Immunopathology of hyperacute xenograft rejection in a swine-to-primate model

Hyperacute rejection is the inevitable consequence of the transplantation of vascularized organs between phylogenetically distant species. The nature of the incompatibility and the pathogenetic mechanisms that lead to hyperacute xenograft rejection are incompletely understood. We investigated these issues by the immunopathological analysis of tissues from swine renal and cardiac xenografts placed in rhesus monkeys. Hyperacute rejection was associated with deposition of recipient IgM and classic but not alternative complement pathway components along endothelial surfaces, the formation of platelet and fibrin thrombi, and the infiltration of neutrophils. In animals from which natural antibody was temporarily depleted by organ perfusion, rejection was observed at 3 days to 5 days posttransplant. The immunopathology of rejection in these tissues revealed focal vascular changes similar to those observed in hyperacute rejection. A xenograft functioning for a prolonged period in a recipient temporarily depleted of circulating natural antibody contained recipient IgM along endothelial surfaces but no evidence for significant deposition of complement, formation of platelet and fibrin thrombi, or infiltration of neutrophils. These results suggest that rhesus IgM contributes significantly to the development of hyperacute rejection in the swine to Rhesus model and that the fixation of complement is a critical factor in the recruitment of the coagulation cascade and platelet aggregation--and possibly in the adherence and infiltration of PMN.     

Immunodepletion in xenotransplantation

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group.     

Hyperacute rejection in ABO-incompatible kidney transplantation: Significance of isoagglutinin subclass

IntroductionABO-incompatible transplantation has expanded the limited donor pool for kidney transplantation. Despite the successful desensitization protocols and immunosuppression, undesirable cases of hyperacute rejection occurs.ObjectiveFlow cytometry was used to measure isoagglutinin titer and its IgG subclasses in assessment of the cause of hyperacute rejection in ABO-incompatible kidney transplantation.Materials and methodsThe recipient was admitted for kidney transplantation due to end-stage renal disease. Pre-transplantation work-up for ABO-incompatible kidney transplantation included blood group typing, HLA DNA typing and HLA antibody analyses. HLA crossmatch analysis was conducted using donor lymphocytes and anti-HLA antibody assay using Luminex panel reactive antibody test (One Lambda, Inc., Canoga Park, CA). Desensitization protocol was composed of therapeutic plasma exchange sessions and rituximab.ResultsDespite negative HLA crossmatch results, a case of hyperacute rejection occurred after living donor kidney transplantation. Rejection resulted in immediate removal of graft, and the patient later received a second kidney transplantation. Retrospective evaluation of isoagglutinin titer and its subclasses using flow cytometry identified the cause of rejection to increased IgG1 subclass. Desensitization protocol for ABO-incompatible kidney transplantation now implements further caution for blood group O recipients.DiscussionHyperacute rejection resulting from increased IgG1 isoagglutinin subclass has not been previously confirmed using flow cytometry. Unfortunate outcome of this rejection case provides insight to how we should approach and ensure successful ABO-incompatible kidney transplantation.     

Experimental multivisceral xenotransplantation

Abstract: Background: Organ shortage impairs the proposition of multivisceral transplantation to treat multiple organ failure. Interspecies (xeno) transplantation is a valid solution for organ shortage; however, suitable models of this advance are lacking. We describe an effective model of multivisceral xenotransplantation to study hyperacute rejection. Methods: Under general anesthesia, we in block recovered the distal esophagus, stomach, small bowel, colon, liver, pancreas, spleen, and kidneys from donors and implanted heterotopically in the lower abdomen of recipients. Animals were divided into four groups: I—canine donor, swine recipient (n = 6); II – swine donor, canine recipient (n = 5); III—canine donor, canine recipient (n = 4); and IV—swine donor, swine recipient (n = 5). Groups I and II comprised experimental (xenotransplantation) and III and IV control groups (allotransplantation). During the experiment, we appraised recipient evolution and graft modification by sequential biopsy up to 3 h. At this time, we killed animals for autopsy (experimental end point). Results: We accomplished all experiments successfully. Every grafts attained customary appearance and convenient urine output immediately after unclamp. Around 15 min after reperfusion, xenografts achieved signs of progressive hyperacute rejection and absence of urine output. At the end of experiments we observed moderate to severe hyperacute rejection at small bowel, colon, mesenteric lymph node, liver, spleen, pancreas, and kidney, while stomach and esophagus achieved mild lesions. In contrast, allograft achieved normal or minimum ischemia/reperfusion injury and constant urine output. Conclusion: The present procedure assembles a simple and effective model to study multivisceral xenotransplantation and may ultimately spread researches toward hyperacute rejection.     

Evidence that deoxyspergualin prevents sensitization and first-set cardiac xenograft rejection in rats by suppression of antibody formation

This study provides evidence of antibodies playing an important role in hamster-to-rat cardiac xenograft rejection and discusses the use of 15-deoxyspergualin (DSG) to suppress this first-set rejection, as well as hyperacute rejection induced by sensitization. The effect of recipient splenectomy (Spx) as an adjuvant to DSG to control first set xenograft rejection was also examined. When hyperimmune serum was taken from control recipients at rejection time and injected i.v. into new recipients of cardiac xenografts, hyperacute graft rejection resulted. Survival depended on the amount of serum injected and ranged from 14.7 +/- 2.5 min with 3 ml of serum to 233.3 +/- 61.1 min with 0.5 ml. Experiments on first-set xenograft rejection revealed that a dose of 2.5 mg/kg/day DSG could prolong xenograft survival from 3.4 +/- 0.5 days in untreated controls to 9.5 +/- 2.6 days (P less than 0.01). A dose of 5 mg/kg/day DSG, though it increased graft survival to 16.4 +/- 5.9 days, proved to be toxic to the recipients. Spx alone prolonged xenograft survival to 5.2 +/- 0.4 days, and, when combined with 2.5 mg/kg/day DSG administration, prolonged graft survival to 22.1 +/- 5.5 days (P less than 0.01 vs. DSG alone). The appearance of cytotoxic antibodies was delayed, and titers decreased from 1:256 in untreated controls to 1:16-1:64 both in the group that underwent Spx only and in the group that received 2.5 mg/kg/day DSG. Combined treatment suppressed antibody response for more than two weeks. Experiments on hyperacute rejection induced by sensitization revealed that 1 ml of hamster whole blood transfused into prospective heart recipients 1 week before grafting resulted in graft loss in 18.2 +/- 6.1 min. Pretransplant transfusion and concomitant daily administration of 5 mg/kg/day DSG until one day after grafting not only prevented hyperacute rejection but prolonged graft survival to 7.0 +/- 0.7 days. This survival was significantly longer than with DSG alone (4.2 +/- 0.8 days, P less than 0.01). We concluded that the marked suppression of antibody formation by DSG plays a major role in preventing first-set xenograft rejection and hyperacute rejection induced by sensitization.     

The Effect of Total Blood Exchange with PHP Solution on Cardiac Xenotransplantation

Abstract: Prevention of hyperacute rejection is a difficult and unsolved problem in xenotransplantation. Natural antibodies and complement activation have been known to play an important role in the xenotransplantation between discordant species pairs. In the present study, total blood exchange (TBE) was performed with pyridox-alated-hemoglobin-polyoxyethylene conjugate (PHP) solution (Ajinomoto Co., Inc., Kawasaki, Japan) before cardiac xenotransplantation in order to remove the immunoglobulins and prolong xenograft survival time. Guinea pigs and rats were used as the discordant species combination for donor and recipient. Two groups were established: Group 1, untreated control (n = 8) and Group 2, TBT with PHP solution (n = 8). The exchange blood transfusion was carried out at the rate of 15–20 ml/h utilizing PHP solution using a blood pump. After the blood exchange was processed, hematocrit (Ht) levels dropped to 4 or 5%, and a cardiac xenotransplantation was performed within 24 h. The levels of serum IgA, IgM, and IgG were decreased to less than 25, 25, and 10% of the base line, respectively, after blood exchange. A mean xenograft survival time in Group 2 was prolonged to 472 ± 74 min and to 10.4 ± 1.8 min in Group 1 (p < 0.01). A titer of the anti-guinea pig lymphocytotoxic antibody in rat serum was decreased to almost nil. The data from this study suggest that total blood exchange with PHP solution may be useful in preoperative removal of xenograft antibodies in xenotransplantation.     

Living related liver transplantation across ABO blood groups with FK506 and OKT3

In living related liver transplantation (LRLT), the use of graft livers across ABO blood groups is unavoidable since the organ donor is usually one of the recipient's parents. This report presents our initial experiences with LRLT, focusing on ABO-incompatible cases. From June 1990 to May 1992, we successfully performed a series of 34 LRLT on children (15 males and 19 females) ranging in age from 7 months to 15 years. Overall recipient survival rates were 90% (25/28) in elective LRLT and 50% (3/6) in emergency LRLT. These cases were classified into three groups: ABO blood group-identical (n=21), compatible (n=10), and incompatible (n=3). The immunosuppressive regimen consisted of FK506 and low-dose steroids in the first two groups. In the incompatible cases, exchange transfusion was performed to decrease anti-A and/or-B antibody titers before LRLT, and prophylactic OKT3 was added to FK506 and steroids after LRLT. No significant difference in recipient and graft survifal was observed among the groups. In the identical group, no rejection episodes have been observed thus far. Rejection occurred in two out of the ten compatible cases. Among the incompatible cases, one recipient had mild rejection and was treated. The remaining two recipients have had no rejection episodes thus far. Although all three recipients had cytomegalovitus (CMV) infection, they were successfully treated with gancyclovir, and no lethal infection has developed in any of these cases. The present results suggest that graft livers from living related donors across ABO blood groups can function well with FK506, low-dose steroids, and prophylactic OKT3 without causing lethal complications.     

猪血管内皮细胞与人血清反应早期PGI2和TXA2的变化

目的 探讨在猪与人异种移植超急性排斥反应中血管内皮细胞的作用。方法 用体外培养的猪血管内皮细胞和不同人的血清共同反应,建立猪与人异种移植超急性排斥反应的体外实验模型。用放射免疫法检测上清液中前列环素（ＰＧＩ２）和血栓素Ａ２（ＴＸＡ２）的稳定代谢产物（ＰＧＦ１α和ＴＸＢ２）含量,将其作为评定血管内皮细胞激活和损伤的标志。结果 各组血清与猪血管骨皮细胞反应０．５ｈ后,正常人血清组ＰＧＦ１α／ＴＸＢ２比     

Pediatric orthotopic heart transplant requiring perioperative exchange transfusion: a case report

An 11-month-old patient with idiopathic cardiomyopathy was scheduled for orthotopic heart transplantation. A perioperative exchange transfusion was performed because of elevated panel reactive antibody levels. This process was accomplished in the operating room prior to instituting cardiopulmonary bypass using a modified cardiopulmonary bypass circuit. In preparation for the procedure, the cardiopulmonary bypass circuit was primed with washed leukocyte-filtered banked packed red blood cells, fresh-frozen plasma, albumin, and heparin. Pump prime laboratory values were normalized prior to beginning the exchange transfusion. The patient's blood was downloaded from the venous line just proximal to the venous reservoir while simultaneously transfusing the normalized prime at normothermia. Approximately 125% of the patients calculated blood volume was exchanged. This technique greatly reduces the likelihood of hyperacute rejection. The exchange transfusion process, in addition to the patient immature immune system, provides additional options in orthotopic heart transplantation for patients that may otherwise not be considered suitable candidates.     

Discordant liver transplantation in the guinea pig to rat model does not lead to classical hyperacute rejection

Abstract: Discordant grafting, the best alternative for future transplantation, is hampered by hyperacute rejection (HAR). Yet, there might be a difference in susceptibility to HAR between organs. In allogeneic transplantation the liver is less sensitive to antibody mediated rejection. In order to investigate whether this might also occur in discordant xenotransplantation, we performed orthotopic liver transplantation (OLT) from Dunkin Hartley guinea pigs (GP) to Brown Norway rats. Five groups were studied. In group 1, untreated controls survived for 1.5 to 4.5 hr (n = 5). In order to investigate how long a recipient could survive without a functioning graft, animals in group 2 underwent total hepatectomy (tHx) with portal-caval shunt, resulting in survival times ranging from 2 to 7 hr (n = 5). Antibody reduction by splenectomy (Spx) on day -5 (group 3) did not increase survival time (1 to 2 hr, n = 5). Complement depletion by cobra venom factor (CVF) prolonged the survival time up to 35 hr (n = 7, group 4). One animal lived for 4 days. The combined treatment of Spx and CVF resulted in similar survival times as following CVF alone, ranging from 2 hr to 6 days (n = 6, group 5). Surprisingly, none of the grafts in either of the groups showed classical signs of hyperacute rejection, like hemorrhage, edema, or obstruction of capillaries and veins as seen in the GP to rat heart transplantation model. Also liver enzyme parameters indicated no ongoing rejection. Immunohistochemistry revealed deposits of complement factors C1q, C3, and C6 on Kupffer cells but not on endothelial cells. These results indicate that, in this particular discordant model, the liver is not affected by the classical features of HAR. The beneficial effect of CVF on recipient survival therefore may rather be due to inhibition of a lethal secondary response evoked by the graft than to inhibition of HAR.     

Prolongation of discordant renal xenograft survival by depletion of complement. Comparative effects of systemically administered cobra venom factor and soluble complement receptor type 1 in a guinea-pig to rat model

Abstract There is an increasing body of evidence to suggest that inhibition of complement activation may be a valuable approach to avert hyperacute rejection. In our study, the guinea-pig to rat discordant kidney xenograft model was adapted for the investigation of renal transplant function and an attempt was made to delay the hyperacute rejection using systemically administered cobra venom factor (CVF) and soluble complement receptor type 1 (sCR1). The saline-treated control recipients experienced a rapid transplant rejection with a xenograft survival averaging 10.5 ± 2.1 min. Administration of a single 60 U/kg i. v. bolus of CVF significantly prolonged renal graft survival to 20.4 ± 2.5 h, and by a single bolus of sCR1 (50 mg/kg) a prolongation of graft survival to 18.8 ± 2.3 h was achieved. The grafts functioned only over periods of 2.5 ± 0.3 and 2.3 ± 0.2 h, respectively. No complications of sCR 1 were noted. We concluded that complement inhibition by sCR 1 may be an important component in the therapeutic approach aiming at the prevention of hyperacute rejection in human organ transplantation.     

Thrombalexins: Cell‐Localized Inhibition of Thrombin and Its Effects in a Model of High‐Risk Renal Transplantation

Allograft transplantation into sensitized recipients with antidonor antibodies results in accelerated antibody‐mediated rejection (AMR), complement activation, and graft thrombosis. We have developed a membrane‐localizing technology of wide applicability that enables therapeutic agents, including anticoagulants, to bind to cell surfaces and protect the donor endothelium. We describe here how this technology has been applied to thrombin inhibitors to generate a novel class of drugs termed thrombalexins (TLNs). Using a rat model of hyperacute rejection, we investigated the potential of one such inhibitor (thrombalexin‐1 [TLN‐1]) to prevent acute antibody‐mediated thrombosis in the donor organ. TLN‐1 alone was able to reduce intragraft thrombosis and significantly delay rejection. The results confirm a pivotal role for thrombin in AMR in vivo. This approach targets donor organs rather than the recipient and is intended to be directly translatable to clinical use.     

Prolonged Survival of Renal Allografts in Outbred Rabbits Treated with Donor Specific F(ab')2 Alloantibody

Renal allograft survival was prolonged in rabbits, a species in which antibody mediated hyperacute rejection can occur, by administering large quantities of donor specific F(ab')(2) alloantibody. In 13 control animals, onset of uremia with histological evidence of rejection occurred at a mean of 6.0 days. Eight of eight rabbits actively immunized and seven of nine rabbits passively immunized with unmodified donor specific IgG alloantibody hyperacutely rejected an allografted kidney. Four rabbits treated with non-specific F(ab')(2) for one week acutely rejected an allografted kidney at a mean of 6.2 days. In 12 recipient rabbits receiving 100-500 mg of donor specific F(ab')(2) alloantibody for a mean of 8.5 days, onset of uremia was delayed to a mean of 14.5 days following transplantation. Recipients were selected so that the donor specific F(ab')(2) alloantibody employed had no activity against recipient antigens. This selection maximized the antigenic difference between the donor and recipient, and also assured us that the donor specific F(ab')(2) was directed against antigens present in the donor but absent in the recipient. Passive administration of donor specific F(ab')(2) allowed antibody mediated suppression of a specific immune response to occur without risk of hyperacute rejection. However, the onset of rejection could not be delayed indefinitely by this treatment. The experimental conditions employed and the difficulties encountered closely resemble those which will occur for clinical utilization of passive immunological enhancement.     

Organ Specificity in Hyperacute Rejection of Canine Heart and Kidney Allografts

To clarify the organ specific nature of hyperacute rejection, 14 puppies were presensitized by multiple skin grafts and spleen cell injections prior to receiving either a heart or kidney allograft from the respective donors. Of this group, 7 received orthotopic heart allografts and 7 received kidney allografts. All heart allografts were rejected between 3 and 28 hours, and all kidneys between 0 and 24 hours as judged by cessation of urine flow from the ureterostomies. In contrast, all 11 animals in a recent series of heart allografts in non-sensitized puppies survived the operation, and rejected between 7 and 17 days. There was a significant correlation in both groups between preoperative cytotoxic antibody titer in the recipient serum and graft survival time. The preoperative titers were all above 1:1,024 but were greatly reduced within 2 hours after transplantation. At the time of rejection, antibody could be eluted from the rejected organs. In contrast to the kidneys, in which 2 of 7 grafts ceased to function immediately after revascularization, all hearts resumed beating and functioned well for at least several hours. At autopsy, the myocardium was pale and edematous and histologically polymorphonuclear leukocytes were prevalent in and around the small vessels and among myofibers. Both IgG and IgM antibody was detected in sarcolemma of the myocardium and to a lesser extent in the intima and adventitia of the small vessels by the fluorescent antibody technique. Biopsies of the rejected kidneys showed polymorphonuclear leukocyte infiltration, typical of hyperacute rejection. Marked fluorescence of IgG and IgM in the glomeruli and peritubular capillaries was observed. This study indicates that both organs rejected hyperacutely in our experimental model and participation of the preformed antibody in effecting this change was strongly suggested.     

A new concept of accommodation in ABO-incompatible kidney transplantation

Abstract:  This work focuses on the mechanism of acute antibody-mediated rejection leading to graft loss and the mechanisms of accommodation permitting graft survival in ABO-incompatible kidney transplantation. As previously noted, accommodation occurs only with (i) post-transplant suppression of glycosyltransferase, a product of ABO histo-blood group genes in the graft and (ii) prevention of antigen-antibody reactions and delayed hyperacute rejection due to reduced antigenicity of enzyme-regulated histo-blood group antigens. This article discusses the mechanism of ABO histo-blood group glycosyltransferase suppression. Accommodation is always established in successful ABO-incompatible organ grafts and ABO-minor mismatch bone marrow transplantation. In the former, accommodation develops even though ABO histo-blood types of the recipient and the donor are incompatible. In the latter, infusion of donor-derived bone marrow causes the recipient's blood to be eventually replaced by blood of the donor's type. However, the recipient's organs retain their original tissue type. In successful bone marrow engraftment, accommodation is established regardless of ABO-incompatibility. In organ transplantation the recipient's ABO histo-blood type regulates the graft's ABO histo-blood type, while in bone marrow transplantation the new ABO histo-blood type from the donor suppresses and regulates the ABO histo-blood type in recipient organs. In other words, bone marrow-derived histo-blood type regulates the histo-blood type of the organs.     

B cell tolerance to xenoantigens

Abstract: Xenotransplantation of pig organs to humans is a possible solution to the shortage of donor organs for transplantation. Multiple immunologic barriers need to be overcome if pig-to-primate transplantation is to be successful. The presence, in humans, of natural antibodies (Abs) directed against Galα1–3Galβ1–4GlcNAc epitopes on pig vascular endothelium provides the major barrier, as antibody–antigen binding initiates the process of hyperacute rejection. Even if hyperacute rejection is prevented, acute vascular rejection develops. Acute vascular rejection is also mediated, in part, by xenoreactive Abs and may be complement-independent. Efforts being made to overcome antibody-mediated rejection include depletion of antibody by extracorporeal immunoadsorption, prevention of an induced Ab response by pharmacologic reagents, B-cell and/or plasma cell depletion, depletion or inhibition of complement, and the use of organs from pigs transgenic for human complement regulatory proteins. The ultimate solution would be the induction of B-cell tolerance to xenogeneic antigens, which is being explored by attempting to induce xenogeneic hematopoietic chimerism. Here, we review the properties of the B cell types responding to xenoantigens and the strategies for tolerizing those B cells.     

Influence of cold ischemia time, pretransplant anti-porcine antibodies, and donor/recipient size matching on hyperacute graft rejection after discordant porcine to cynomolgus kidney transplantation

Organs transplanted between phylogenetically disparate species, such as from the pig into the primate, are subject to hyperacute rejection (HAR). This form of xenograft rejection is mediated by preformed natural antibodies and is believed to occur invariably in discordant xenografts thus leading to rapid destruction and complete thrombosis of the graft. Recent data, however, have shown that in the porcine to cynomolgus monkey setting, HAR is not inevitably seen after porcine kidney transplantation. The influence of preoperative antiporcine antibody levels in the recipient, cold ischemia time, and donor organ weight on the onset of HAR was investigated by using unmodified large white pigs (aged 3-12 weeks) as organ donors and adult cynomolgus monkeys (aged 1.5-3.5 years) as recipients. Porcine kidney xenotransplantation was performed in either a non-life-supporting model (n=7) or in a life-supporting model (n=8). In both models, no correlation was found between cold ischemia time and HAR. When preoperative anti-porcine antibody levels were investigated, a significant increase in incidence of HAR was observed in animals with elevated anti-porcine IgM (P<0.05) but not IgG levels (P=NS). Interestingly, although 5 of 12 grafts with an organ weight of less than 50 g underwent HAR, none of three grafts with a donor organ weight of more than 70 g showed signs of HAR. In addition, all three larger grafts showed intraoperative and postoperative urine production, although only in 1 (48 g) of the 12 grafts weighing less than 50 g primary graft function was observed. In one animal, a second porcine kidney (23 g) was successfully transplanted (without HAR) immediately after HAR and subsequent removal of a first porcine kidney (20 g). These results indicate that in the porcine to cynomolgus monkey setting anti-porcine IgM rather than IgG anti-porcine antibody levels seem to be of predominant importance for the induction of HAR. By increasing the donor organ size and weight the frequency of the onset of HAR can be at least reduced. This is most likely due to immunoabsorption of the recipients preformed antibodies in the porcine kidney without lethal damage for the graft.     

Chimeric pig hearts resist hyperacute rejection in ex vivo perfusion model

With surrogate tolerogenesis. the recipient immune system is engrafted within the donor pig before organ transplant. Chimeric pig hearts may resist hyperacute rejection by inducing accommodation. This hypothesis was tested using an ex vivo isolated piglet heart perfusion model. Processed sheep marrow was infused into fetal pigs at 45 days gestation. Heart explants from chimeric or nonchimeric pigs were suspended in a Langendorff apparatus and perfused with plasma from unsensitized sheep or sensitized sheep. Nonchimeric hearts perfused with plasma from unsensitized functioned for 240 min (N = 3). Nonchimeric hearts perfused with sensitized plasma deteriorated rapidly, functioning at 19+/-12 min (N = 6); Immunohistochemistry of heart graft revealed extensive deposition of IgG, IgM in the microvascular. In contrast, chimeric hearts perfused with sensitized plasma functioned for 183+/-46 min (N = 3)(p <.001); Deposition of IgG, IgM had substantially less. Heart grafts procured from chimeric pigs survived in the presence of antidonor IgG, IgM, and complement, demonstrating that chimeric pig hearts resist hyperacute rejection.     

中华眼镜蛇蛇毒因子在豚鼠—大鼠异种心脏移植中的作用

目的 应用中眼镜蛇蛇毒因子（CVF）消耗补体,观察豚鼠心脏在移植入Wistar大鼠腹腔内后对超急性排斥反应的变化。方法 按0．2μg/g体重CVF大鼠腹腔内分两次间隔6小时注射,18小时后进行心脏移植。脾切除及腹腔内注射环磷酰胺（Cy）均在移植前一天进行。设计分为四组：A组为对照组,不用任何药物;B组仅用CVF;C组应用CVF＋Cy＋脾切除;D组Cy＋脾切除。Cy的用量为60mg/kg体重腹腔内注射。检测各组受体的供心存活时间,并在供心停跳后取出行光镜、电镜检查。结果 A、B、C、D各组供心存活时间分别为15－3120分钟。供心存活时间的统计学分析：A组与B、C两组比较P值＜0．01,A组与D组比较,B组与C组比较P值＞0．05,B组与D组比较,C组与D组比较P值＜0．01。光镜、电镜结果提示：B、C组与A、D组有明显不同。结论 CVF能明显抑制补体活性,减轻或延缓超急性排斥反应的发生,使供体器官存活时间延长。CVF具有异种器官移植的基础研究和临床开发意义。