First Successful Delivery after Uterus Transplantation in MHC-Defined Cynomolgus Macaques

Abstract

Delivery following uterus transplantation (UTx)—an approach for treating uterine factor infertility—has not been reported in nonhuman primate models. Here, six female major histocompatibility complex (MHC)-defined cynomolgus macaques that underwent allogeneic UTx were evaluated. Antithymocyte globulin and rituximab were administered to induce immunosuppression and a triple maintenance regimen was used. Menstruation resumed in all animals with long-term survival, except one, which was euthanized due to infusion associated adverse reaction to antithymocyte globulin. Donor-specific antibodies (DSA) were detected in cases 2, 4, and 5, while humoral rejection occurred in cases 4 and 5. Post-transplant lymphoproliferative disorder (PTLD) developed in cases 2 and 3. Pregnancy was attempted in cases 1, 2, and 3 but was achieved only in case 2, which had haploidentical donor and recipient MHCs. Pregnancy was achieved in case 2 after recovery from graft rejection coincident with DSA and PTLD. A cesarean section was performed at full-term. This is the first report of a successful livebirth following allogeneic UTx in nonhuman primates, although the delivery was achieved via UTx between a pair carrying haploidentical MHCs. Experimental data from nonhuman primates may provide important scientific knowledge needed to resolve unsolved clinical issues in UTx.

Involving Animal Models in Uterine Transplantation

“…In macaques, a protocol using antithymocyte globulin, cyclosporine, tacrolimus, mycophenolate mofetil, and methylprednisolone was used but found to be not enough effective ( 79 ). When rituximab was added to this protocol, it enabled a good immunological control ( 77 ).…”

“…Normal fetal development was observed at post-mortem examination. Pregnancy was achieved lately in the macaque uterus allotransplantation ( 77 ). Gestation was attempted for three macaques in allotransplantation but only one could give birth after 3 miscarriages.…”

Keio Uterus Transplantation Research: From Basic Research toward Future Clinical Application

“…We have experienced various severe cases of cellular and humoral rejections induced by donor-specific anti-body production in allogeneic UTx models in cynomolgus macaques. [34][35][36] Based on this experience, we established our diagnostic rejection criteria for the uterus in a cynomolgus macaque, 34 which partially referred to the grading system proposed by a Swedish group for monitoring rejection. 37 We believe that rejection of cellular and humoral components is more likely to develop in cynomolgus macaques, whose uteri may exhibit high levels of antigenicity compared with those of humans.…”

“…37 We believe that rejection of cellular and humoral components is more likely to develop in cynomolgus macaques, whose uteri may exhibit high levels of antigenicity compared with those of humans. 34,35 Another concern regarding UTx is whether a uterus with irreversible rejection should be removed. In our experimental series of allogeneic UTx in cynomolgus macaques that were unresponsive to treatment with immunosuppressants, irreversible rejection occurred but the general condition remained good; however, temporary swelling of the uterus was observed by ultrasonography and temporary increases in white blood cells, lactate dehydrogenase, and C-reactive protein were evident.…”

Uterus Transplantation: From a Deceased Donor or Living Donor?

“…Uterus transplantation (UTx) is a new alternative to surrogacy or adaption for women with uterine factor infertility to have a child. It was built after great achievements in basic research with animal experiments, including non-human primates, accumulated over a decade [ 1 , 2 , 3 ]. While UTx is still at the clinical experimental stage, this new reproductive and organ transplant technology is spreading rapidly worldwide, mainly in Europe and the USA, as well as Asia [ 4 , 5 ].…”