Common Effects of TCDD and CsA on T Cell Development

The developing immune system has been demonstrated to have a high sensitivity to TCDD. This, coupled with evidence that increased autoimmune disease may result following TCDD exposure in adult animals, has raised questions regarding possible relationships between prenatal exposure to TCDD and increased postnatal autoim-munity. Low-level maternal TCDD exposure results in atrophy of the developing thymus as well as inhibition of thymocyte differentiation (Table 13.2). T-progenitor cells from the fetal liver seed the developing thymus and are initially double negative (DN) with respect to CD4 and CD8 surface antigens. Subsequently, thymocytes develop sequentially through immature CD8lQ and CD4+8+ double positive stages in the thymic cortex, to mature CD4+ SP or CD8+ SP thymocytes in the thymic medulla by GD 18 to 19 (Hussman et al. 1988; Penit and Vaddeur 1989). TCDD produces a significant maturational delay in fetal thymocyte development as evidenced by these CD4 and CD8 surface antigens, which has been described as similar to the maturational inhibition produced in fetal thymic organ culture by the therapeutic

Table 13.2 Fetal Thymocyte CD Surface Marker Expression and Thymus Weight after TCDD Treatment

CD Marker Expression (% Positive)

TCDD

Vehicle 1.5 mg/kg

3 mg/kg

Note: CD4 and CD8 surface antigen expression determined in GD 18 fetal mice after maternal exposure to 1.5 or 3.0 mg/kg/day TCDD from GD 6 to 14. Values represent mean ± SEM of 5 mice per treatment group.

Source: Modified from Holladay et al. 1991.

immunosuppressive drug cyclosporin A (CsA) (Blaylock et al. 1992). Fetal thymic organ culture was used rather than in vivo exposure to study the effect of CsA on developing T cells because CsA crosses the placenta poorly (Nandakumaran and Eldeen 1990). Fetal mouse exposure to TCDD or ex vivo exposure of fetal mouse thymi to CsA decreased the percentage of DP cells (the most mature phenotype present in significant numbers in the end-gestation mouse fetus) and increased the percentage of both DN cells and immature (i.e., TCR-) CD8lD thymocytes. Positive and negative selection occur in the developing thymus and any intrinsic (hormonal) or extrinsic (chemical) insult on thymocyte maturation during critical periods of thymocyte selection for induction of self-tolerance may have significant and detrimental consequences on immune function in postnatal life (Billingham 1966); thus, this pattern of inhibition by TCDD or CsA raises questions about interference with neonatal development of tolerance by these chemicals.

MHC class II antigen expression in the thymus is reduced in rodents by CsA (Kosugi et al. 1989), an effect associated with development of autoimmune disease in Lewis rats exposed to CsA following lethal irradiation and syngeneic bone marrow reconstitution (Hess et al. 1985). Specifically, these studies demonstrated a T cellmediated autoimmune disease in the rats treated with CsA after bone marrow transplant, manifested as a syngeneic graft-vs.-host response (SGVHR). Briefly, the development of a chronic GVH-like disease, typical of that seen in rodents or humans following allogeneic marrow transplantation, was observed in the CsA-exposed rodents who had received syngeneic bone marrow transplants. This observation of a SGVHR was in fact the demonstration of an immune system rejecting "genetic self' (i.e., autoimmunity), indicating that CsA produced a fundamental disruption in development of self-tolerance. These authors went on to demonstrate that the CsA-induced autoreactivity was transferred with the CD8+ subpopulation of T cells, suggesting that CsA interfered with deletion of these cells during the establishment of a new immune system in the irradiated animals (Hess et al. 1990). More recently, human patients have been observed to develop SGVHRs after autologous hematopoietic stem cell transplantation and CsA treatment, indicating a similar altered pattern of T cell selection by CsA during reestablishment of the human immune system (Baron et al. 2000).

Relatively few papers have evaluated potential long-term immunologic alterations in offspring of human mothers who received therapeutic immune suppression with CsA during pregnancy. The papers that do exist are difficult to interpret in terms of effects of individual immunosuppressive drugs, since the pregnant women were most often exposed to drug combinations. It is clear that the developing human immune system can be at least transiently affected by maternal immunosuppressive therapies. For instance, numbers of B and mononuclear cells were significantly lower in neonates from transplant-recipient mothers who received CsA, azathioprine (AZA), and methylprednisolone during pregnancy (Takahashi et al. 1994). Ersay et al. (1995) similarly reported reduced B cell numbers and depressed serum IgG values at 3 and 6 months in infants whose mothers received CsA, AZA, and prednisolone during pregnancy. In one clinical report, the 23-year-old daughter of a renal transplant recipient developed multiple autoantibodies during her first pregnancy, while her second pregnancy was complicated by systemic lupus erythematosus (Scott et al. 2002). It was uncertain whether these autoimmune manifestations were related to fetal exposure to immunosuppressive drugs. Lytton et al. (2002) also recently observed autoantibodies against cytochrome P450 enzymes (e.g., CYP3A4, CYP3A5) in sera of children treated with immunosuppressive drug regimens that included CsA. For reasons such as these, other authors have suggested that long-term follow-up for autoimmune disease is warranted in individuals exposed in utero to immunosuppressive drugs (Prevot et al. 2002). This subject is covered in more detail in Chapter 11 of this textbook, "Developmental Immunotoxicity of Therapeutic Agents." The heavy metal lead is an additional developmental immunotoxicant that may increase risk of autoimmune responses following in utero exposure; this subject is covered in detail in Chapter 10 of this textbook, "Toxicity of Lead to the Developing Immune System."

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