Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery

Abstract

Background: The use of inbred mice housed under standardized environmental conditions has been critical in identifying immuno-pathological mechanisms in different infectious and inflammatory diseases as well as revealing new therapeutic targets for clinical trials. Unfortunately, only a small percentage of preclinical intervention studies using well-defined mouse models of disease have progressed to clinically-effective treatments in patients. The reasons for this lack of bench-to-bedside transition are not completely understood; however, emerging data suggest that genetic diversity and housing environment may greatly influence muring immunity and inflammation. Results: Accumulating evidence suggests that certain immune responses and/or disease phenotypes observed in inbred mice may be quite different than those observed in their outbred counterparts. These differences have been thought to contribute to differing immune responses to foreign and/or auto-antigens in mice vs. humans. There is also a growing literature demonstrating that mice housed under specific pathogen free conditions possess an immature immune system that remarkably affects their ability to respond to pathogens and/or inflammation when compared with mice exposed to a more diverse spectrum of microorganisms. Furthermore, recent studies demonstrate that mice develop chronic cold stress when housed at standard animal care facility temperatures (i.e. 22-24°C). These temperatures have been shown alter immune responses to foreign and auto-antigens when compared with mice housed at their thermo-neutral body temperature of 30-32°C. Conclusions: Exposure of genetically diverse mice to a spectrum of environmentally-relevant microorganisms at housing temperatures that approximate their thermo-neutral zone may improve the chances of identifying new and more potent therapeutics to treat infectious and inflammatory diseases.

Overexpression of TcNTPDase-1 Gene Increases Infectivity in Mice Infected with Trypanosoma cruzi

“…Santi-Roca (2017) [ 59 ] observed that BALB/c mice infected with different strains of T. cruzi (DTUs 1 to 6) showed variation in tissue damage and immune response between the acute and chronic phases of the infection. Another limitation of our study may have been the choice of outbred animals that, due to the fact that they are not isogenic animals and not free of specific pathogens (SPF), the genetic variability between individuals is large, allowing for greater disease resistance and requiring a greater number of animals for a robust result [ 60 , 61 ]. Therefore, it is possible that in our model, and with the use of outbred mice, the electrocardiographic changes observed were less pronounced and the use of a chronic phase model and isogenic mice, which has greater genetic homogeneity [ 62 ] and possibly increased susceptibility, needs to be evaluated.…”

The Immunomodulatory Effects of Social Isolation in Mice are Linked to Temperature Control

“…Finally, we used outbred CD-1 mice rather than widely used inbred C57BL/6 mice. We have consciously made this decision as it is now widely accepted that "the use of inbred mice to model human disease is tantamount to using multiple copies of one individual" (146,147).…”

Pneumocystis Pneumonia: Pitfalls and Hindrances to Establishing a Reliable Animal Model

“…However, care should be taken when interpreting the outcomes in these models because of redundancy in the immune system or compensatory hyperactivity that can lead to confounding effects [87]. In addition, scientists have to keep in mind that the use of such genetically modified or defined mice under standardized environmental conditions may influence host immunity and inflammation [88]. While the generation of such mice still remains complicated, expensive, and time consuming, they represent very useful biological tools for studying the host immune response to Pneumocystis.…”