Prenatal TCDD causes persistent modulation of the postnatal immune response, and exacerbates inflammatory disease, in 36-week-old lupus-like autoimmune SNF1 mice.

BACKGROUND: Prenatal exposure to the persistent environmental pollutant and model Ah receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to permanently suppress postnatal cell-mediated immunity. More recently, skewing of select adult T and B cell responses toward enhanced inflammation has also been described in C57BL/6 mice after prenatal TCDD. This raises questions about adverse postnatal immune consequences of prenatal TCDD in animals genetically predisposed to inappropriate inflammatory responses. METHODS: Lupus-prone SNF(1) mice were exposed to 0, 40, or 80 µg/kg TCDD on gestation day (gd) 12 and examined at 36 weeks-of-age for immunomodulatory effects that correlated with worsened lupus pathology. RESULTS: Bone marrow pro- and large pre-B cells were decreased by prenatal TCDD, in both adult male and female mice, as were pre- and immature B cells. Splenic CD23(-) CD1(hi) and CD19(+) CD5(+) B cells were increased in males, as were B220(hi) B cells in females, further suggesting persistent disruption of B cell lymphopoiesis by prenatal TCDD. Female mice displayed decreased IL-10 production by ConA-activated splenocytes, while males underproduced IL-4. Autoreactive CD4(+) Vß17a(+) spleen T cells were increased in both sexes by 80 µg/kg TCDD. Male mice but not females showed increased anti-ds DNA and cardiolipin autoantibody levels. CONCLUSIONS: Prenatal TCDD augmented the hallmark indicators of SLE progression in the lupus-prone SNF(1) mice, including renal immune complex deposition, glomerulonephritis, and mesangial proliferation. Prenatal TCDD therefore caused persistent modulation of the postnatal immune response, and exacerbated inflammatory disease, in lupus-like autoimmune SNF(1) mice.

Prenatal TCDD in mice increases adult autoimmunity.

Two immunologically different mouse strains, C57BL/6 and SNF(1), were exposed to a mid-gestation dose of TCDD. The C57BL/6 mouse has a high-affinity aryl hydrocarbon receptor (AhR) and is sensitive to TCDD. The SNF(1) mouse has a low-affinity AhR but spontaneously develops autoimmune nephritis. Autoreactive Vß(+)CD4(+)17a and Vß(+)CD3(+) T cells were increased at 24-weeks-of-age in offspring of C57BL/6 mice, more so in females than males. The cytokine IFN-γ was elevated in the females, while IL-10 was elevated in males. Phenotypic changes in B-lineage cells were present in bone marrow and spleen, and circulating autoantibodies were increased after prenatal TCDD. Kidneys of males showed significant anti-IgG and anti-C3 deposition, suggesting early-stage autoimmune disease. The SNF(1) offspring similarly showed increased peripheral Vß(+) cells in the females, increased autoantibody production in both sexes, and increased IFN-γ production in females. Male SNF(1) mice had increased anti-IgG and anti-C3 deposition in kidneys. Both mouse models therefore showed clear signatures of enhanced autoimmunity after prenatal TCDD.

Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts B-cell lymphopoiesis and exacerbates autoimmune disease in 24-week-old SNF1 mice.

Female SNF(1) hybrid mice spontaneously develop an immune complex-mediated glomerulonephritis as early as 24 weeks of age, whereas the disease onset in males is much slower. Further, a rise in concentration of glomerulus-specific autoantibodies via autoreactive B cells is critical to progression of the disease in this strain. Environmental factors contributing to the onset or degree of such autoimmunity are of interest yet poorly understood. In the present study, time-pregnant SWR x NZB dams (10/treatment) were gavaged on gestational 12 with 40 or 80 mg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the SNF(1) offspring were evaluated at 24 weeks of age. Bone marrow B220(low)CD24(-)AA4.1(+) committed B lineage progenitors were increased in female offspring by TCDD, however, committed progenitors and pro-B cells were decreased in males. Splenic marginal zone B cells (CD21(hi)CD24(low-int)) were decreased and follicular B cells (CD21(int)CD24(low)) were increased across sex by prenatal TCDD, whereas transitional-2 B cells (CD21(int)CD24(hi)) and (CD23(low-int) CD1(low-int)) were decreased in males only. Antibodies to double-stranded DNA were significantly increased across sex by TCDD. Anti-IgG and anti-C3 immune complex renal deposition was visibly worsened in females, and present in TCDD-treated males. These data suggest that developmental exposure to TCDD permanently and differentially alters humoral immune function by sex, and exacerbates a type III hypersensitivity lupus-like autoimmune disease in genetically predisposed mice.

Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters postnatal T cell phenotypes and T cell function and exacerbates autoimmune lupus in 24-week-old SNF1 mice.

BACKGROUND: Untreated, more than 95% of female SWR x NZB: F(1) (SNF(1)) mice spontaneously develop a fatal lupus-like glomerulonephritis by 8 months-of-age, while disease onset in males is much slower. METHODS: : Timed-pregnant SNF(1) mice (10 per treatment) were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestational day (GD) 12 by oral maternal gavage with 0, 40, or 80 microg/kg TCDD. RESULTS: Offspring of the TCDD-exposed dams showed numerous alterations in T lineage cells at 24 weeks-of-age. Females but not males showed decreased CD4(+)8(+) and increased CD4(-)8(-) thymocytes. Females also showed increased autoreactive CD4(+)Vbeta17(a+) axillary and inguinal lymph node T cells. Concanavalin A-stimulated splenocytes from prenatal TCDD-treated mice produced decreased interleukin 17 (IL-17) in the females while males showed increased IL-2 and IFN-gamma, and diminished IL-4. Mitogen-stimulated pan-lymphoproliferative responses were significantly increased across sex by TCDD. Anti-IgG and anti-C3 immune complex deposition in kidneys was present in the males after TCDD, and visibly worsened in females. CONCLUSIONS: Developmental TCDD exposure can permanently alter T lymphopoiesis in autoimmune-prone SNF1 mice. The alteration profile is beyond the classic immune suppression response, to also include exacerbation and induction of a lupuslike autoimmune disease.

Mid-gestation exposure of C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin causes postnatal morphologic changes in the spleen and liver.

Pregnant C57BL/6 mice were exposed to 5 microg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or vehicle by oral gavage between gestation days (GDs) 11 and 13. The thymus, spleen, and liver of the pups were examined histologically, and cell surface antigen expression was assessed on postnatal days (PNDs) 1, 14, 25, and 46. In addition to the expected decrease in thymic weight on PND 1, TCDD caused an increase in splenic weight on PND 14 and in hepatic weight on PNDs 14 and 25. The apoptotic index was increased and the corticomedullary border poorly defined in thymuses of TCDD-exposed mice on PND 1, but not at later endpoints. T lymphocytes were increased and B lymphocytes decreased in spleens of the TCDD-exposed mice on PND 46. TCDD-exposed mice had a nearly significant (p =.051) decrease in the number of splenic germinal centers on PND 46. Foci of extramedullary hematopoiesis (EMH) were increased in number in the livers of TCDD-exposed mice on PND 14, suggesting possible increased production of immune cells of unknown phenotype and function in this organ. These results suggest that late-gestation thymic architectural changes caused by TCDD resolve shortly after birth: however, abnormalities in other immunologically important areas may appear later in postnatal life.

Regulation of interleukin-2-induced vascular leak syndrome by targeting CD44 using hyaluronic acid and anti-CD44 antibodies.

Previous studies from our laboratory demonstrated that CD44 knockout mice exhibit marked decrease in interleukin (IL)-2-induced vascular leak syndrome (VLS), thereby suggesting a role for CD44 in VLS. In the current study, we tested whether treatment with mAbs against CD44 or hyaluronic acid (HA), the ligand for CD44, can abrogate IL-2-induced VLS. Interestingly, administration of HA caused a marked increase in IL-2-induced VLS in the lungs and liver of C57BL/6 mice. In contrast, use of anti-CD44 mAbs reduced IL-2-induced VLS in the lungs and liver. Treatment with HA enhanced the IL-2-induced edema and lymphocytic infiltration in these organs and caused marked increase in IL-2-induced lymphokine-activated killer (LAK) cell activity, whereas administration of anti-CD44 mAbs caused a significant decrease in edema and LAK activity but similar levels of lymphocytic infiltration. Anti-CD44 mAbs, but not HA caused marked downregulation of CD44 expression on LAK cells. These studies demonstrate that molecular targeting of CD44 may serve as a useful tool to selectively alter the LAK activity and to prevent endothelial cell injury induced by IL-2.