摘要:

Background.It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice.Methods.Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+and CD8+T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay.Results.BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+T cells. In vitro studies indicated that CD8+T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice.Conclusion.In the absence of CD28 and CD40 costimulatory signals, CD8+T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.We investigated the occurrence of apoptosis during and after resolution of cardiac allograft rejection. Apoptosis could play different roles in graft survival depending on the target cells; thus, we also determined the cell types involved.Methods.Endomyocardial biopsy specimens were evaluated during the first 6 months after transplantation as follows: group I, no current or prior rejection; group II, during an episode of moderate rejection; and group III, histologic resolution after an episode of moderate rejection.Results.Groups II and III showed significantly increased apoptotic activity, indicated by increased caspase-8 and caspase-3 activity; however, activated caspase-3 was undetectable in group I. Activated caspase-3 was detected only in groups II and III. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling was detected in groups II and III but not group I and predominantly in inflammatory cells.Conclusions.Increased caspase activity and apoptosis of infiltrating cells not only occurs during acute cardiac allograft rejection but persists after histologic resolution. Thus, programmed cell death occurs beyond the period of histologic resolution and may play a role in regulation of the rejection process.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the humanMDR1gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption.Methods.The area under the time-concentration curve from 0 to 2 hr (AUC0–2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis.Results.No association was found between polymorphisms in theMDR1and CsA AUC0–2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0–2/dose/kg (706.2 &mgr;g·hr/L to 819.2 &mgr;g·hr/L,P<0.05). Furthermore, we attempted to compareMDR1polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference.Conclusions.There is no relationship between polymorphisms forMDR1and CsA absorption, suggesting polymorphisms forMDR1cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Some statins have been reported to suppress the immune system and increase the expression of bone morphogenetic protein-2 gene that plays a pivotal role in bone regeneration.Methods.The effects of cerivastatin on skeletal reconstruction by vascularized bone allograft were investigated in a rat tibia-fibula graft model. After transplantation, the recipient rats were treated with vehicle, low-dose cerivastatin, high-dose cerivastatin, or cyclosporine A.Results.Transplanted bones treated with low-dose cerivastatin and vehicle failed to unite with the recipient bones. In contrast, high-dose cerivastatin induced the bone union as effectively as cyclosporine A. Histologically, high-dose cerivastatin-treated transplanted bones were nonvital, but new bone formation occurred at the outer layer of the nonvital cortex.Conclusion.These results indicate that statins could promote fracture healing. Because transplant recipients have the increased risks of osteoporotic fracture and hypercholesterolemia, statins may be a good choice in the treatment of these patients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Hepatocellular carcinomas (HCC) that originate de novo in liver transplants without preceding HCC in the explanted organ have only rarely been reported. Because recent data demonstrated a mixed hepatocellular chimerism caused by the integration of host-derived stem cells, a study was conducted on the origin of tumor cells in de novo HCC.Methods.From two cases of de novo HCC arising in liver transplants after hepatitis B reinfection, tumor cells and non-neoplastic liver cells from the patient’s own liver and donor liver were isolated by laser microdissection, and highly polymorphic short tandem DNA repeats (STR) were investigated.Results.Isolated tumor cells revealed donor-specific STR genotypes that could clearly be discriminated from the genotype of the host.Conclusions.Hepatitis B virus-associated de novo HCC in liver transplants is of donor but not of host origin. The new technique described here can also discriminate between true recurrence of the original tumor and new recipient tumors.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The poison hemlock plant (Conium maculatum) has been a known poison since early in human history, most notably as the agent used for the execution/suicide of Socrates in ancient Greece. No experience has been reported regarding the suitability of a hemlock victim’s organs for transplantation.Methods and Results.This report documents successful transplantation of the liver, kidney, and pancreas from a 14-year-old girl who died of anoxic encephalopathy from asphyxia after the accidental ingestion of fresh hemlock while on a nature hike. Predonation laboratory values were not remarkable, and liver and kidney biopsy results were normal. All organs in the three recipients had immediate function, and no recipient had any clinical evidence of transmitted toxin. All recipients are well, with functioning transplants at greater than 6 months after transplantation.Conclusions.Poison hemlock intoxication does not seem to be a contraindication to organ donation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Nonmyeloablative allogeneic stem-cell transplantation (alloNST) is the focus of investigations searching for less-toxic transplantation regimens. We report studies on the kinetics of lymphodepletion and safety of pentostatin (PT) conditioning in alloNST. Patients with hematologic malignancy received mobilized blood from human leukocyte antigen-matched related (n=4) or unrelated (n=8) donors. PT 4 mg/m2was administered on days −21, −20, and −19 and 200 cGy of total-body irradiation was administered on day −1, followed by cyclosporine A and mycophenolate mofetil. Mononuclear cell adenosine deaminase after PT was inhibited 84%. The absolute CD3+cells decreased significantly by day −7 (49%) and CD19+cells declined 92% by day −1. CD4+cells were depressed more than CD8+cells. Neutrophils and monocytes were minimally affected by PT. Median posttransplant peripheral blood chimerism on day 70 showed 95% donor leukocytes and 82.5% donor CD3 lymphocytes. PT demonstrated lymphodepleting effects and promising safety, supporting alloNST as early as 7 days after initiation of PT.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID