Compatible Grafts Research Articles

OUTCOME OF ABO-INCOMPATIBLE LIVER TRANSPLANTATION IN CHILDREN WITH NO SPECIFIC ALLOANTIBODIES AT THE TIME OF TRANSPLANTATION1

The shortage of suitable liver donors for children has motivated the use of ABO-incompatible (ABO-I) grafts for transplantation in urgent situations. However, survival after ABO-I liver grafts has been reported at about 30% as compared with 80% in cases of ABO-identical or -compatible liver grafts. This difference has been attributed to antibody-mediated, hyperacute or chronic liver rejection, due to preformed ABO antibodies (alloantibodies). In this study, we report our results with ABO-I livers in children without alloantibodies at the time of transplantation. From January 1988 to June 1993, 143 OLT were performed in 122 children. Eight children received 8 ABO-I liver grafts. Of these, 7 patients were included in the study. All 7 were alloantibody free before OLT. Five children were spontaneously alloantibody free, while in 2 children, the plasma alloantibodies were eliminated before and after transplantation using intravenous infusion of specific blood group antigens of the donor blood group (soluble antigens). Immunosuppression consisted of a triple-drug treatment combining CsA, AZA, and steroids. The follow-up period was between 10 and 48 months. One child died from a surgical complication. Six children survived, but 1 died 10 months later from intestinal obstruction. There were no graft losses and no episodes of hyperacute or chronic rejection. The graft and patient survival rate was 71%. There was a 28% incidence of rejection, but all were mild (requiring steroid boluses only). Our results suggest that the absence of ABO alloantibodies at the time of and after transplantation can protect ABO-I liver grafts against antibody-mediated rejection, whether hyperacute or chronic, and that soluble antigens are effective in eliminating alloantibodies in children.

Living related liver transplantation in children

We reviewed 37 living related liver transplantations (LRLT) performed by our department during the last 27 months on children with end-stage liver disease. The patients were 15 boys and 22 girls aged 7 months to 15 years with biliary atresia (27), cryptogenic cirrhosis (3), Budd-Chiari syndrome (2), progressive intrahepatic cholestasis (2), protoporphyria (1), Wilson's disease (1), and fulminant hepatitis (1). The donors were 14 fathers and 23 mothers. Grafts were made from the left lateral segment (19), left lateral segment with partial S4 (11), left lobe (6), and right lobe (1). After graft harvesting all donors resumed normal liver function and normal life. The recipient underwent total hepatectomy with preservation of the inferior vena cava. FK506 and low-dose steroids were used for immunosuppression. The survival rate was 90% (27/30) in elective cases and 57% (4/7) in emergency cases. Six recipients had functioning grafts but died of extrahepatic complications. Hepatic vein stenosis occurred in 3 cases at 3 months after LRLT and was successfully treated by balloon dilatation. Portal vein stenosis occurred in 1 case at 8 months after LRLT and was also safely dilated. We incurred no hepatic artery thrombosis after introducing microsurgery techniques. Among 12 viral, 5 bacterial, and 3 fungal postoperative infections, 1 Candida pneumonia and 1 EBV-associated lymphoma were lethal. Three patients with ABO-blood group compatible grafts and one with an incompatible graft developed acute rejection, which was controlled in evey case by steroid bolus and/or increasing the dose of FK506. There were no definite episodes of rejection in ABO-identical cases. Children with moderate growth retardation (> or = -1.5 SD of normal growth) caught up in growth soon after LRLT, but those with severe retardation (<-1.5 SD) were slow to attain age-normal height. Appropriate timing, meticulous surgical procedures, and comprehensive management of complications are crucial for successful outcome with LRLT. LRLT is a promising option for alleviating the shortage of livers for pediatric transplantation and may be regarded as an independent modality to supplement cadaver donation.

Increased bile duct complications in liver transplantation across the ABO barrier.

This study evaluated the outcome of liver grafts from ABO incompatible donors, focusing on biliary complications, and compared the results to an ABO compatible control group. Also, the expression of donor ABH antigens in the liver graft was analyzed. The outcome of liver transplantation using an ABO incompatible graft is still debated. These blood group related (ABH) antigens are known to be expressed not only on the surface of the erythrocytes, but also on the epithelial cells of large bile ducts. Because the biliary epithelium of hepatic allografts may continue to express donor ABH antigens, it may be more susceptible to immunologic bile duct injury after transplantation across the ABO barrier. Eighteen ABO incompatible grafts were compared with 18 ABO compatible grafts in patients who were matched according to medical urgency, primary liver disease (PLD), and recipient age. After transplantation, the grafts were analyzed with cholangiography, Doppler ultrasound, or arteriography and liver histology according to protocol. Immunoperoxidase staining for ABH antigens was performed on hepatic tissue. Biliary complications developed in 82% of the ABO incompatible donors, compared to 6% of the ABO matched controls. Hepatic artery thrombosis occurred in 24%. Cellular rejection was diagnosed in 65% versus only 28% in the control group. The 1-year actuarial graft survival rate was 44% versus 78% in the control group. ABH antigens of the donor were expressed on vascular endothelium and bile duct epithelial cells as long as 150 days after transplant. Using ABO incompatible allografts, a high incidence of biliary and hepatic artery complications and decreased graft survival in liver transplantation were found. An immunologic injury to the bile duct epithelium and/or to vascular endothelium is suspected.

EXPERIENCE WITH FK506 IN LIVING-RELATED LIVER TRANSPLANTATION

The new immunosuppressive agent FK506 was used with steroids to treat 22 pediatric patients who received living-related partial liver transplantation. Seventeen recipients survived and 5 died between one and 16 months after transplantation. Three of the 5 patients who died had required intensive care preoperatively. Autopsy findings showed no evidence of rejection. There was no episode of rejection that required retransplantation in any of the patients. Liver allograft dysfunction, which was suspected to be a rejection response, was encountered in 2 recipients with ABO-nonidentical but compatible grafts. However, their clinical and biochemical findings were ameliorated upon steroid pulse therapy or upon augmented FK506 administration without additional potent immunosuppressive agents. Steroid treatment has been discontinued in all surviving patients at 1-9 months after transplantation. Infectious complications encountered in 9 patients included 2 bacterial, 5 viral, and 2 fungal infections. One recipient died of fungal pneumonia. Abnormal increase of serum creatinine level was confined to the complicated patients. Hypertension was a temporary adverse reaction in the early postoperative period, and only one patient needed an antihypertensive drug at 2 months after transplantation. Acute pancreatitis with hyperamylasemia was observed in one patient who was treated successfully with reduction of FK506 administration. Tremor was observed in 8 patients, itching in 4, insomnia in 2, and vomiting in one. Hirsutism, gingival hypertrophy, and lymphoma were not observed. FK506 was highly effective in living-related partial liver transplantation not only in terms of immunosuppressive potential but also because it produced fewer adverse effects.

Carbon and nitrogen partitioning in peach/plum grafts.

Modifications in root-shoot relationships induced by graft incompatibility were studied in peach/plum graft combinations by means of carbohydrate and nitrogen analyses and isotope labeling. Mobilization of stored carbon, phloem transport of carbon, and mobilization, assimilation and distribution of nitrogen were studied in one compatible peach/plum graft (Prunus persica L. Batsch cv. springtime grafted on Prunus cerasifera L. Ehrh cv. myrobalan P 2032) and one incompatible graft (Prunus persica L. Batsch cv. Springtime grafted on Prunus cerasifera L. Ehrh cv. myrobalan P 18) for 89 days after grafting. Carbon and nitrogen reserves were mobilized in the rootstock in both graft combinations during the first 78 days following grafting. After that, sorbitol concentration was lower in the roots of the incompatible graft than in the roots of the compatible graft, whereas soluble sugars and starch accumulated in the peach scion of the incompatible graft. In both graft types, carbon was allocated mainly to the scion. Labeling with (13)CO(2) from 78 to 81 days after grafting showed that carbon partitioning among the different plant organs was only slightly affected by graft incompatibility. Carbohydrate concentrations provided indirect evidence that carbon transfer to the roots was hindered in the incompatible graft. Labeling with (15)NO(3) showed that nitrogen distribution and the rate of nitrogen assimilation were similar in the two graft combinations from 57 to 78 days after grafting. Nitrogen assimilation in the incompatible graft ceased 78 days after grafting, whereas it continued in the compatible graft.

Acute and subacute fulminant hepatic failure: the role of liver transplantation

To report the experience of the Australian National Liver Transplant Unit with patients with fulminant hepatic failure and to describe the role of liver transplantation. Twenty-seven patients presented with acute or subacute fulminant hepatic failure during the period from January, 1986, to March, 1990. Twenty-two had acute and five had subacute fulminant hepatic failure. The causes were hepatitis B in 10 patients, presumed non-A, non-B (NANB) hepatitis in eight patients, drug-induced hepatic damage in five patients, and Wilson's disease in four patients. There were 13 males and 14 females. Ages were 2-43 years (mean, 23). Twenty patients (74%) were in grade IV encephalopathy on presentation. Six patients (22%) began to improve soon after admission and went on to full recovery. Spontaneous recovery was more frequent in patients with drug-induced hepatic damage (four patients [80%]) and was less frequent in those with hepatitis B (one patient [10%]) and NANB hepatitis (one patient [12%]). The other 21 patients (78%) were considered for orthotopic liver transplantation. Eight (30%) were judged to be unsuitable and went on to early death. Thirteen (48%) were suitable for transplantation. Of these five (19%) died before a liver donor became available and eight (30%) received liver grafts and went on to full recovery. Overall, 14 patients (52%) survived and 13 (48%) died. Patients with Wilson's disease (four [100%]) were most suitable for orthotopic liver transplantation whereas eight (44%) of those with hepatitis B or NANB hepatitis were unsuitable. Of the eight patients receiving liver grafts one had hepatitis B, three had NANB hepatitis and four had Wilson's disease. Five were in grade IV encephalopathy at the time of operation. The mean waiting time for transplantation was 6.4 days. Five patients received ABO blood group compatible grafts and three received ABO incompatible grafts. Of the latter group, two subsequently required secondary orthotopic liver transplantation with ABO compatible grafts. All eight patients who received transplants are alive and well 3-24 months after the operation. No patient has any neurological sequelae. Orthotopic liver transplantation is a preferred option for patients with fulminant hepatic failure whose condition is not responding to conservative management. ABO incompatible livers transplanted in emergency circumstances may prove life-saving either by functioning successfully or by providing time during which ABO compatible grafts become available.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth, cambial activity and phloem structure in compatible and incompatible peach/plum grafts.

Peach (Prunus persica L. Batsch) shoots grafted onto compatible or incompatible clones of rootstocks of myrobolan plum (Prunus cerasifera L. Ehrh. cv. myrobolan) were observed in a greenhouse for 100 days after grafting. The incompatible grafts showed foliar symptoms of incompatibility and reduced shoot growth about 60 days after grafting. Light microscopic studies revealed that cambial activity stopped earlier in the rootstocks, than in the scions, of incompatible grafts. Structural modifications were also observed in the phloem of incompatible grafts. Compared with the compatible graft rootstock, the number of sieve elements differentiated from the cambial zone was reduced in the incompatible graft rootstock, whereas the production of parenchyma cells was not affected. No important ultrastructural alteration was observed in the sieve tubes of the incompatible grafts. However, osmiophilic granulations near the plasma membrane of sieve plates were observed more frequently in the rootstocks of incompatible grafts than in ungrafted myrobolan controls. It is concluded that the external symptoms of incompatibility are not related to massive structural modifications or degeneration of the conducting tissues.

Growth and the composition and transport of carbohydrate in compatible and incompatible peach/plum grafts.

The growth of scions and rootstocks of compatible (Prunus persica L. Batsch cv. Springtime/Prunus cerasifera L. Ehrh. cv. myrobolan P2032) and incompatible (Prunus persica L. Batsch cv. Springtime/Prunus cerasifera L. Ehrh. cv. myrobolan P18) peach/plum grafts were compared. The composition of soluble carbohydrates in phloem and cortical tissues of both peach/plum grafts and ungrafted plums and the translocation of these compounds across the union of grafted plants were examined. Sorbitol and sucrose were the dominant sugars in the phloem and cortical tissues of plum. A cyanogenic glycoside, prunasin, was present in peach tissues in amounts equivalent to those of sorbitol or sucrose, whereas only small amounts of prunasin were detected in plum tissues. The concentration of prunasin was significantly higher in the phloem of the P18 rootstock of the incompatible graft. Sorbitol was the only sugar significantly depleted in rootstock tissues of the incompatible graft when the first foliar symptoms of graft incompatibility became evident. Translocation studies with 1-(14)C-deoxyglucose showed that the relative distribution of radioactivity across the graft union was similar in both compatible and incompatible grafts. However, the total amount of radioactivity translocated across the incompatible graft was less than one-third of that translocated across the compatible graft. The results are consistent with the hypothesis of a progressive poisoning of the root system in the incompatible graft by a compound synthesized in peach foliage. The role of prunasin as a possible candidate is discussed.

Graft formation in Solanum pennellii (Solanaceae)

Three phases of cohesion were observable during the development of compatible autografts in Solanum pennellii. Phase I cohesion 1) lasted 4-5 d after grafting, 2) was characterized by an average increase in tensile strength of 4 g breaking weight (BW) mm(-2) graft area (GA) d(-1), and 3) correlated positively with cellular interdigitation at the graft interface. The fresh weight of the scion increased by approximately 5% d(-1) during the first 2 d after grafting. Phase II cohesion occurred 5-15 d after grafting, during which time 1) the tensile strength of the graft union increased by 14 g BW mm(-2) GA d(-1), 2) vascular differentiation across the graft interface was completed, and 3) the fresh weight of the scion increased by 9% d(-1). Phase III cohesion occurred subsequent to 15 d after grafting, during which time 1) the tensile strength of the graft union leveled off at a value similar to that of an ungrafted internode, and 2) the fresh weight of the scion increased by 14% d(-1). These results are discussed relative to mechanisms underlying the formation of compatible grafts.

Studies of vegetative compatibility–incompatibility in higher plants. V. A morphometric analysis of the development of a compatible and an incompatible graft

A morphometric analysis of graft development in (i) the compatible autograft in Sedum telephoides, and (ii) the incompatible heterograft between Sedum telephoides and Solanum pennellii was performed to characterize ultrastructural responses of grafting cells in compatible and incompatible unions. In the compatible autograft, relative volume of hyaloplasm (in the protoplasm) increases 750% by 3 days after grafting. This increase in hyaloplasmic volume is accompanied by a 61% decrease in relative volume of the vacuome during the same period. Relative volume of dictyosomes (in the protoplasm) increases fourfold during the first 8 h after grafting. Relative volumes of mitochondria, endoplasmic reticulum, nuclei, and nucleoli increase less dramatically during early stages of graft development. The time required to reestablish control (i.e., 0 h) volumes for these organelles is quite variable, ranging from 7 days for dictyosomes to 28 days for the vacuole and hyaloplasm. These results indicate that the intensity and duration of the responses of cellular components to the wound recovery associated with a compatible graft union are organelle specific. In the incompatible heterograft, the responses of all cellular organelles (except nuclei and components of the endomembrane system) are similar to that of the compatible autograft through the first 24 h after grafting. By 3 days after grafting, however, nuclei and components of the endomembrane system exhibit significantly lower relative volumes in the incompatible heterograft than in the compatible autograft. Therefore, nuclei and components of the endomembrane system are the first cellular components to exhibit signs of cellular incompatibility during graft formation in the incompatible heterograft between Sedum and Solanum.

Cadaver donor renal transplantation by centers of the Southeastern Organ Procurement Foundation.

This report summarizes the results after two years of a continuing prospective study of cadaver donor renal transplantation being conducted by the Southeastern Organ Procurement Foundation (SEOPF). Data are presented on 942 first grafts. Blood transfusions were found to be a major (if not the major) determinant of allograft survival. HLA-A and -B matching was of significant value and the effect of compatibility became more significant as time passed. ALS provided for better long-term survival of more compatible grafts, but it was not a "safer" immunosuppressant. Autogenous nephrectomy appeared to aid in the survival of more incompatible allografts, but not more compatible allografts. Kidneys obtained and implanted locally and kidneys obtained at one center and implanted at another had the same incidence of acute tubular necrosis (ATN) as well as the same patient and graft survival. Preservation time did not relate to ATN, patient survival, or graft survival (within the limits of the study); however, ATN did adversely affect graft survival. The final systolic pressure of the perfusion pump was the only perfusion characteristic which predicted ATN. Race, sex, pregnancy, and duration of dialysis did not correlate with graft survival if the effects of transfusions and compatibility were controlled.

HLA‐B 12 AND HLA‐B 27 ANTIGENS AND SUSCEPTIBILITY TO THE CORNEAL ALLOGRAFT REACTION

Our series comprised 100 penetrating corneal transplantations: 36 cases with HLA-B 12 and/or B 27 antigen in the recipient and, as controls, 64 cases without these antigens. The cornea was vascular in 44% of the HLA-B 12/B 27 group and in 40% of the controls. In the HLA-B 12/B 27 group AR developed in 13 of 36 cases, 36%; but in the control group only in one case (2%). In vascular and avascular cases the incidence of AR was equal. Among the high-risk cases of the HLA-B 12/B 27 group with definite mismatching of B 12 or B 27 antigens, 9 of the 14 recipients had developed AR. Six further recipients of this group had untyped grafts, and AR occurred in 4 of the 6, but in none of the 16 cases that were matched for B 12 or B 27 antigens. The value of a compatible graft, at least to the carriers of HLA-B 12 and/or B 27 antigens, is thus confirmed.

Effect of 6-Mercaptopurine on Response to Major and Minor Histocompatibility Antigens

Pregraft treatment of chicks with 6 mercaptopurine-palladium complex (6-MP-Pd) resulted in a 16% survival of skin allografts incompatible at the major histocompatibility locus B. These incompatible grafts survived beyond 16 weeks postgrafting and showed profuse feather growth. No form of postgraft treatment was necessary. All nontreated incompatible grafts were rejected prior to 4 weeks postgrafting with no evidence of feather development.The same treatment, however, did not significantly suppress rejection of B-system compatible grafts which differed at minor histocompatibility loci. The rate of feather growth in successful B-system compatible grafts was significantly enhanced by the 6-MP-Pd treatment through 2 weeks postgrafting. Though the drug appears to affect the cellular immune system, the humoral immune response was unaffected as evidenced by a high antibody titer following turkey erythrocyte challenge.

The influence of histocompatibility and transplant site on parathyroid allograft survival

Despite the finding that even weakly histo-incompatible parathyroids were usually rejected promptly in transplant sites of rich lymphatic vascularity, parathyroid allografts did seem to enjoy a significant advantage in longevity over skin and heart transplanted across the same barriers in our laboratory [1, 2], sustaining the impression that parathyroid tissue is immunologically privileged. The influence of histocompatibility and transplant site on parathyroid allograft survival was studied in inbred rats. Ag-B compatible grafts survived longer than Ag-B incompatible ones in all transplant sites. However when care was taken to place parathyroid allografts in transplant sites having rich lymphatic drainage, prolongation of survival was minimal and rejection took place within 23 days in almost every instance. In other transplant sites sharing the characteristic of absent or abnormal lymphatic drainage (skin islands, muscle, and possibly testicle), prolonged parathyroid survival was seen in a high percentage of animals. The possibility is advanced that previous reports of inconsistencies in parathyroid allograft survival may be explained on the basis of variation in the lymphatic revascularization of the individual glands in different transplant sites.

Histocompatibility in the Rabbi Identification of the Major Locus12

Cytotoxic antisera were produced either by skin graft exchange between related rabbits from the same partially inbred line or by graft exchange between rabbits from different inbreeding lines. By pedigree analysis and correlation with known antisera, these antisera were all shown to detect antigens controlled by a single locus. This locus has been assigned the symbol RL‐A. Skin grafts between siblings incompatible for the RL‐A were all rejected within twelve days, and graft survival time could not be prolonged with relatively mild immunosuppressive treatment with 6‐mercaptopurine. However, a significant number of grafts compatible for the RL‐A locus were maintained for twelve days or longer and graft survival time of compatible grafts could be significantly prolonged with mild immunosuppression, suggesting that the RL‐A locus is the major histocompatibility locus of the rabbit.

Serotyping for homotransplantation. XXIV. Heart transplantation

Forty-eight heart transplant recipients and their donors were typed for 12 HL-A antigens. Of the patients receiving grafts from donors with two antigenic groups of incompatibilities, 16 of 21 have died. Among those with transplants having one HL-A group of incompatibility, 11 of 19 have died. Four of the 7 patients with compatible grafts have died. The difference between those with two antigenic groups of mismatch and those with one or no mismatch was of marginal statistical significance ( p 0.06). Survival curves were also correlated with compatibility for HL-A antigens, although the small numbers have restricted the analysis. Preformed antibodies were found in only 7 (4.3 per cent) of 161 prospective heart transplant recipients. Thus, in contrast to kidney transplantation, immediate failures associated with preformed antibodies can be expected to be less frequent in heart transplantation

Influence of defined incompatibilities and area of burn on skin-homograft survival in burned subjects

Abstract BALB/c and C3H skin grafts were applied to CBA mice, which had been subjected to full-skin thickness burns of 15-35% total surface area. Observations were also made on the survival of HL-A compatible and incompatible skin grafts in severely burned patients. Graft survival was prolonged in burned hosts, and the prolongation depended on the extent of burning and on the genetic disparity between donor and host.

Predictive value of results of mixed leukocyte cultures for skin allograft survival in man.

We have transplanted skin between siblings who were matched by one-way stimulation in mixed leukocyte cultures (MLC). Grafts were done in a blind study between siblings who were reproducibly identical in MLC (did not stimulate each other) and between siblings who did stimulate. We took as our hypothesis that grafts between siblings whose cells did not stimulate in MLC should survive longer than grafts between siblings whose cells did stimulate in MLC. Our comparisons were made between the survival of an incompatible graft and two compatible grafts on each individual. Graft survival data for the two families shows a median graft survival of 1225 days for 4 MLC incompatible grafts (range 11–13) days and an average of 26 days for 8 MLC compatible grafts (range 15–36 days) without any overlap between the groups.

Immune status of irradiated mice treated with adult bone marrow and fetal hematopoietic tissue.

The inconsistent antibody response by the long-term survivors of isologous bone marrow (IBM)-treated mice was in contrast to past studies indicating a completely normal immune mechanism. The following explanations for the extrems variation in response observed in the 4 strains reported here are possible: (a) irreversible damage to the host's immune system by the lethal irradiation and failure of the grafted donor tissue to effect a recovery; or (b) a genetic alteration in either the grafted isologous hematopoietic cells or the host tissue, sufficient to simulate a homologous donor-host situation and consequently to lead to an immunologic disorder. To what extent these variables may influence the immune mechanism of IBM- and also the homologous fetal liver (HFL)- and homologous adult bone marrow (HBM)-treated animals is only speculative. In any event, it is apparent that transplantation of a compatible graft in the irradiated recipient does not neccessarily connote a normal physiologic status. The inability to distinguish by gross histologic examination those animals that were poor responders in the HFL-treated mice suggests that future studies on immune status of irradiated chimeras be performed by the in vivo cell tissue culture techniques developed by Makinodan et al., rather than by utilizing the wholemore » animal. In this manner, individual organs such as the spleen and lymph nodes could be tested individually and more quantitative estimations be made on their functional immune status relative to the normal. (auth)« less