Preclinical report on allogeneic uterus transplantation in non-human primates

Liza Johannesson, Anders Enskog, Johan Mölne, Cesar Diaz-Garcia, A Hanafy, Pernilla Dahm-Kähler, A Tekin, P Tryphonopoulos, P Morales, K Rivas, P Ruiz, Andreas Tzakis, Michael Olausson, Mats Brännström

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Abstract

STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?

SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used.

WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks.

PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated.

MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity.

LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection.

WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed.

STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Original languageEnglish
Pages (from-to)189-98
Number of pages10
JournalHuman Reproduction
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

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Homologous Transplantation
Primates
Uterus
Immunosuppression
Papio
Tacrolimus
Iliac Artery
Research
Iliac Vein
Antilymphocyte Serum
Graft Survival
Therapeutics
Hysterectomy
Infertility
Blood Vessels
Veins
Adrenal Cortex Hormones

Cite this

Johannesson, L., Enskog, A., Mölne, J., Diaz-Garcia, C., Hanafy, A., Dahm-Kähler, P., ... Brännström, M. (2013). Preclinical report on allogeneic uterus transplantation in non-human primates. Human Reproduction, 28(1), 189-98. https://doi.org/10.1093/humrep/des381
Johannesson, Liza ; Enskog, Anders ; Mölne, Johan ; Diaz-Garcia, Cesar ; Hanafy, A ; Dahm-Kähler, Pernilla ; Tekin, A ; Tryphonopoulos, P ; Morales, P ; Rivas, K ; Ruiz, P ; Tzakis, Andreas ; Olausson, Michael ; Brännström, Mats. / Preclinical report on allogeneic uterus transplantation in non-human primates. In: Human Reproduction. 2013 ; Vol. 28, No. 1. pp. 189-98.
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abstract = "STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used.WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks.PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated.MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity.LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection.WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed.STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.",
author = "Liza Johannesson and Anders Enskog and Johan M{\"o}lne and Cesar Diaz-Garcia and A Hanafy and Pernilla Dahm-K{\"a}hler and A Tekin and P Tryphonopoulos and P Morales and K Rivas and P Ruiz and Andreas Tzakis and Michael Olausson and Mats Br{\"a}nnstr{\"o}m",
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Johannesson, L, Enskog, A, Mölne, J, Diaz-Garcia, C, Hanafy, A, Dahm-Kähler, P, Tekin, A, Tryphonopoulos, P, Morales, P, Rivas, K, Ruiz, P, Tzakis, A, Olausson, M & Brännström, M 2013, 'Preclinical report on allogeneic uterus transplantation in non-human primates' Human Reproduction, vol. 28, no. 1, pp. 189-98. https://doi.org/10.1093/humrep/des381

Preclinical report on allogeneic uterus transplantation in non-human primates. / Johannesson, Liza; Enskog, Anders; Mölne, Johan; Diaz-Garcia, Cesar; Hanafy, A; Dahm-Kähler, Pernilla; Tekin, A; Tryphonopoulos, P; Morales, P; Rivas, K; Ruiz, P; Tzakis, Andreas; Olausson, Michael; Brännström, Mats.

In: Human Reproduction, Vol. 28, No. 1, 01.2013, p. 189-98.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Mölne, Johan

AU - Diaz-Garcia, Cesar

AU - Hanafy, A

AU - Dahm-Kähler, Pernilla

AU - Tekin, A

AU - Tryphonopoulos, P

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N2 - STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used.WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks.PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated.MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity.LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection.WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed.STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

AB - STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used.WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks.PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated.MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity.LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection.WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed.STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

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Johannesson L, Enskog A, Mölne J, Diaz-Garcia C, Hanafy A, Dahm-Kähler P et al. Preclinical report on allogeneic uterus transplantation in non-human primates. Human Reproduction. 2013 Jan;28(1):189-98. https://doi.org/10.1093/humrep/des381