Developmental Immunotoxicity In Rodents Exposed To Therapeutic Immunosuppressants During Pregnancy

Studies employing rodent fetal thymic organ cultures have showed that this type of ex vivo cyclosporine A exposure alters early development of thymocytes within the fetal thymus, completely blocking the generation of mature T cells (Kosugi et al. 1989). Laboratory mice exposed perinatally to cyclosporine A were found to display hypoplastic peripheral lymphatic organs, impaired intrathymic thymocyte differentiation, absence of mature T cells in lymph nodes and spleens, and lack of functional T-cell reactivity (Heeg et al. 1989). In these studies, mice were exposed to cyclosporine A during the third trimester of pregnancy, with continued postnatal exposure for as long as 28 days. Thus, the consequences of earlier prenatal exposure, as well as the contribution of prenatal exposure alone, to these immune alterations could not be delineated. However, rat pups exposed to cyclosporine A by lactation only displayed significant reduction in thymus cellularity with almost complete loss of medullary cells (Padgett and Seelig 2002). The thymocyte population from these rats showed increased immature CD4+8+ cells and decreased mature CD4+CD3hi and TCRhi subsets.

Cyclosporine A has also been found to interfere with tolerization of developing T lymphocytes in irradiated rodents following syngeneic bone-marrow reconstitu-

tion, resulting in increased autoimmunity (i.e., syngeneic graft-vs.-host disease) in the host animals (Glazier et al. 1983). Such results raise clear questions about the ability of cyclosporine A to induce or exacerbate autoimmune disease in gestationally exposed individuals. In support of this possibility, newborn mice dosed daily with cyclosporine A for the first week of postnatal life developed organ-specific autoimmune disease (Sakaguchi and Sakaguchi 1988, 1989). Such disease elicited in rodents appeared to be related to interference by cyclosporine A with the production or expansion of self-reactive T cells in the thymus (Sakaguchi and Sakaguchi 1992). Similarly, Classen (1998) found that cyclosporine A exposure during pregnancy in mice greatly increased prevalence of autoimmune disease in the offspring. These collective observations in irradiated and perinatal rodent exposure models, where new immune systems are being established in the presence of cyclosporine A, may suggest a heightened sensitivity to this and other agents that disrupt selection for autoreactive cells. In this regard, Zacharchuk et al. (1991) found that susceptibility of thymocytes to clonal deletion changes during ontogeny. Studies by these authors indicate that there is a relatively synchronous wave of maturing thymocytes that are susceptible to deletion signals during fetal life and shortly after birth, but not seven days after birth. This observation is in agreement with current understanding of neonatal tolerance, and further suggests that failure to induce tolerization in gluco-corticoid-exposed 1-week-old mice reflects an alteration in susceptibility to normal clonal deletion during that time (Zacharchuk et al. 1991).

Free Yourself from Panic Attacks

Free Yourself from Panic Attacks

With all the stresses and strains of modern living, panic attacks are become a common problem for many people. Panic attacks occur when the pressure we are living under starts to creep up and overwhelm us. Often it's a result of running on the treadmill of life and forgetting to watch the signs and symptoms of the effects of excessive stress on our bodies. Thankfully panic attacks are very treatable. Often it is just a matter of learning to recognize the symptoms and learn simple but effective techniques that help you release yourself from the crippling effects a panic attack can bring.

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