Hum. Reprod. Advance Access originally published online on October 27, 2005
Human Reproduction 2006 21(2):436-442; doi:10.1093/humrep/dei349
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Rejection patterns in allogeneic uterus transplantation in the mouse
1 Department of Obstetrics and Gynaecology, 2 Department of Surgery and 3 Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
4 To whom correspondence should be addressed: Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: randa.racho{at}obgyn.gu.se
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BACKGROUND: Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. METHODS: Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2–28. RESULTS: Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3+) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. CONCLUSION: A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.
Key words: allogeneic/mouse/rejection/transplantation/uterus
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Introduction |
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Uterine transplantation is currently being developed as a potential treatment for patients with absolute uterine factor infertility (Altchek 2003
; Brännström et al., 2003a, b). Patients who could be considered for this procedure are women who have preserved ovaries but with absence of the uterus due to either a congenital Müllerian anomaly or previous hysterectomy. Additionally, patients with a preserved but non-functioning uterus in regard to implantation of an embryo or the maintenance of pregnancy (due, for example, to leiomyoma or intrauterine adhesions) may be considered for this procedure (Brannstrom et al., 2003b). A case of a human uterus transplant was recently reported in a woman who had previously lost her uterus at peripartum hysterectomy (Fageeh et al., 2002). This transplanted uterus survived only for 99 days despite initial immunosuppression with cyclosporin A, azathioprine and prednisolone, subsequently boosted by antithymocyte globulin. Thus, we feel that the attempt was premature since important issues, such as the mechanisms of uterine rejection, suitable immunosuppressants and the tolerability of the transplanted uterus in regard to pregnancy, had not been tested in any animal model.
When a new type of organ is considered for transplantation, the surgical technique, the process of rejection of that particular organ and the means of suppressing rejection have to be thoroughly investigated. The mechanism of rejection of the uterus has not been particularly investigated, although allogeneic transplantation was reported in the dog (Yonemoto et al., 1969; Scott et al., 1970; Wingate et al., 1970; Paldi et al., 1975), rabbit (Confino et al., 1986) and rhesus monkey (Scott et al., 1971) some decades ago. These reports merely concluded that rejection occurred and they did not characterize the process in any detail. Recently, data have been presented on methods for en bloc uterus–oviduct–ovarian transplantation in the rat, and it was stated that severe rejection occurred within 2 days (Lee et al., 1995; Jiga et al., 2003; Motoc et al., 2003).
Our group has chosen to develop a uterine transplantation model in the mouse (Racho El-Akouri et al., 2002) since this species has apparent advantages over other animal models in this research because of its well-characterized reproductive physiology and immunology and the ready availability of inbred and gene-deleted mouse strains. In the syngeneic mouse uterine transplantation model, normal rates of implantation and pregnancy are seen (Racho El-Akouri et al., 2003).
Knowledge about the mechanisms of organ specificity with respect to the intensity and type of rejection is increasing. The uterus, with its special local immunology during pregnancy, when the semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens, may have unique features. Since the uterus may have special immunological properties also with respect to local mechanisms of rejection, it is important to study the rejection process in detail in this organ and later on to develop ways to control rejection or to induce tolerance, in both the pregnant and the non-pregnant state. Immune-mediated graft rejection would be the principal challenge in uterine transplantation, as in the transplantation of other organs.
In the present study, the rejection pattern of transplanted uteri in a fully allogeneic mouse model was characterized by several methods.
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Animals
Inbred female C57BL/6 and BALB/c (M&B, Ry, Denmark) mice 6–8 weeks of age were housed in controlled conditions (21–23°C, relative humidity 50–60%, illumination between 07.00 and 19.00 h) with water and pelleted food ad libitum. Thirty-two out of a total of 63 operated recipient mice were excluded from the study due to immediate postoperative complications. These 32 animals were lost, either because of haemorrhage (n = 11) or because the transplanted uteri did not show any blood flow through the uterine artery and/or vein (n = 21) at immediate inspection after vascular anastomosis had been performed. The experiments were approved by the local animal ethics committee and were carried out according to the principles and procedures outlined in the Guide for the care and use of laboratory animals (National Institutes of Health, USA).
Donor operation
BALB/c mice served as uterus donors. Isolation of one uterine horn, including the cervix and connecting vasculature, was done as previously described (Racho El-Akouri et al., 2002, 2003). The reason for using a unilateral uterine horn rather than a complete uterus was that the unilateral procedure enabled isolation of the pelvic vasculature on the dorsal aspect of the uterus (Racho El-Akouri et al., 2002). Briefly, under isoflurane (2%) anaesthesia, the right uterine horn and the cervix together with the feeding and draining vessels (right uterine vessels, right hypogastric vessels, right common iliac vessels, vena cava and aorta) were gently isolated by microsurgical dissection. Other branching vessels (right inferior mesenteric vessels, right inferior epigastric vessels, left common iliac vessels, caudal artery, right external iliac vessels, right pudendal vessels and lumbar vessels) were cauterized and cut to prevent leakage from the specimen. The bladder was removed and the cervix was transected below its attachment to the bladder. The aorta and vena cava were then separated from the level of the branching of the renal vessels and 3–4 mm caudally. A ligature was placed cranially to the tip of the right uterine horn and the uterus was divided from the oviduct and ovary and dissected free from the dorsal peritoneum. The aorta and the vena cava were tied off caudally to the branching of the ovarian vessels and, after cannulation of the aorta (30 G needle) and incision into the vena cava, the specimen was gently flushed with 0.154 mol/l NaCl (4°C) supplemented with 100 IU/ml heparin sulphate (Leo Pharma, Malmö, Sweden) and 0.2 mg/ml xylocaine (Astra Zeneca, Göteborg, Sweden) to remove blood from the uterus. The uterus was then kept in 0.154 mol/l NaCl (4°C) for 20 min during surgical preparation of the recipient animal (see below) and back table preparation of the specimen.
Recipient operation
C57BL/6 mice served as uterine graft recipients. Surgery (under isoflurane anaesthesia) was performed through a midline laparotomy incision after subcutaneous administration of 15 IU heparin sulphate. The aorta and vena cava were mobilized and haemostatic clamps were placed en bloc around the vessels. Aortic–aortic and caval–caval end-to-side-anastomoses were performed using interrupted and continuous (11–0 nylon) suture techniques, respectively. The cervix of the graft was then exteriorized through a circular incision on the right side of the abdomen and sutured to the skin to create a stoma. The laparotomy scar was closed and 1 ml of a solution containing 0.154 mol/l NaCl and glucose (50 mg/ml) was administered subcutaneously to adjust for fluid loss and to correct any hypoglycaemia.
Gross morphology and laser Doppler flowmetry
The mouse was anaesthetized and a midline laparotomy was performed. The uteri and stomas of the recipients were initially examined with the aid of an operating microscope at days 2, 5, 10, 15 and 28 after surgery, during anaesthesia. A laser Doppler flowmetry method (Öberg, 1990) was then used to estimate tissue blood perfusion. The method has previously been used for studies of blood flow in ovaries of the rat (Zackrisson et al., 2000) and mouse uterus (Racho El-Akouri et al., 2002) at specific times (see above). A laser Doppler miniprobe (Perimed, Järfälla, Sweden) was placed in the lumen of both the transplanted uterus and the native uterus to record blood flow (Periflux 5000 flowmeter; Perimed) for periods of 2–3 min. The blood flow was expressed as arbitrary perfusion units (PU).
Light microscopy and immunohistochemistry
The mice were killed by cervical dislocation during anaesthesia at specific times (see above). The native and grafted uteri were dissected out and bisected. One part of the bisected uterus was fixed in solution containing 4% w/v paraformaldehyde in 0.1 mol/l sodium cacodylate buffer (pH 7.4). The tissue was then dehydrated, embedded in paraffin and sectioned (~ 4 µm) for light microscopy. Staining with haematoxylin and eosin, elastin–van Gieson, van Gieson and periodic acid–Schiff was performed. The slides were examined in a light microscope and digital images were obtained with a SPOTTM camera (Diagnostic Instruments, Sterling Heights, MI, USA).
The other half of the uterus was frozen in OCT (Sakura Finetek Europe, Zoterwoude, The Netherlands). This uterine tissue (native, graft) of postoperative days 2, 5 and 10 was sectioned (~ 4µm), fixed in acetone for 5 min and then blocked in 1.5% normal rabbit serum in phosphate-buffered saline (PBS; NaCl 0.13 mol/l, Na2HPO4 0.015 mol/l, KH2PO4 0.004 mol/l) for 30 min. The sections were incubated at room temperature for 1 h with the primary monoclonal antibody (rat anti-mouse CD-3 molecular complex; BD PharMingen, San Diego, CA, USA) at 1:1000 dilution in PBS and 1.5% normal rabbit serum. After three washes in PBS, the sections were incubated in peroxidase-conjugated, biotinylated, mouse-adsorbed, rabbit anti-rat IgG (Vector Laboratories, Burlingame, CA, USA) in PBS and Vectastain ABC reagent (Vector Laboratories) for 30 min, followed by incubation with the peroxidase substrate diaminobenzidine tetrahydrochloride for 5 min. The sections were counterstained with haematoxylin. Negative controls were performed by replacing the primary antibody with PBS.
The number of positive cells was estimated by counting the number of stained cells within a lined grid (10 x 10 squares) occupying an area on the section of 0.125 mm2 using a 20x objective and 10x eyepiece. In each uterus, five randomly chosen areas were counted within the myometrium and five areas were counted within the endometrium (defined as the region from the luminal surface to the most basal glandular epithelium). The mean of these values was calculated and this value was used as a data point. One section from the native and one section from the grafted uterus from each of the five animals in each group were counted. Counting was performed independently by two observers, both being blind to the treatment protocol. The values obtained by the two observers differed by no more than 15%.
Statistical analysis
Non-parametric tests (Kruskal–Wallis rank test, Mann–Whitney U-test) were used in data analysis, since we did not assume a normal distribution of the data points. A P value of <0.05 was considered to be statistically significant.
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Gross appearance
The overall results regarding gross appearance are summarized in Table I. Visual and tactile examination of the transplanted uteri on day 2 showed a gross appearance similar to that of the native uteri. The pulsations in the aortic segment of the transplant and bleeding of the uterine tissue were normal. At day 5, a majority of transplanted uteri showed signs of swelling and a change to a more reddish colour (Figure 1a). The aortic pulsations and the uterine tissue bleeding were still normal. The stomas were soft and had a normal colour (Figure 1b). At day 10, all uteri were abnormal in colour, with either a reddish or a blackish appearance. Three out of five uteri were of apparent firmer texture and uterine tissue bleeding was not seen in any transplant. None of the uteri were swollen but two out of five showed a change in the appearance of the stoma. Fully abnormal texture and swelling of the uterus were evident at day 15 (Figure 1c). At this stage, aortic pulsations were present in four out of five of the grafts and most stomas (four out of five) were shrunken, the mucosa showing a darker colour (Figure 1d). At day 28, the size of the uteri had decreased considerably and they were typically whitish in colour (Figure 1e) and of firm texture. The majority of stomas showed marked shrinkage (Figure 1f), and pulsation in the feeding aorta was seen in only one out of five grafted uteri.
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Histology and density of T lymphocytes
At day 2, the histological appearances of the native and transplanted uteri were similar, with small populations of inflammatory cells and minimal oedema (Figure 2a and b).
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At day 5, there were signs of increased abundance of inflammatory cells in the muscle layer of the transplanted uteri, as well as oedema (Figure 2c). Additionally, scattered lymphocytes were detected on the epithelial side of the basal lamina of both the glandular and the luminal epithelium. Blood congestion in small vessels (mainly venules) was also observed (Figure 2c). However, there was no evidence of endarteritis in the arteries or of endothelialitis in the larger veins.
At days 10 and 15, the typical features overlapped somewhat between the animals of the two groups. At day 10, the uteri were heavily inflamed throughout the uterine wall and numerous lymphocytes were present in the glandular epithelium (Figure 2d, g). Focal apoptosis was also observed, but necrosis was not apparent at this time point. The blood vessels were congested and there was evidence of endarteritis in larger arteries, with lymphocytes invading the endothelial layer into the intima (Figure 2h). At day 15, four out of five of uterine transplants showed histological signs of severe rejection, with arterial thrombi and necrotic parenchyma (Figure 2f). One transplant of day 15 had a histological appearance similar to those of day 10. The native uteri of day 15 (Figure 2e) appeared slightly oedematous but without any visible increase in inflammatory cells. At day 28, no viable parenchyma was present in any of the transplanted uteri. There was massive central necrosis and only a peripheral rim of fibrotic tissue.
The density of T-cells in the myometrium (Figure 3a) and the endometrium (Figure 3b) was higher in the grafted uteri (Figure 2i) compared with the native uteri (Figure 2j) from day 2 and day 5, respectively. There was no time-dependent change in the T-cell density in the myometrium or endometrium in the native uterus (Figure 3a, b). However, the density of T cells in both the myometrium and endometrium in the grafted uteri was significantly higher at days 5 and 10 compared with day 2 (Figure 3a, b).
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Blood flow
The blood flow was significantly lower in the grafted uteri compared with the native uteri at all time points (Figure 4). There was no significant time-dependent change in the blood flow of the native uteri. In the grafted uteri there was a significant change in blood flow, with lower levels at days 15 and 28 compared with days 2 and 5.
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Discussion |
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To achieve a suitable model system for basic studies on the issue of uterine transplantation, we have developed a mouse model using microsurgical vascular anastomosis and heterotopic placement of the grafted uterus parallel to the native control uterus (Racho El-Akouri et al., 2002
). In the latter study, the surgical technique was developed and established using inbred mice (B6 CBAF1) as both donor and recipient, and the transplanted uterus showed the capacity to harbour pregnancies (Racho El-Akouri et al., 2002) and to produce offspring with a normal postnatal growth trajectory (Racho El-Akouri et al., 2003). Collectively, these initial studies demonstrated the feasibility of this model in research to develop uterine transplantation as a clinical procedure for the treatment of uterine infertility. In the present study, we characterized the rejection mechanisms by making observations at several levels in a fully allogeneic uterine transplantation model in mice.
A fully allogeneic mouse model with mice of the BALB/c strain as uterus donors and mice of the C57BL/6 strain as recipients was used. The reason for using C57BL/6 mice as recipients was that this strain is the background strain used in the development of most knockout and transgenic mice. We anticipate that these knockout or transgenic mice will be used in future research designed to investigate in more detail the mechanisms of rejection in a transplanted uterus or in experiments on the physiology of pregnancy. Moreover, our previous experiments involving syngeneic transplantation were performed in F1 hybrids of the recipient strain of the present study, C57BL/6, and CBA mice (Racho El-Akouri et al., 2003). The donor mouse strain (BALB/c) used in the present study is the albino mouse strain which is most widely used in biomedical research (Potter, 1985).
The major histocompatibility (MHC) complex of the mouse, H-2, has its genetic loci on chromosome 17 and is homologous to HLA in the human. Haplotypes of the H-2 complex are determined by combination of alleles of the class I, class II and class III genes (Klein et al., 1983). The H-2 haplotypes of BALB/c and C57BL/6 mice are termed H-2d and H-2b respectively. These two haplotypes show dissimilarity in all alleles except one (the Q1 locus of class Ib). Thus, the almost fully allogeneic situation chosen in the present study would correspond to a clinical situation of donor and recipient with MHC disparity at both major and minor MHC loci.
The mouse model for organ transplantation has become increasingly popular with advances in microsurgery and molecular biology. However, knowledge about the rejection patterns in these murine models is limited. Experiments involving heart, kidney, liver and intestinal transplantation between different mouse strains have evaluated C57BL/6 mice as donors and BALB/c mice as recipients (Zhang et al., 1996). This is the opposite situation to the present study, and no evaluation was performed concerning BALB/c as donor and C57BL/6 as recipient. In the study of Zhang and colleagues, spontaneous acceptance was seen in 72 and 20% of liver and kidney allografts respectively. However, the heart and intestine allografts were rejected after around 9 days. The results were similar when BALB/c were used as donors to CBA mice. In a study using orthotopic transplantation of carotid allografts to test the effects of immunosuppressive drugs, C57BL/6 and BALB/c mice were tested both as donors and recipients (Matsumoto et al., 2004). It was shown that rejection by C57BL/6 recipients was not suppressed by immunosuppressant drugs as much as when BALB/c were recipients. Taken together, these data indicate that an organ such as the heart, which is similar to the uterus in its large content of muscular tissue, would be rejected within a shorter time than 9 days when BALB/c donors and C57BL/6 recipients were used. This time of rejection is somewhat shorter than what was found in the present study concerning the uterus.
In the present study, a fairly large proportion of animals had to be excluded due to immediate postoperative complications. This is most likely a consequence of the technically very difficult dissection and microsurgery involved in this procedure. The failures were most likely not attributable to the so-called immunologically mediated hyperacute rejection, since a similar portion of mice with unsuccessful grafts was seen in our previous study using a syngeneic model (Racho El-Akouri et al., 2003). During the study it was found that the manipulation of the graft and the warm ischaemic time had to be reduced to a minimum to prevent these complications.
The macroscopic appearance of the transplanted uteri of the present study was recorded with respect to both the cervical mucosa (stomal end) and the intra-abdominal serosal surface appearance. The first obvious signs of rejection were swelling and a colour change, which was seen only by intra-abdominal appearance at day 5. This time corresponds with the first histological signs of inflammation. These results of early macroscopic signs of rejection are comparable to what has been reported previously in rat cardiac allografts, with oedema seen around day 4 (Hayashi et al., 1991). Similarly, uterine allografts in the dog were swollen and hyperaemic at days 4–5 (Wingate et al., 1970).
The macroscopic changes which were observed in the stoma of the uterine allograft correlated fairly well with the macroscopic intra-abdominal appearance as well as with the histological signs of rejection. The first macroscopic sign of rejection seen in the stoma was on day 10, which was at a stage when marked increases were seen in the density of T cells in both the endometrium and myometrium. Thus, the exteriorized cervical end of the uterus can be used conveniently to assess the viability of the organ and the different phases of rejection of the transplants. A similar situation is present in the newly developed mouse model for small bowel transplantations (He et al., 1998; Dindelegan et al., 2003), with a similar cutaneous stoma. The stoma would also allow a non-invasive means of obtaining biopsies from the organ for more detailed assessment of rejection by histology or immunohistochemistry.
The rejection of the grafted uterus became macroscopically more evident with time when the uteri became more blackish in colour, with a fully abnormal texture. The stomas became darker in colour and shrank. In the tissue sections, increased infiltration of inflammatory cells, endarteritis and arterial thrombi with necrotic parenchyma were seen at days 10 and 15. These results correspond to severe acute rejection and are similar to those of cardiac allografts at days 8–15 (Zhang et al., 1996; Riederer et al., 2002). The allograft survival and severity of rejection is not only dependent on the MHC mismatch but is also dependent on the specific organ that is transplanted. Thus, spontaneous acceptance of transplanted liver and kidneys is seen in the mouse (Zhang et al., 1996). From this point of view it seems as if the heart and the uterus are similar, with no spontaneous acceptance and a similar timing of the rejection phases.
The endometrium is part of the common mucosal immune system that has special features to allow immunological tolerance of semen and conception while actively defending the uterus from pathogenic bacteria and viruses. The histological examination in the present study indicated that rejection of the endometrium is more rapid than that of the myometrium. Thus, early lymphocyte infiltration was seen in the endometrial glands, whereas lymphocyte infiltration occurred later in the myometrium. The myometrium appeared to have the greatest resistance to rejection and retained its tissue structure for the longest time. These results are comparable to the results of a study of allotransplanted uteri performed in the dog (Scott et al., 1970), in which the grafted uterus showed total necrosis of the endometrium but only a mononuclear infiltration and marked oedema of the myometrium 2 weeks after transplantation. The mechanism behind the early rejection of the endometrium is most likely an early invasion of leucocytes, as illustrated by the increase in T lymphocytes in the endometrium already at day 2.
In the present study, reduced uterine tissue blood flow was seen in the grafted uteri compared with the native uteri at all time points. In our previous study in the syngeneic mouse model (Racho El-Akouri et al., 2002), we were not able to demonstrate any difference in blood flow when assessed 2 and 4 weeks postoperatively. It may well be that the blood flow in those syngeneic grafts was lower during the first weeks after transplantation and that the blood flow then increased to levels similar to that of the native uterus. An explanation of this normalization of blood flow in the syngeneic graft may be that the acutely decreased blood flow, due to the absence of blood flow in the uterine branches of the ovarian artery, is slowly compensated for by blood flow from the uterine artery. In the allogeneic model of the present study, early rejection events will prevent the normalization of blood flow and eventually lead to a decrease in blood flow. However, in small bowel transplants in a mouse model no decrease in blood flow was seen after syngeneic transplantation when evaluated from day 1 to day 8, but a decrease was seen in allogeneic transplants from day 3 (Dindelegan et al., 2003).
The histological correlate to this decrease in uterus blood flow is naturally the major perivascular changes which were seen from around day 15. Furthermore, thrombosis was seen in the rejected grafts after allotransplantation of the uterus in the dog (Wingate et al., 1970). In that study, thrombosis was mainly seen in the large and medium-sized arteries and veins from day 3 to day 28 after transplantation.
In conclusion, uterine allotransplants show early signs of rejection from day 5 and severe rejection from day 10 to day 15 after transplantation. The rejection pattern of this murine model is fairly uniform, in contrast to several murine strain combinations of kidney transplantations, which showed both spontaneous acceptance and rejection (Zhang et al., 1996). The rejection pattern of the uterus in a murine model seems to be most similar to that of heart transplants.
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We would like to thank Ann Wallin, Department of Obstetrics and Gynecology, Sahlgrenska Academy at Göteborg University, for technical assistance. The study was supported by grants from the Swedish Research Council (no. 11607), Medical Faculty of Sahlgrenska Academy and Hjalmar Svensson’s Research Foundation.
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Submitted on July 4, 2005; resubmitted on August 28, 2005; accepted on September 20, 2005.
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