Animal Species for the Model

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To answer all preclinical questions the model should manifest the human disease process under evaluation and possess immunologic characteristics similar enough to humans to allow an estimation of autoimmune and allogenic rejection. Models for many human endocrine diseases have been established in mice, including type 1 diabetes mellitus (DM) (64-67), type 2 DM, thyroiditis (68), and osteoporosis (Table 2) (69,70). But nonhuman primates, who share similar immune systems to humans, do not spontaneously develop all of the human diseases of interest, in particular type 1 DM. Because there is not a single animal model that is ideally suited to answer all preclinical questions, careful integration of the results collected from multiple animal models into a coherent framework may be the only viable alternative.

Even though representative animal models do not exist for every human disease, several are represented, among them genetically based diseases, several species of cancer, and autoimmune conditions. Rodents are typically the first choice for a model as they have a very high reproduction rate, a short life-span, and mature quickly. This makes it possible to follow the effect of an intervention over many generations and to develop genetic models of disease with the help of molecular biologic techniques including transgenics and gene knockouts. One mouse model is the SCID mouse, which models have been used to identify pluripotent stem cells (41). Intravenous injection of irradiated SCID mice with human bone marrow, cord blood, or granulocyte-colony stimulating factor (G-CSF) cytokine-mobilized peripheral blood mononuclear cells resulted in the engraftment of a human hematopoietic system in the murine recipient demonstrating uniform donor acceptance in these animals. The SCID mice model will be used in the first critical stem cell transplant experiments allowing evaluation of the stem cells in the absence of immuno-modulatory drugs.

Rodent models for genetic diseases have also originated through spontaneous mutations as opposed to genetic manipulation. The NOD mouse model represents a naturally occurring model genetically predisposed to autoimmune diseases including type 1 DM (64). NOD mice generally develop diabetes between 12 and 16 weeks of age. Given the reliable and early onset of diabetes and the

Table 2

Animal Models for Endocrine Diseases

Table 2

Animal Models for Endocrine Diseases

Disease state

Animal model




Type 1 DM,

BB-DP rat

Autoimmune; lower

Increased non-insulin-mediated



NOD mouse

maintenance costs

glucose disposal; ease in reversing disease; differences in immune system

Type 1 DM,


Glucose disposal

No autoimmunity



similar to humans;


onset of disease regulated

Type 2 DM

GK rat ZDF rat

Obesity, insulin resistance


Ob/ob mouse

Obesity, insulin


Db/db mouse


Rhesus and cynomolgus

Obese, spontaneous DM

No transgenic approach



Spontaneous, amyloid


Spontaneous amyloid deposition in islets



Dog (beagles)

Spontaneous lymphocytic infiltration


BALB/c mice

Th2 thyroiditis



Graves disease model


OVX rat


Weight gain suppress loss


Increased sensitivity to

of cancellous bone


loss of estrogen

On-going longitudinal growth

OVX baboon

Closes model to humans

Increased bone turnover at 6 months



Drug induced decrease in bone

Doesn't mimic all aspects of human





Aging cynomolgus

Similar pathophysiology

Length of time to


and rhesus monkey

to humans

manifest disease (10-30 years) Difficulty in handling

DM, diabetes mellitus.

DM, diabetes mellitus.

autoimmune nature of the disease process, this model is ideal for beginning in vivo testing of stem cell therapies for autoimmune-based endocrine diseases. However, there are substantial differences between rodent and primate physiology that limit the translation of information from any murine model to humans. Differences in p-cell physiology have been noted between species, which could be important in assessing the p-cell phenotype (71). In the case of diabetic therapies, rodents have much higher non-insulin-dependent glucose disposal; thus, the use of a rodent model may over estimate the clinical benefit of cell therapy.

Primates and rodents also have notable differences in their immune responsiveness that could affect the transplantation of stem cells (72). Such differences have been noted in prior testing of autologous transplantation and, along with differences in islet isolation, have contributed to significant delay in the development of successful human islet transplantation protocols (73). The use of nonhuman primates, including the rhesus macaque, has provided invaluable, clinically relevant information including tissue quantities, graft sites, and immune responsiveness not available from the rodent model (74,75). These results have contributed to the development of successful whole islet transplantation protocols.

Finally, primate (monkey and human) ES cells differ from mouse ES cells in their morphology, cell-surface marker expression, and sensitivity to leukemia inhibitory factor (76). Moreover, the nonhuman primate shares genetic diversity in MHC proteins demonstrated by humans but not by rodents. As such, the immune sensitivity to donor tissue is similar between nonhuman and human primates. For these reasons, it will be necessary to reassess the clinical efficacy of these therapies established in rodent studies, in nonhuman primates before beginning clinical trials in humans.

Nonhuman primates such as baboons and Old World macaques have long been used as animal models for basic and preclinical studies (74,75,77-81). By virtue of their anatomic, physiological, and genetic similarities to humans, studies have been performed during the entire spectrum of development from embryonic to pubertal and from adult to aging. For the most part, the research results can be translated readily to human biology, and in some cases to clinical trials. However, only a few nonhuman primate models are available for therapeutic studies limiting the potential needs of stem cell-based trials. For example, a monkey model of autoimmune (type 1) DM has not been established; therefore, it will not be possible at the present time to perform allogenic transplantation of insulin-producing phenotypes derived from monkey embryonic stem cells into monkeys with this form of diabetes. Development of a primate model of autoimmune diseases would greatly strengthen the preclinical trials of stem cell therapies for endocrine disorders. Short of developing an autoimmune primate model, surrogate primate models using chemically induced, p-cell failure can be used.

In addition, an obese monkey model is available to evaluate cell-based therapy as a type 2 DM preclinical model.

There are other nonhuman primate models established for research in cell-based replacement therapies, including a model of radiation-induced myelo-suppression (ablation of hematopoiesis and blood cells) for bone marrow or hematopoietic stem cell transplantation (82,83), a model of Parkinson's disease (loss of dopaminergic neurons in the midbrain and striatum) induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) for preclinical trials of striatal transplantation of fetal mesencephalic neurons (84-86), and a model of Huntington's disease (loss of GABAergic and cholinergic neurons in the striatum and thalamus) induced by quinolinic acid administration is also available

(87). Monkey models have also been used for AIDS research and vaccine development (77) and for myoblast transplantation for the treatment of myopathies

(88). Therefore, given the strengths and drawbacks of nonhuman primates and other animal models, it will be necessary to perform in vivo testing in a progressive, stepwise manner beginning with rodent studies and progressing to nonhuman primates studies (see Fig. 1). Integration of results from all animal and in vitro studies will be essential to understand and define the risks and the benefits of stem cells transplantation before clinical trials in humans

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