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This review article states the importance of uterus transplantation in solving quality of life issues. It is regarded as an alternative treatment for women suffering from uterine hypoplasia or absence of uterus1. Uterus is an exclusive organ to be studied in the field of organ transplantation1. The immunological mechanism involved in uterus transplantation related to its rejection pattern and subsequent immunosuppression is studied using various animal models.
Transplantation of solid organs has made tremendous advancements during last few decades7. It is regarded as an efficient therapeutic alternative for patients suffering from organ failure or certain other diseases2 and also solves quality of life issues1. This technique was introduced a century ago with cornea transplant in 1998 followed by a controversial hand transplant1. Kidney transplant was a pioneering step in transplantation7. These achievements opened an eye to new clinical fields of transplant of reproductive organs7 and Uterine transplant was proposed as another quality of life transplant to permanently cure uterine factor infertility1. This treatment was not very successful as experiments in this area was restricted to small scale laboratory animals like rats and mice and larger animals such as pig, sheep and non-human primates4 and the area of fertility research was dominated by in vitro fertilization which has an advantage of achieving genetic motherhood 1,3. The disadvantages associated with this were ethical/legal issues and even health and welfare of gestational carrier and future child7. Moreover people opted for adoption as it had lesser risk factors involved. If uterus transplant was a safe procedure with high chances of positive outcome, patients may accept significant risks in their pursuit of family5,9 . For many women, giving birth and bringing up child are very important aspects of quality-of-life and thus the need for uterus transplant may be justified 7
Majorly there are two types of donor which are classified as deceased donor (DD) and live donor (LD)3. Deceased donors are brain dead donor where circulation is maintained by ventilators support. DD have an advantage of eliminating the risk of the donor and other large central and vital vessels like vana cava, aorta, iliac vessels can also be retrieved along with the organ. Live donors are generally maternal or elder sibling and they have an advantage of tissue matching. It also allows necessary studies and treatment to be performed at preoperative stage to eliminate the risk of any major organ anomalies which is unsuitable for organ transplantation. The major disadvantage in LD is the risk of surgery to the donor which may pose a danger of excessive bleeding and damage to other vital organs.
In uterus transplantation the transplantation can be carried out by considering syngeneic donor where transplantation is carried out between two non-identical genetic individuals2, another pattern that can be followed is allogeneic transplantation where the donor and recipient belong to different strains of the same species8.
Uterus transplantation in rats was carried out using syngeneic donor to avoid rejection of the organ and the donor was of the DD type where the donor was sacrificed after harvesting the uterus along with other larger vessels of vascular pedicle including iliac vessel, aorta or inferior vana cava3. Another mice model of BALB/c strain and C57BL/6 mice were used as donor and recipients to undergo allogenenic transplantation as the MHC complex, H-2 of these models has its genetic loci on chromosome 17 and is homologous to HLA in humans 8.
In this experimental model the donor was sacrificed after retrieval of uterus along with arteries and veins. Auto-transplantation was studied using pig as experimental models
Sheep was regarded amongst the live donors undergoing auto-uterus transplantation in which the uterus was removed from one the experimental model and then transplanted back in the same model in vivo. This method reveals its clinical application in hysterectomy as a part of transplantation procedure.
Auto-transplantation was also studied in non-human primates. Cynomolgus macaques an experimental model was used to study auto-transplantation. In case of baboon used as a donor, auto-transplantation was carried out and uterus along with ovaries and oviducts was separated. However allogeneic transplantation in human case would not be possible where ovaries would not be transplanted, hence a modified baboon donor was considered where organ retrieval did not include ovaries and oviducts.
The main aim to study the means of organ retrieval in these animal models is to study the uterus transplantation in humans to treat patients suffering from AUFI.
POTENTIAL PATIENT GROUP FOR UTERINE TRANSPLANT:
Women with absolute uterine factor infertility (AUFI) are considered as being unconditionally infertile1. Infertility may be caused due to congenital uterine malformation which is prevalent among 6.7% in general female population and 7.3% in infertile female patients, however most of them are fertile and 20% among them generally those suffering from MRKH syndrome remain infertile. Out of these patients the one suffering from typical type of MRKH syndrome which is seen in 50% of these patients, can be regarded as suitable patients for uterus transplant.
Another largest group of female population suffering from AUFI that can be treated by uterus transplant comprises of hysterectomized patients. Hysterectomy is performed to treat certain cases of cervical cancer and in other malignancies where chemotherapy leads to decreased size of uterus. Certain cases of intrauterine adhesion also known as Ashermanâ€™s syndrome caused due to genital tuberculosis or endometriosis and even Leiomyoma which is tumour of uterine smooth muscle or that of digestive tract, can be treated by hysterectomy. Patients that have undergone emergency peripartum hysterectomy due to severe bleeding caused by uterus rupture during Caesarean section are also included as potential patients for uterus transplant.
The potential groups of patients mentioned, have uterus transplantation as a permanent cure to AUFI other than IVF and adoption. The only human trial took place was in the year of 2000 where the uterus from a 46 year old lady was donated to a 26 year old female who had undergone hysterectomy due to postpartum hemorrhage. This transplantation was carried by a team in Saudi Arabia as the donor was suffering from benign ovarian disease and had to hysterectomize the uterus. However the graft was removed after 99 days as they observed necrosis of uterus transplant due to thrombosis of uterine vasculature1.
This case revealed the need to study the effects on the recipient after transplantation which included study of rejection and tolerance patterns, immune mechanism involved during transplant and the type of immunosuppresion required.
REJECTION PATTERN AND DIAGNOSIS:
Rejection of the graft occurs due to destruction of the donor graft by hostsâ€™ immune response which is activated against the graft alloantigens because of different genetic pattern. Rejection pattern can be classified according to the time when rejection occurs: hyper acute (immediate rejection within few days), acute (rejection within a month) and chronic acute (rejection from months to years)3. Rejection pattern also includes histological changes, changes in physiological function and according to the innate and adaptive immune responses3.
In uterine transplant, hyperacute rejection occurs macroscopically due to peri-operative complications and on microscopic level due to host antibodies activated to attack the Human Leukocyte Antigens (HLA) on the donor graft. Acute rejection would be observed due to the risk of HLA mismatch1. Acute rejection is generally antibody mediated which is induced by membrane attack complex (C5b-C9) causing subsequent necrosis and apoptosis and therefore leads to destruction of the graft due to inflammatory response. T cell mediated acute rejection is also observed when the graft alloantigens are presented on hostâ€™s T cell leading to its activation and subsequent immune response1. Chronic rejection occurs due to diminished effect of immunosuppression over a period of time leading to accumulation of various assaulting factors activating the host immune system against the transplanted graft. However chronic rejection is not regarded as a severe threat as the uterus graft can be removed after the purpose is solved1.
In order to avoid rejection of the uterus graft and to increase the efficiency of uterus transplant by improving its tolerance by the host, the immune response of the host against the transplanted graft needs to be suppressed. Immunosuppression is carried out by administration of various drugs and its efficiency depends on its effect on various fertility hormones like estrogen and progesterone1. Cyclosporine A, azathioprine and prednizolone are classic examples of immunosuppresants used in the case of uterus transplantation which was reported in the human case study in the year 20009.the effect of cyclosporine A using different doses was studied in rat models by diluting in 90% propylene glycol9. The study clearly showed that Cy A doses does not inhibit rejection but slows down its rate and was reported that injection of 30 mg/kg/day for 30 days showed 89% graft survival and 15 mg/kg/day for 100 days showed 100% survival9. Modern technique of immunosuppression in allogeneic uterus transplants involves calcineurin inhibitor which hinders cytotoxic T cell proliferation by blocking synthesis of interlikin-21. The effect of immunosuppressant in near future can be improvised by using cyclosporine A in combination with other drugs3.
However it is required to be vigilant about the side effects of immunosuppressing drugs on the hostsâ€™ mechanism and further studies should be carried out to avoid prolonged treatment with immunosuppressant and to reduce its toxic effect on the host during pregnancy. The uterus has been considered as immune-privileged organ due to its capacity to carry pregnancy, but transplanted uterus triggers a rejection process which can be prevented using these immunosuppresion strategies3. However it is therotically proven that pregnancy itself reduces the risk of rejection and can be regarded as one of the immunosuppression strategies that can be incorporated7.
The ultimate aim of uterus transplantation is to achieve fertility with a final result of carrying the foetus in the grafted uterus and delivering a healthy offspring. No pregnancy has been observed in humans or non-human primate models until now7. However pregnancy was first evident in mouse model in syngeneic transplant after embryo transfer7. Pregnancy with the birth of live offspring was also evident in dog model after auto-transplantation of uterus7.
This review gives a significant insight about uterus transplantation as one of the effective treatment to infertility and since last century there are many advances made in this field of research. Experimental studies on different types of animal models revealed the risk of rejection and allowed study of its rejection pattern and its subsequent treatment by immunosuppresion. It should be considered that any future uterus transplantation trial on human should take place only after sufficient groundwork done to avoid any risk to donor and to reduce any threat posing to the recipients health and to its offspring.