IMMUNOLOGY: ANIMAL MODELS

Observations in animal models have substantially advanced our knowledge of immune system adaptation, changes during the aging process, and age-associated degenerative diseases with autoimmune characteristics.

Animal models of immune adaptation

Animal models provided early proof that discrimination of self (that which the immune system identifies as belonging to the body) and nonself (that which the immune system identifies as foreign to the body) is determined not entirely at conception, but, to a large extent, during early fetal development by a process called immune adaptation. In 1945, Ray D. Owen reported that nonidentical cattle-twin embryos frequently share a common placenta, resulting in the exchange of blood between the fetuses. Owen discovered that this chimerism led to immune tolerance of skin grafts between the adult cattle. Their immune systems did not recognize allogeneic cells shared during the period of immune adaptation, when the immune system identifies cellular and molecular components of the body and memorizes them as self. Later, Milan Hasek connected the circulatory systems of chicken embryos and demonstrated tolerance of the adult birds to each other's tissues. In 1953, Peter B. Medawar and his colleagues demonstrated that the injection of foreign spleen cells into newborn mice resulted in adult tolerance of skin grafts from these foreign donors. These animal experiments confirmed the premise that immune adaptation is determined by the fetal or neonatal environment, rather than inherited.

Immunologic aspects of aging

Most immunologic activities decline with age, but some show an increase, and a few show no significant change. In principle, two types of cellular changes could alter immune functions: changes in the number of immune cells (quantitative change), and changes in the functional efficiency of immune cells (qualitative change).

Quantitative change. A modest loss of circulating lymphocytes (15 percent) has been observed in aging humans, but in mice the total number of immune cells does not change appreciably with age. Thus, cell loss does not appear to contribute significantly to changes in immune function with age.

Qualitative change. Metabolic, morphologic, and genetic studies present impressive evidence for age-related qualitative changes in immune cells. An important role in the regulation of immune reaction belongs to monocytederived cells (MDCs). These cells originate from monocytes, which leave the blood and differentiate into various types of tissue macrophages. Lymphocytes are the mediators of immunity, but their function is under the control of MDCs. The MDC system not only activates lymphocytes, it also makes lymphocytes tolerant or unreactive to self antigens, lymphocytes to self-antigens, thereby minimizing autoimmune reactions.

Studies in mice have shown that, with age, MDCs have a reduced capacity to stimulate proliferation and differentiation of lymphocytes. These results suggest an age-related shift in the regulatory activities of MDCs in the absence of a change in their numbers.

Age-associated diseases

Normal aging is inevitably associated with an overall decline of functional performance of all tissues (systemic change). However, some individuals develop degenerative diseases with autoimmune characteristics, resulting in the aging of tissue-specific cells (organ-specific change).

Systemic change. Although the complex mechanisms of the primary processes of aging are unknown, many theories have been proposed. The most popular concern pertubations of biologic systems, such as neuroendocrine or immune systems, or of the genetic program, as well as phenomena such as somatic-cell mutation, error accumulation and repair, entropy, and cell loss. The maximum life span of mammals (the life span of the longest-lived survivors) shows marked variations among species. Figure 1 shows that the extent of skin aging, as determined by the pentosidine level in skin collagen, substantially increases with the maximum life span for each species. Yet, the progressive increase begins with the onset of immune senescence, i.e., dimunution of T lymphocyte function accompanying age-associated involution of thymus and coinciding with the decline of immune-system function. These observations indicate that the onset of both immune senescence and skin aging are not dependent on time, but are genetically programmed for each species.

Studies of animal models have also shown that epigenetic factors, i.e., exogenous (environmental) substances and influences, which may silence or enhance the activity of genes, can influence longevity of individuals and prevent systemic changes. Early caloric restriction significantly extends the life span, retards the aging rate, and delays immunologic, biologic, and pathologic changes. The immune system of long-lived mice matured more slowly and declined later in life when subjected to a life-extending, calorically restricted (but nutritionally adequate) diet.

Organ-specific change. Along with gradual systemic aging, some individuals exhibit an accelerated organ-specific aging known as degenerative diseases with autoimmune characteristics. These diseases may affect virtually any tissue, but most frequently affected are neural tissues (multiple sclerosis and presenile dementia), the cardiovascular system (atherosclerosis), synovial tissue (rheumatoid arthritis), and the pancreas (diabetes mellitus). Degenerative diseases may have different etiologies, but they have in common an accelerated aging of tissue-specific cells caused by an inappropriate relationship of the immune system toward self.

In normal individuals, the first organ affected by aging is the ovary. Ovarian aging is not only of major importance in its own right, but is also of interest for its relationship to the general biology of senescence. There is a striking correlation between the period at which an organ is present during early ontogeny and that organ's functional longevity (see Figure 2). For instance, the liver, which differentiates very early, can (in human beings) function for over one hundred years. However the ovary, which differentiates much later, does not function for more than a half of that period.

Animal models have shown that additional restriction of ovarian development in early ontogeny, for instance by injection of androgens during immune adaptation, results in the premature aging of the ovary. Hence, epigenetic (or, in certain individuals, inherited) restriction of organ development prior to the end of immune adaptation can result in the reduction of tissue's functional longevity.

Conclusion

Animal models have substantially enhanced our understanding of the role of the immune system in tissue physiology and pathology. The dominant role belongs to MDCs, which influence the function of lymphocytes. The relationship between immune system and self is determined during immune adaptation, when the immune system may be programmed to ensure preservation of normal mature cells in self tissues. Epigenetic (environmental), or inherited alteration to early tissue development may contribute to the manifestation of organ-specific degenerative disease later in life. The knowledge gained from animal models offers hope for future modification of the human immune system to combat a number of disease processes.

Antonin Bukovsky Michael R. Caudle

See also Immune System; Nutrition, Caloric Restriction; Theories of Biological Aging.

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