摘要:

Background.In discordant xenogeneic species combinations, vascularized transplants are hyperacutely rejected, due to binding of xenoreactive natural antibodies (XNA) to selected tissues of the graft, followed by activation of the complement and coagulation cascades. A major epitope recognized by human XNA is the terminal disaccharide Galα(1,3)Gal. Poorly defined, early cell-mediated events also contribute to recognition and rejection of discordant xenografts, and we have suggested a role of natural killer (NK) lymphocytes in this process.Methods.Human NK cells were used as effectors in functional assays of adhesion to and lysis of xenogeneic discordant endothelial cells in vitro. Adhesion and lysis inhibition experiments were performed using a large panel of carbohydrates, as well as F(ab′)2fragments of human XNA. COS cells transduced with the porcine α-galactosyltransferase were also used as targets for NK cell adhesion.Results.We demonstrate that XNA-reactive carbohydrate epitopes expressed by xenogeneic cells, including Galα(1,3)Gal, are also directly recognized by human NK cells. First, selected carbohydrates in solution displace with comparable efficiency both XNA and NK cell binding to xenogeneic endothelium; second, XNA F(ab′)2fragments selectively inhibit human NK cell adhesion to porcine endothelium, but not to human endothelium; third, unstimulated NK lymphocytes adhere selectively to COS-7 cells expressing the porcine glycosyltransferase that encodes the Galα(1,3)Gal epitope.Conclusions.Collectively, our findings suggest that humoral and cellular components of the natural immune response against heterologous species independently evolved recognition patterns directed against overlapping carbohydrate determinants.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.In this study, we describe the development of a novel experimental system in which rejection of porcine skin grafts by human peripheral blood cells can be studied directly in vivo in immunodeficient mice.Methods.To construct a small animal model of discordant xenograft rejection, recombinase-activating gene-deficient mice (R-) lacking both mature B and T cells were grafted with porcine skin grafts and administered, by adoptive cell transfer, human cells stimulated in vitro with irradiated porcine peripheral blood cells to create Hu-R-mice.Results.R-mice accepted porcine skin grafts indefinitely without the need for immunosuppression. In contrast, Hu-R-mice were able to reject porcine skin grafts. Immunohistochemical analysis of rejecting skin grafts revealed the accumulation of human T cells around dermal porcine vessels and focally in the epidermis. Graft rejection was manifested by vascular endothelial cell proliferation, edema at the dermal-epidermal border, and perivascular hemorrhage. The tissue damage observed in the rejecting grafts was similar to that observed in delayed primate anti-porcine cell-mediated rejection of vascularized organ xenografts.Conclusions.The development and characterization of a small animal model, to study cellular immune responses of human cells to discordant xenografts in vivo, should provide a convenient means for asking mechanistic questions related to discordant xenotransplantation, and may also provide a practical system for testing new approaches designed to prevent xenograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Renal allografts were performed in rhesus monkeys using FN18-CRM9, a potent immunotoxin capable of depleting T cells to less than 1% of baseline levels in blood and lymph nodes, as a preparative agent. We have recently reported that animals pretreated with FN18-CRM9 1 week before transplantation without further immunosuppression had prolonged graft survival time compared with control animals, and frequently became tolerant.Methods.This report examines the alloimmune responses of recipient monkeys to the donor, including cytotoxic T lymphocyte precursor (CTLp) frequency, mixed lymphocyte response, and antidonor IgG response.Results.CTLp frequencies declined significantly (P<0.01) after FN18-CRM9 treatment and renal transplantation. This decline in CTLp was initially nonspecific, as CTLp frequencies against third-party animals also declined (P<0.01). The decrease in CTLp was maintained in five of five animals tested 6 months after transplant. However, unresponsiveness was limited to the CTL arm of the immune response as antidonor IgG was detected in four of four animals tested, and the 5-day mixed lymphocyte response stimulation index and relative response were not significantly different before and after transplant. In long-term survivors (>150 days), an increase in anti-third-party CTLp was detected 1 month after grafting with third-party skin. No change was seen in the antidonor CTLp frequency after donor skin grafting, indicating that a specific defect in the antidonor CTL response had developed.Conclusions.These data suggest that FN18-CRM9 treatment of rhesus monkeys allows the development of specific down-regulation of antidonor CTL activity in renal allograft recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Studies of the influence of human leukocyte antigen (HLA) matching on cardiac transplant outcome have proved inconclusive, mainly due to the lack of well-matched grafts. However, a growing number of studies report improved clinical course and patient survival in cases with increased HLA compatibility. Opelz et al. believe these benefits justify the introduction of prospective HLA-matching strategies.Methods.We performed univariate and multivariate analyses to examine the short- and medium-term influence of HLA matching on 556 consecutive primary heart transplants performed at a single center between 1983 and 1994. Overall graft survival at 1, 3, and 5 years was 80%, 74%, and 67% respectively. Sixteen (2.9%) grafts failed within 5 days and were not considered in the analysis of the HLA matching and graft survival data.Results.Complete HLA-A, -B, and -DR typing data were available on 477 transplant pairs. The results demonstrate a 12% 1-year survival advantage for 31 patients with zero to two HLA antigen mismatches compared with three to six mismatches. The influence of each individual locus was 6.1%, 8.4%, and 5.4% for zero HLA-A, -B, and -DR mismatches, respectively, compared with two mismatches. However, when outcome from 1 to 5 years was considered, analysis of the role of each locus revealed marked differences. HLA-A-matched grafts (n=45) had a 24% lower survival rate compared with two-antigen-mismatched grafts (n=148; 88% [SE 3.1] vs. 64% [SE 8.2], respectively;P=0.009). Furthermore, 34% of HLA-A-matched grafts failed between 1 and 5 years, compared with only 5% of HLA-B-matched grafts (P=0.013).Conclusions.These data suggest that although HLA matching is effective at reducing acute graft loss, in the longer term, HLA-A matching may impair survival. HLA-A may serve as a restriction element for indirect presentation of allopeptides or tissue-specific minor histocompatibility antigens, facilitating chronic graft loss. Therefore, we advocate a differential role for HLA matching over two epochs. A blanket approach to prospective matching for heart transplants may be premature for optimal long-term survival.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Matching for the HLA class I loci A and B and for the HLA class II locus DRB is known to influence the survival rate of kidney transplants. It is unknown whether matching for the HLA class II locus DPB also exerts an influence on graft outcome.Methods.The influence of matching for the HLA-DPB locus was analyzed based on DNA typing results obtained in more than 3600 first and 1300 repeat cadaver kidney transplants.Results.HLA-DPB mismatches had no deleterious influence on the outcome of first cadaver transplants. However, the influence was statistically significant for retransplants. One-year graft survival rates were 83±2% with no mismatch (n=345), as compared with 76±2% with one mismatch (n=702,P=0.02), and 73±3% with two mismatches (n=258,P=0.003). The deleterious influence of HLA-DPB mismatches was particularly strong in retransplant recipients with >50% reactivity of preformed lymphocytotoxic antibodies, for which the 1-year graft survival rate was 70±4% with no mismatch, as compared with 69±3% with one mismatch (P=0.05) and 61±5% with two mismatches (P=0.003).Conclusions.These results indicate that HLA-DPB is a clinically relevant histocompatibility locus in cadaver kidney retransplantation. It is proposed that prospective typing and matching for HLA-DPB should be implemented for cadaver kidney retransplants.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Although islet cell transplantation is considered an ideal form of endocrine replacement for type I diabetes, clinical application in humans is still not feasible. New immunosuppressive strategies are clearly needed to control inexorable rejection. CD45 is a family of transmembrane protein tyrosine phosphatases critically involved in the regulation of lymphocyte activation signals. Anti-CD45RB monoclonal antibody can prevent rejection of murine renal allografts.Methods.Here, we examine the consequences of targeting CD45 in murine islet cell transplantation. Diabetic mice recipients received islet allografts under the kidney capsule and were divided into seven groups. Recipients received no treatment (controls) or anti-CD45RB monoclonal antibody (mAb; MB23G2 or C363.16A) at different dosages and treatment intervals.Results.All untreated control animals lost islet function, becoming hyperglycemic within 10-17 days after transplantation. Animals treated with either anti-CD45RB mAb showed a significant prolongation of islet allograft survival when compared with controls. Anti-CD45RB MB23G2 at 100 μg/day, given on days -1, 0, and 5 was particularly effective, inducing indefinite islet allograft survival in 60% of recipients.Conclusions.These results indicate that anti-CD45 mAbs are potent immunomodulatory agents, able to sustain indefinite islet allograft function after a short treatment course in the highly immunogenic model of islet transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.An increasing demand for cardiac allografts for the treatment of end-stage cardiac failure has led to a shift in the traditional views about donor criteria. The use of allografts exposed to high concentrations of carbon monoxide is still under discussion. The current literature on this topic is contradictory. We describe our experience with orthotopic cardiac transplantation, using cardiac allografts after carbon monoxide poisoning.Methods.Between March 13, 1989 and August 1, 1996, 770 orthotopic heart transplantations were performed in our center. Within this period, we accepted five cardiac allografts from brain-dead, carbon monoxide-poisoned donors. Donor history showed carbon monoxide intoxication in all cases. At the time of organ explantation, donor hemodynamic parameters were feeble in all patients.Results.The postoperative course was uneventful in three of the five recipients. The overall 3-year survival rate in this small group is 40%. Induction therapy or rescue therapy with mono/polyclonal antibodies was not necessary. Myocardial right-ventricular biopsies did not show any specific signs of carbon monoxide poisoning.Conclusions.In our opinion, cardiac allografts from donors exposed to carbon monoxide can be transplanted successfully in infants and adults, if there are no signs of severe hemodynamic dysfunction in the presence of a normal central venous pressure and low-dose support with catecholamines and there are no electrocardiographic changes in combination with elevated transaminase. With extended donor criteria, the hearts of carbon monoxide-poisoned victims could increase the number of suitable organs and lower the death rate of patients on the United Network for Organ Sharing and Eurotransplant International Foundation waiting lists.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.We describe a 1-year-old female who underwent living-related liver transplantation for biliary atresia and developed Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder. This disorder was resolved after withdrawal of immunosuppression therapy and administration of a high dose of acyclovir.Methods.To quantify the extent of EBV activation and EBV load in peripheral blood, we measured the levels of EBV-infected peripheral lymphocytes by in situ hybridization (ISH) of EBV-encoded small mRNA 1 (EBER1).Results.The decline in the number of EBER1-positive lymphocytes (from 362/50,000 mononuclear cells to 0/50,000) after treatment was in accord with the patient's clinical improvement.Conclusions.This finding showed that quantitative analysis of EBV-infected peripheral lymphocytes by ISH of EBER1 is very useful for monitoring the EBV load and response to treatment of patients with EBV-related disorders. Furthermore, ISH may become an important tool for the early diagnosis and prevention of life-threatening posttransplant lymphoproliferative disorder in posttransplant patients.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Human cytomegalovirus (CMV) has been associated with allograft rejection and, in particular, with transplant-associated arteriosclerosis. However, the role CMV plays in the development of transplant-associated arteriosclerosis remains unclear. CMV can infect the endothelium, the interface between allograft tissue and the host immune cells, but the direct induction of endothelial human leukocyte antigen (HLA) class II by CMV remains controversial. Our previous studies with venous endothelial cells (EC) have shown that CMV does not directly induce this antigen on infected EC and, furthermore, renders these cells refractory to interferon (IFN)-γ induction. However, questions have arisen regarding the relevance of these findings to arterial endothelia. Thus, we have extended these studies to determine whether similar interactions occur in arterial EC. EC derived from human coronary artery, aorta, and umbilical artery were assayed by immunofluorescence flow cytometry and dual immunohistochemical staining following IFN-γ treatment and/or inoculation with CMV. Data generated by these experiments demonstrate that regardless of vascular origin: (1) CMV does not directly induce endothelial surface or cytoplasmic HLA class II, and (2) although uninfected arterial EC are HLA class II inducible by IFN-γ, infected cells are completely refractory to this effect. These results suggest that CMV-mediated inhibition of HLA class II expression is a phenomenon shared by human arterial and venous endothelia of both fetal and adult origin.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID