| 1. |
- Akhi, Shamima N, et al.
(author)
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Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus.
- 2013
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In: Fertility and sterility. - : Elsevier BV. - 1556-5653 .- 0015-0282. ; 99:3, s. 862-870
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate the effects of the immunosuppressant tacrolimus on rejection of a transplanted uterus and on uterine expression of markers of inflammation and implantation. DESIGN: Experimental study. SETTING: University laboratory. ANIMAL(S): Female rats. INTERVENTION(S): Uteri from brown Norway rats were transplanted to Lewis rats, receiving either tacrolimus or no treatment. Sham groups underwent either hemihysterectomy or tacrolimus treatment. MAIN OUTCOME MEASURE(S): Gross morphology, histology, density of T-lymphocytes by immunohistochemistry, and mRNA levels of interleukin (IL)-1α, leukemia inhibitory factor (LIF), galectin-1, CD200, IL-15, interferon-inducible protein-10 (IP-10), and nuclear factor-κB (NF-κB) at 14 days' post-transplantation. RESULT(S): Nontreated uterine grafts showed rejection with necrosis. Sham groups and the tacrolimus-treated transplanted group exhibited normal uterine morphology with low numbers of T-lymphocytes in all uteri except in two out of seven uteri of the tacrolimus-treated transplant group. Uteri of the nontreated transplanted group showed elevated mRNA expression of IL-1α and IP-10 and reduced galectin-1, compared with the tacrolimus-treated transplanted group. There was no difference between any groups concerning uterine expression of LIF, NF-κB, IL-15, and CD200. CONCLUSION(S): Tacrolimus monotherapy suppresses rejection of an allotransplanted uterus and normalizes the expression of IL-1α and IP-10 and prevents T-lymphocyte infiltration.
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| 2. |
- Akhi, Shamima N
(author)
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Uterus transplantation: an experimental study in the rat model
- 2012
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Doctoral thesis (other academic/artistic)abstract
- One of the last frontiers to conquer in infertility research is to find a treatment for uterine factor infertility, which affects around 2500 Swedish women. These women cannot become pregnant or carry a pregnancy due to absence of uterus or presence of non-functioning uterus. During recent years, several animal models have been used in research to develop uterus transplantation into a clinical treatment for uterine factor infertility. In the present study, the rat was used as a uterus transplantation model to look at various aspects of the procedure. A first model for uterus transplantation in the rat, with vascular anastomosis, was developed. In this model, the native uterus was compared to a heterotopically placed grafted uterus within the same strain of inbred rats. There was good viability of the tissue and an untrained surgeon could master the procedure after around 20-30 surgeries. In the second study, the uterus transplantation model was modified further to allow for spontaneous mating and test of pregnancy. Pregnancy was achieved after natural mating and the number of pups and growth trajectory of the pups in this model was similar to that of controls. In tests of allogeneic uterus transplantation, effects of immunosuppression were evaluated. Transplanted rats received either no treatment or tacrolimus as monotherapy. One sham-surgery group and one sham-group treated with tacrolimus were included as controls. It was shown that rejection occurred in the non-tacrolimus treated transplanted group but that normal uterine morphology was seen in the tacrolimus treated transplanted group. Low numbers of T-cells were seen in most allografts treated with tacrolimus. Levels of the cytokines IL-1 and IP-10 were increased in the non-treated transplanted group and levels of the implantation marker galectin-1 were normalized after tacrolimus treatment. Different sites of diagnosis of rejection were tested. In a fully allogeneic model, the histology of the graft was analysed at day 4 or 7. On day 4, morphological signs of early rejection were found both in the myometrium, endometrium, uterine cervix and in the blood vessels. Inflammation with primarily neutrophils and lymphocytes was seen. At day 7, the inflammation was greater with also focal hemorrhage. It can be concluded that early events of rejection in a uterus transplantation model is seen in all the examined compartments and the cervix may be an appropriate site for clinical diagnosis of early rejection. The most important functional issue to test in uterus transplantation is whether uterine allografts can carry a pregnancy. Rats with allogeneic uterine transplants were treated with tacrolimus. The pregnancy rate was similar in the transplanted and tacrolimus-treated group as in the control groups. These experiments ended during late gestation and no further follow-up of the pregnancy was performed. In a follow-up paper of allogeneic transplantation, the pregnancies went to term. Birth weight was similar in the transplanted group that was treated with tacrolimus as in the control groups. The post-natal growth up to 100 days was also similar, but with somewhat larger weight for males born from the uterus transplanted group. In summary, the thesis presents important background data for further development of uterus transplantation towards clinical introduction.
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| 3. |
- Díaz-García, César, et al.
(author)
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First report on fertility after allogeneic uterus transplantation.
- 2010
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In: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 89:11, s. 1491-4
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Journal article (peer-reviewed)abstract
- Uterus transplantation may become the first available treatment for uterine factor infertility, which is due to the absence or malfunction of the uterus. Here we describe for the first time pregnancy after allogeneic uterus transplantation, as a proof of concept of uterine function in a transplanted uterus in a standardized animal model (rat) under immunosuppression.
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| 4. |
- Diaz-Garcia, César, et al.
(author)
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The effect of warm ischemia at uterus transplantation in a rat model.
- 2013
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In: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 92:2, s. 152-159
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Journal article (peer-reviewed)abstract
- Objective: Uterus transplantation (UTx) has been proposed as a method to treat women with absolute uterine factor infertility. The aim of this study was to evaluate the viability of the transplanted rat uterus after exposure to long warm ischemic times, in order to mimic a time frame likely to occur in a human situation during complicated pelvic vascular anastomosis surgery. Design: Experimental study. Setting and population: Obstetrics and Gynecology Department. Female Lewis rats. Methods: Pseudopregnant rats were randomly allocated into two intervention groups: standardized syngeneic UTx procedure (Control; n= 10) and modified UTx protocol with a 4hour extended period of warm ischemia (n= 10). Main outcome measures: Scoring systems of gross morphology and histology at 3 and 6 days after transplantation. Results: Evident signs of necrosis were seen in five of 10 animals in the warm ischemia group compared to only one of 10 in the control group. Overall, uterine grafts from the warm ischemia group obtained poorer gross morphology scores. Histological findings correlated with the surgical findings at inspections day 3 and 6 after surgery. Conclusion: An extended warm ischemic time has detrimental effects on the survival of the uterus after transplantation.
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| 5. |
- Groth, Klaus, et al.
(author)
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Effects of immunosuppression by cyclosporine A on allogenic uterine transplant in the rat.
- 2012
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In: European journal of obstetrics, gynecology, and reproductive biology. - : Elsevier BV. - 1872-7654 .- 0301-2115. ; 163:1, s. 97-103
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Journal article (peer-reviewed)abstract
- OBJECTIVE(S): : Research on uterine transplantation (UTx) is conducted in preparation for its introduction in the human as a treatment for absolute uterine factor infertility. A major area of research in experimental animals is to ascertain that immunosuppressants that will be used at UTx do not negatively affect the potential of the uterus to implant an embryo and to carry a pregnancy to term. This study investigates the effects on a uterine transplant in the rat of the calcineurin inhibitor, cyclosporine A (CsA), on uterine morphology and expression patterns of some mediators involved in implantation/inflammation. STUDY DESIGN: : Donor rats were of Brown Norway strain and recipients were of Lewis strain. The uterus was transplanted to an orthotopic site by vascular anastomosis. The recipients were given CsA (10mg/kg) sc once daily or no CsA until they were sacrificed at postoperative day 7. Syngenic transplanted Lewis rats were used as controls. Uteri were analyzed regarding histology, immunohistochemistry against T-cells and mRNA levels of the implantation/inflammation-related markers leukaemia inhibitory factor (LIF), galectin-1, CD200, interleukin (IL)-1α, and IL-15. RESULT(S): : There was pronounced inflammation with abundance of CD8-lymphocytes in uterine grafts of non-CsA-treated animals and only mild inflammation in treated animals. The uterine mRNA levels of IL-1α were decreased after CsA in comparison to uteri of non-treated transplanted animals. The mRNA levels of galectin-1 were decreased in the rejected uteri and were higher in the CsA-treated. The levels of mRNA of IL-15 were lower in the syngenic transplanted group compared to the CsA-treated transplanted. There was no difference between the groups concerning mRNA levels of CD200, or LIF, with wide variation of the levels of the two latter mediators in all groups. CONCLUSION(S): : Cyclosporine A suppresses rejection of an allogenic rat uterine transplant, with normalization of mRNA levels of the proinflammatory cytokine IL-1α and the glycan-binding protein galectin-1.
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| 6. |
- Wranning, Caiza, 1963, et al.
(author)
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Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat.
- 2011
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In: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 26:3, s. 553-8
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Journal article (peer-reviewed)abstract
- Uterus transplantation (UTx) research aims towards the introduction of UTx as a treatment for uterine factor infertility. The rat model is the principal rodent model used and this study aims to assess the potential for pregnancy and to assess effects on pregnancy outcome.
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| 7. |
- Wranning, Caiza, 1963, et al.
(author)
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Uterus transplantation in the rat: model development, surgical learning and morphological evaluation of healing.
- 2008
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In: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 87:11, s. 1239-47
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Experimental uterus transplantation is a growing research field with the aim to develop a treatment for women with absolute uterus factor infertility. The potential risks of surgery and immunosuppressive treatment involved in uterus transplantation need to be identified and minimized in appropriate animal models before clinical trials commence. The aim of the present study was to develop and evaluate a model for uterus transplantation in the rat that can be reproduced and used in future studies concerning critical aspects of uterine function after transplantation. DESIGN: Animal study. SETTING: University Hospital. SAMPLE: Uterine tissue sampled at different post-operative time points after non-rejecting uterus transplantation in rats. METHODS: Adult, virgin female rats of inbred Lewis strain served as donors and recipients of uterine transplants. Two individuals with no previous microsurgical training performed the transplantations and learning curves were recorded. When transplant survival exceeded 70% for both surgeons, 15 animals were transplanted and grafted uteri were evaluated at 1, 7 and 21 days after surgery by assessment of morphology and enumeration of infiltrating neutrophilic granulocytes. MAIN OUTCOME MEASURES: Animal survival, graft survival, surgery times, uterine morphology, enumeration of infiltrating neutrophilic granulocytes. RESULTS: Both surgeons gained the necessary microsurgical skills needed to achieve above 70% transplant survival at a similar rate. The signs of post-operative inflammation on day one after transplantation were minor and further reduced at later time points. CONCLUSION: A reproducible model for uterus transplantation in the rat was developed, which can be used in future studies concerning uterine function after allogenic transplantation.
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