Animal models

Related article: In vitro studies

Animal models have long been used to test theories of and therapies for chronic inflammatory diseases. Among the different animal models, the rodent may be the most widely used. Because they are quick to reach sexual maturity and are easily kept and bred in captivity, rodents have been praised as prime experimental subjects.

Unfortunately, rodents and humans are strikingly different in a number of important ways, especially with regard to their immune system. Animal models of disease are not a valid mode for emulating chronic disease, including cancers. For this reason, there have yet to be any major breathroughs from murine (mouse) work; and there may never be.

Widespread use of rodents in human disease research

The use of rodents is widespread among researchers: mice have been used for models of cancer and any number of chronic diseases. So widely accepted is the use of mouse models that it has become difficult to identify which contributions are based on mouse models and which contributions are based on human models.

Unraveling the intricacies of human [Vitamin] D metabolism is often made extremely difficult by the intermingling of murine [mouse] and human biologies in the literature.

Trevor Marshall, PhD

According to a 2009 report, “Statistics of Scientific Procedures on Living Animals,” which examined research conducted in the United Kingdom, there has been a steady decrease in the number of scientific procedures using rats. (this graph page 12)

The Methuselah Foundation, an institute focused on human longevity, funds the Methuselah Mouse Prize or MPrize, a multi-million dollar award designed to hasten the research into effective life extension interventions. The MPrize awards researchers who stretch the lifespan of mice to unprecedented lengths. Even if the prize were awarded, there is legitimate reason to be concerned that the advances in curtailing murine diseases of the aging could not be successfully applied to humans.

Inconsistency among competing mouse models

It is sometimes the case that different rodent models lead an observer to competing conclusions.

To cite but one example, while the FDA currently accepts carcinogenicity studies of pharmaceutical drugs based on murine models, competing mouse models often conflict with each other. For example, during the FDA acceptance testing (2002) of the ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. olmesartan (Benicar)Medication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor., possible carcinogenicity observed in hamsters was not able to be duplicated in rats or in transgenic mice.

Failing to consistently account for microbes

Often, the implementation a mouse model will produce unexpected results, because it does not account for the role of microbes in causing disease, especially when it comes to microbes infecting immune cells.

How can one hypothesize a human environment where some classes of immune cells are infected and some are not? You can create those conditions in a lab, but not in-vivo.

Trevor Marshall, PhD

As described in the magazine, The Scientist, Stephen Miller from Northwestern University attempted to recreate virus-triggered demyelinating diseases such as multiple sclerosis in mice.

Working with these transgenic mice, he noticed that animals that normally develop autoimmunity did not do so when reared in a supersterile environment. Although the mice were engineered to express lots of T cells specific to myelin, the T cells were not attacking the central nervous system. The missing factor was their gut microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms.. “Now the big question is,” Wekerle says, “which bacteria in the gut are responsible for activation and triggering of the disease? Could it also be that in people with MS, the initial step has been in the gut?”

Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response., human and rat with the ARB olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. docked into the ligand binding pocket. Note how the orientation of the tetrazoles–that is, the five member rings seen on the top and bottom–have strikingly different orientations between one receptor and the next.

Differences between human and rodent immune function

Multiple studies have demonstrated that the immune systems of rats and humans are inherently different. Molecular modeling research has revealed that the activity of the human innate immune system is controlled by the Vitamin D Receptor. In humans, the Vitamin D Receptor performs several fundamental roles. Not only does it control the activity of the innate immune system, but it transcribes 913 genes, and possibly more. It also controls the production of many of the antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens.. These peptides kill bacteria, viruses, and fungi by a variety of mechanisms, including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell.1)2)

In contrast, the rat innate immune system is not controlled by the Vitamin D Receptor. It depends on a cascade of nitric oxide (an important signaling molecule) that functions in a manner yet to be fully understood. Rats do have Vitamin D Receptors, but they transcribe different genes than the human VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.. By using molecular modeling software, researchers at McGill University in Canada found many differences in the genes targeted by the rat and human Vitamin D Receptors. For example, the gene encoding a calcium binding protein called osteocalcin is “robustly” transcribed by the VDR in humans, but not in mice. In what proves to be a fundamental difference between mice and men, Manisha Brahmachary and team recently determined that the rat Vitamin D Receptor does not express the cathelicidin Family of antimicrobial peptides found primarily in immune cells and transcribed by the Vitamin D Receptor. antimicrobial peptides (AMPs)–marking an important difference in the way the two species kill invading pathogens.3) This means that rats and humans respond differently to molecules or drugs that affect the VDR and subsequently the innate immune system.

According to Mestas et al., there are significant differences between the way the rat and human immune systems develop, which affect “activation, and response to challenge, in both the innate and adaptive arms [of the immune system].” Such differences should not be surprising, as rats and humans diverged somewhere between 65 and 75 million years ago and differ hugely in both size and lifespan. According to Mestas, “They have also evolved in quite different ecological niches where widely different pathogenic challenges need to be met–after all, most of us do not live with our heads a half-inch off the ground.” Consequently, he argues that, “There has been a tendency to ignore differences and in many cases, perhaps, make the assumption that what is true in mice is necessarily true in humans. By making such assumptions we run the risk of overlooking vital aspects of human immunology that do not occur, or cannot be modeled, in mice.”4)

Validity of murine models

While there are certainly exceptions,5) generally speaking the murine immune system tends not to be a valid approximation of the human immune system.

In a systematic review comparing the treatment effects of animal experiments and clinical trials, Perel et al. review a number of examples where interventions used on animals are not duplicated in humans. These include head injury, antifibrinolytics in hemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroidsA first-line treatment for a number of diseases. Corticosteroids work by slowing the innate immune response. This provides some patients with temporary symptom palliation but exacerbates the disease over the long-term by allowing chronic pathogens to proliferate. to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis.

The evidence against the validity of many animal models is prompting some researchers to question the validity of animal studies.

Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.

Pablo Perel et al. 6)

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===== Notes and comments =====

obsolete links to Science journal, acceptance testing removed — Sallie Q 08.21.2017 non-functioning link to 2009 article replaced with link to UK govt archive

Pearce, B. D. (2003). “Modeling the role of infections in the etiology of mental illness.” Clinical Neuroscience Research 3(4-5): 271-282.

There are numerous psychiatric disorders of unknown etiology that have been tentatively linked with microbial pathogens, particularly viruses. These include autism, major depression, bipolar disorder, schizophrenia, and chronic fatigue syndrome. These disorders likely have multiple contributing etiologies, and viruses or bacteria may be tapping into pathophysiological pathways that are shared by other environmental triggers. Animal models have been important for elucidating such pathways. Experiments in animals have demonstrated that infections can influence neurotransmission, cause neurobehavioral abnormalities, and produce developmental changes in the brain that become manifested latently, i.e. after sexual maturity. Animal models are helping to clarify the role of cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. in sickness behavior, which could be relevant to major depression and chronic fatigue syndrome. Cytokines may also hold a central position in the neurodevelopmental origin for schizophrenia since there is emerging evidence that elevations in cytokines are associated with non-infectious obstetric complications (e.g. hypoxia) that have likewise been implicated as antecedents of schizophrenia. Nevertheless, infectious disease models in psychiatry have not come fully to fruition, and to realize their potential, they must continually incorporate new data from in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory. and human studies.

I think this is an interesting quote since HLA is used for linking to susceptibility to many autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body and other diseases. This points to the role of infection.


“Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells”

This is an interesting paper, as it explores the differences between the adaptive immune systems of primates. Sadly, they don't explore the human-disease-related haplotypes DRBx and DQBx except in their supplementary attachments, but they do mention the multiple functions of immune cells (in pregnancy and throughout life) (Biological complexity strikes again)…

..Trevor.. ps: Thanks to Ragnar for the link :)

pps: MHC - https://en.wikipedia.org/wiki/Major_histocompatibility_complex

Joyce liked this –

«A remarkable reversal of this trend occurred in Southeast Asia during the last ~55–65,000 years [45], where HLA-B*46, a recombinant allele that carries C1 and functions well as a ligand for KIR2DL2/3 [46], underwent a selective sweep to become the most frequent HLA-B allele. Resolution of human hepatitis C virus infection was associated with homozygosity for KIR2DL3 and its C1 ligand [55]. The potential benefit of HLA-B*46 is that it allows individuals to express three or four C1-bearing HLA-B and C allotypes. Thus the selective sweep of B*46 could have been driven by epidemic infection caused by a pathogen like the hepatitis C virus that is preferentially resisted by individuals having enhanced representation of C1 and its cognate inhibitory KIR. Interestingly, several reports describe B*46 as a risk factor for various current infectious diseases (Figure S8), illustrating the dynamic nature of these polymorphic genetic factors and the variable pressures placed on them by functions in both immune defense and reproduction.»

Parasites Unite!


What I like most : “In natural populations you have a complexity that has nothing to do with the extremely simple environmental conditions that laboratory animals face in their cages. We tend to study simple associations: one host and one parasite. The problem is that these are completely unrealistic situations, because we know that in nature a given host will never just encounter a single parasite. There is always a community of parasites that interacts, competes, and cooperates and faces a common host environment. So these things that interact and cooperate might completely change the outcome of the association we are studying.”


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1) , 3)
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