Cyclosporine A exposure during pregnancy in mice: effects on reproductive performance in mothers and offspring.

BACKGROUND: Pregnancies after organ transplantation and under immunosuppressive treatment are associated with slightly elevated risks for obstetric and post-natal complications but can usually be managed well. However, little is known about the effects of intrauterine exposure (IUE) to immunosuppressants in the growing and adult offspring. One major issue is the potentially negative effects of immunosuppressive medication on reproduction. This study investigates the effect of exposure during pregnancy to the most commonly used immunosuppressant in organ transplantation, cyclosporine A (CsA), on the reproductive outcome in mothers and offspring. METHODS: Female C57CBA-F1 mice received 0, 10, 20 or 30 mg/kg bodyweight of CsA daily by subcutaneous mini-osmotic pumps during mating and pregnancy. Blood concentrations of CsA, implantation rates, resorption rates and fetal weights were analysed. In addition, female and male mice exposed to CsA in utero were mated to unexposed partners and pregnancy outcomes were analysed. RESULTS: Direct maternal exposure to CsA at high doses reduced implantation rates and fetal survival. IUE to CsA reduced adolescent growth but did not affect fertility, although a reduction in birthweight was seen in offspring of females exposed to CsA in utero. CONCLUSIONS: CsA exposure during pregnancy correlates with impaired reproductive outcome, but offspring fertility is not affected. The cause of reduction in adolescent weight gain and low birthweight in offspring of females exposed to CsA in utero need further investigation.

Fertility after autologous ovine uterine-tubal-ovarian transplantation by vascular anastomosis to the external iliac vessels.

BACKGROUND: Transplantation of the uterus has been suggested as a treatment of uterine factor infertility. This study investigates whether the sheep uterus can resume its capacity to harbour normal pregnancies after autotransplantation by vascular anastomosis. METHODS: From 14 ewes, the uterus, excluding one uterine horn, was isolated along with its oviduct and ovary and preserved ex vivo and then transplanted back with end-to-side anastomosis of the vessels of the graft to the external iliac vessels. After recovery, the ewes underwent surgical examination and serum progesterone measurements to ascertain healing and ovarian activity. Afterwards, five autotransplanted and five control ewes were placed with a ram for mating. Caesarean sections were performed before the estimated term of pregnancy and data on fetal measures were compared. RESULTS: Of the 14 ewes, seven survived surgery with ovarian activity intact and grafts showing normal appearance. Mating occurred in four of five transplanted ewes and in five out of five controls, and three transplanted animals and five control animals conceived. In one transplanted ewe, torsion of the uterus was observed after spontaneous initiation of labour. Foeti from transplanted mothers were comparable in size to those of controls. CONCLUSIONS: Despite the encountered complications, this is the first report to demonstrate fertility and pregnancies going to term after autotransplantation of the uterus in an animal of a comparable size to the human.

Rejection of allogenic uterus transplant in the mouse: time-dependent and site-specific infiltration of leukocyte subtypes.

BACKGROUND: Animal models of uterus transplantation are being developed ahead of a possible treatment for absolute uterus infertility in women. Our knowledge of inflammatory cell involvement in acute rejection of a uterus transplant is limited; therefore, we examined the pattern of invasion of leukocyte subtypes into an allogeneic uterus transplant. METHODS: The uterus and its vasculature were removed from BALB/c mice and transplanted into C57Bl/6 recipient mice at a heterotopic position, with the native uterus left in situ. Both uteri were removed on post-operative day 2 (D2, n = 5), D5 (n = 5) and D10 (n = 6). Immunohistochemistry for neutrophilic granulocytes, macrophages, cytotoxic CD8(+) T-cells, CD4(+) T-helper cells and B-cells was performed and cell density was evaluated in both myometrium and endometrium. RESULTS: Neutrophil density was increased in graft versus native uteri at D5 and D10 in myometrium and D10 in endometrium, and in endometrium was higher in the D5 than D2 graft (all P < 0.05). Infiltration of macrophages occurred from D2 in myometrium and from D5 in endometrium (P < 0.05, graft versus native). Density of CD8(+) cytotoxic T-cells increased in the graft versus native uteri at D5 in both uterine layers and for the graft versus D2 density (P < 0.01). In contrast, CD4(+) T-helper cells increased only transiently in graft endometrium at D5 (P < 0.05). Overall CD19(+) B-cell density was low, with no time-dependent changes in graft myometrium or endometrium. CONCLUSIONS: Acute rejection of an allogeneic uterus transplant in the mouse involves influx of predominately neutrophils, macrophages, CD8(+) T-cells and CD4(+) T-cells between D2 and D5 post-operatively.

Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model.

BACKGROUND: A mouse uterus transplantation model has previously been developed for studies of various aspects of uterine transplantation, which in the future may be used as treatment for uterine infertility. The aim of the study was to evaluate the effect of the immunosuppressant cyclosporine A (CyA) on the rejection of the allotransplanted uterus in the mouse. METHODS: C57BL/6 mice were recipients of uteri from F1 hybrids (C57BL/6 x CBA/ca). Transplanted mice received vehicle (control, n=5), 10 or 20 mg/kg/day of CyA (CyA10, n=5 and CyA20, n=5). Untreated F1 hybrids with syngeneic transplants (n=3) were negative controls. On day 10 post-transplantation, the grafted uteri were examined, and biopsies were taken for histology and quantification of T cells. RESULTS: Histology analysis revealed necrosis of the uterine transplants in controls and to a lesser extent in the CyA groups. Apoptosis and inflammation was prominent in grafts from the CyA10 group but suppressed in the CyA20 group. A similar increase of CD4+ cells was seen in all groups, whereas the number of CD8+ cells was higher (P < 0.05) in the two allogeneic groups receiving CyA compared with the allogeneic vehicle group. CONCLUSIONS: CyA treatment clearly delays the progress of rejection of grafted uteri but is insufficient to suppress T cell infiltration. Interestingly, the number of CD8+ cells was higher in groups receiving CyA, possibly reflecting a CyA-dependent depression of activation-induced cell death (AICD) of cytotoxic T cells.