These results show the anastomosis of at least the bilateral uterine arteries and the unilateral ovarian vein is required for uterus transplantation. This is the first report of a natural pregnancy in a primate following uterine autotransplantation.

Anergic T cells generated ex vivo are reported to have immunosuppressive effects in vitro and in vivo. Here, we tested this concept in nonhuman primates. Alloreactive T cells were rendered anergic ex vivo by coculture with donor alloantigen in the presence of anti-CD80/CD86 mAbs before adoptive transfer via renal allograft to rhesus monkey recipients. The recipients were briefly treated with cyclophosphamide and cyclosporine A during the preparation of the anergic cells. Thirteen days after renal transplantation, the anergic T cells were transferred to the recipient, after which no further immunosuppressive agents were administered. Rejectionfree survival was prolonged in all treated recipients, and 3 of 6 animals survived long term (410-880 days at study's end). In the long-surviving recipients, proliferative responses against alloantigen were inhibited in a donor-specific manner, and donor-type, but not third-party, skin allografts were also accepted, which demonstrated that antigen-specific tolerance had been induced. We conclude that anergic T cells generated ex vivo by blocking CD28/B7 costimulation can suppress renal allograft rejection after adoptive transfer in nonhuman primates. This strategy may be applicable to the design of safe clinical trials in humans.

Background Infusion of recipient regulatory T cells (Treg) promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic BMT with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. Methods CD4+CD25high Treg that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and MHC-mismatched BMT with or without Treg infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. Results Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg (N=3). In contrast, the 2 of 5 recipients of Treg + BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, >90% of donor T cells were CD45RA+CD31+, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted >294 days without immunosuppression, whereas non-Treg BMT recipients rejected delayed donor kidneys within 3-4 weeks. Early cytomegalovirus reactivation and treatment was associated with early failure of chimerism, regardless of Treg administration. Conclusions Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), co-transplantation of host Treg can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.

Aim: Uterine transplantation (UTx) is a potential option for child-bearing in women with uterine infertility. Recovery of uterine function after allogeneic UTx in non-human primates has not been reported. The objective of this study is to establish the functional uterine transplant model in non-human primates. Methods: Uteri of two cynomolgus monkeys were simultaneously removed, cooled at 4°C and perfused with heparin saline. The uteri were interchanged with each other and then orthotopically transplanted. Immunosuppressive protocols included use of three agents (tacrolimus, mycophenolate mofetil and methylprednisolone) in case 1 and two agents (tacrolimus and methylprednisolone) in case 2. Transabdominal ultrasonography, vaginoscopy and biopsy of the transplanted uterine cervix were routinely conducted to monitor rejection after surgery. Results: The blood concentration of tacrolimus decreased 11 days after surgery and evidence of rejection was found in biopsy of the uterine cervix in both cases. The suspected rejection disappeared 23 days after surgery in case 1 and temporary menstruation resumed at 3 months after surgery. In case 2, blood flow to the uterine artery gradually decreased and the uterus resulted in atrophy due to ischemia, which has been triggered by rejection. Conclusion: Allogeneic UTx in the cynomolgus monkeys resulted in temporary recovery of menstruation with three immunosuppressants and uterine atrophy with two immunosuppressants. This preliminary experience suggests that recovery of uterine function after allogeneic UTx in non-human primates is possible but more experiments are required.

Of the 256 transplanted kidneys from DCD donors, 38 (15%) functioned immediately after transplantation. The incidence of delayed graft function (DGF) was 72%. Warm ischemic time and total ischemic time were 7.4 ± 9.4 min and 11.9 ± 5.6 h, respectively. The overall graft survival rates at 1, 5 and 10 years were 80%, 72% and 53%, respectively. Graft survival rates in each group have continually improved over time (5-year graft survival; 23% vs. 64% vs. 74% vs. 91%, respectively). However, there was no significant difference in graft survival rates between the groups of patients who survived with a functioning graft for more than 1 year. A multivariate Cox regression analysis showed acute rejection and donor age to be independently associated with graft outcome. DCD donors are a valuable source of kidneys for transplantation with promising long-term outcomes.