 ± 0.19; P < 0.005). Furthermore, prior to infliximab, TNFΔARE males had a 26% risk of failing to sire any litters. This was reduced to 7% after the introduction of infliximab. This study is the first to report that regular administration of infliximab is effective at suppressing disease activity and improving animal welfare in TNFΔARE animals. In addition, we have shown that infliximab is highly efficacious in improving breeding behaviour and increasing the number of litters sired by TNFΔARE males.

Highlights

Transgenic tumour necrosis factor alpha (TNFa)-driven models of polyarthritis such as the TNFÁARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans
Regardless of the underlying mechanism, when combined with our observations with disease activity and joint destruction, this study clearly demonstrates that regular administration of infliximab in TNFÁARE animals represents a significant refinement in their maintenance in breeding programmes, and markedly improves animal welfare
Non-significant trends were observed in the numbers of pups sired per litter, favouring increased numbers of males per litter. This result was perhaps unsurprising given that these mice survive longer without exceeding the criteria for their humane endpoints; and it undoubtedly reflects an improvement in animal welfare through reduced pain and distress – factors that are known to suppress mating behaviour in male rodents.[10]. These results clearly demonstrate that the application of regular infliximab injections in TNFÁARE breeding males represents a significant refinement in practice, allowing a reduction in animal numbers required in routine breeding to generate experimental animals

Summary

Introduction

Transgenic tumour necrosis factor alpha (TNFa)-driven models of polyarthritis such as the TNFÁARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans. Clinical scores of joint inflammation were assessed in TNFÁARE males receiving either infliximab (10 mg/kg) or saline by twice-weekly intraperitoneal injection. Prior to infliximab, TNFÁARE males had a 26% risk of failing to sire any litters This was reduced to 7% after the introduction of infliximab. In the seminal study by Keffer et al, a once-weekly injection of infliximab completely abrogated disease activity in hTNFtg mice, contributing to the commonplace application of biological anti-tumour necrosis factor alpha (TNFa) therapies as a gold standard in the treatment of chronic inflammatory disease.[2,7,8]

Methods

Results

Discussion

Conclusion