摘要:

Chemoattractant cytokines, chemokines, are likely to play a critical role in directing leukocytes to graft sites and in amplifying intragraft inflammation during rejection. Since second-set graft rejection occurs at an accelerated rate, we hypothesized that chemokine genes would be expressed earlier during secondary allograft rejection than during rejection of primary allografts. We have tested this hypothesis by using Northern blot analysis to compare intragraft expression levels of genes encoding interleukin (IL) 1β and six chemokines during rejection of C57BL/6 skin grafts on naive and C57BL/6-sensitized BALB/c recipients. Expression levels of IL-1β, interferon-γ inducible protein, macrophage inflammatory protein-1 (MIP-1) α, and MIP-1β genes were 10- to 17-fold higher on day 5 after transplantation in C57BL/6 grafts on C57BL/6-presensitized recipients than in C57BL/6 grafts on unprimed recipients. Intragraft expression of the chemokines regulated upon activation, normal T cell expressed and secreted (RANTES), during primary C57BL/6 graft rejection was virtually undetectable at day 7 after primary transplantation, but was expressed at high levels by day 5 after secondary transplantation. In third-party CBA/Ca allografts on unsensitized and C57BL/6-presensitized BALB/c mice, similar levels of IL-1β, MIP-1α, and MIP-1β expression were observed. High levels of RANTES and interferon-γ inducible protein expression, however, were observed at day 5 after transplantation in CBA/Ca grafts on C57BL/6-presensitized recipients and correlated with accelerated rejection of the third-party grafts. Although T cells from C57BL/6-presensitized recipients did not express increased reactivity to CBA/Ca stimulator cells in vitro, serum antibodies from these recipients demonstrated reactivity to cells from CBA/Ca and A/J mice. When compared with transfer of unprimed cells, transfer of C57BL/6-primed lymphoid cells to sublethally irradiated BALB/c mice engrafted with C57BL/6 grafts resulted in increased intragraft proinflammatory cytokine gene expression. Deletion of T cells before transfer abrogated the increased intragraft expression of proinflammatory cytokine genes. Collectively, these results indicate that the accelerated expression of chemokine genes during second-set rejection of allogeneic skin grafts is mediated by immune T cells.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Indefinitely surviving WF.1L (RT11) cardiac allografts transplanted to LEW (RT11) recipients provide an ideal model for controlled comparative studies of chronic vascular rejection (CVR). To determine the stage of development at which the progressive CVR can be reversed when deprived of an ongoing recipient alloimmune response, WF.1L-LEW cardiac allografts were retransplanted back into syngeneic donor strain WF.1L recipients at specific time periods after initial allogeneic engraftment and were maintained in WF.1L syngeneic hosts for a further 40 days. The vascular changes in the retransplanted allografts were compared with those of nonretransplanted allografts and with nonretransplanted and retransplanted LEW-LEW isografts examined at similar time periods. The early vasculopathic inflammatory changes were consistently reversed by retransplantation of the cardiac allografts back into syngeneic recipients after 20 days and 40 days of allotransplantation. Syngeneic retransplantation of the cardiac allografts at 60 days after allotransplantation did not reverse the essentially nonvasculitic occlusive vasculopathy invariably present in WF.1L-LEW cardiac allografts at this time period. Thus, the vasculitic and minimal subocclusive myointimal changes associated with early CVR in this model are alloantigen dependent and reversible. Irreversible CVR occurs only after advanced proliferative vasculopathy has been established in the allogeneic host.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Delayed xenograft rejection (DXR) is characterized by inflammation and vascular thrombosis. Activation of coagulation may occur as a result of tissue factor (TF) expression on both activated donor endothelial cells (EC) and recipient infiltrating monocytes (Mo). In addition, natural anticoagulants associated with porcine endothelial cells may not function adequately across species.Methods.In the present study, we examined the interaction of the TF pathway of coagulation with the natural anticoagulant TF pathway inhibitor, in xenogeneic leukocyte-EC cultures in vitro, and during rejection of discordant xenografts in vivo.Results.Coculture of human Mo with pig aortic EC (PAEC) resulted in 1.7-fold and 2-fold higher induction of Mo TF and Mo intercellular adhesion molecule-1, respectively, when compared with coculture with human aortic endothelial cells (HAEC). In addition, TF-dependent and -independent activation of coagulation factor X was higher on PAEC than on HAEC. Low levels of mRNA for tissue factor pathway inhibitor (TFPI) and its variant, TFPI-2, in resting PAEC were up-regulated by stimulation with tumor necrosis factor α. Procoagulant activity of recombinant human TF complexed to activated factor VII was inhibited by PAEC and HAEC-associated TFPI by 22% and 56%, respectively. In contrast, human activated factor X (factor Xa) activity was inhibited by human, but not porcine, EC-associated TFPI, suggesting functional incompatibility of PAEC for human factor Xa. Endothelial TFPI was detected in pig control organs and after hyperacute rejection, but was lost from the vasculature during DXR.Conclusions.Lack of appropriate human factor Xa inhibition by porcine EC during hyperacute rejection and loss of porcine EC TFPI during DXR could promote the development of a procoagulant environment leading to xenograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Up-regulated expression of adhesion molecules on vascular endothelial cells (ECs) is an initial event in leukocyte adhesion to ECs, which is a crucial step in the process of inflammatory or immune reaction leading to organ transplant rejection. Verapamil and other calcium channel blockers have been reported to improve transplantation outcome and seem to possess immunosuppressive functions. Therefore, we tested the effect of verapamil on adhesion molecule expression of ECs and adherence of leukocytes to ECs. Verapamil was added to replicate human umbilical vein EC cultures, before adding cytokines. Protein and mRNA expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 were measured by cell-ELISA and by Northern blot analysis after stimulation of ECs. Adherence of leukocytes to ECs was analyzed after stimulation of ECs by tumor necrosis factor-α, with pretreatment of verapamil. Verapamil selectively inhibited cytokine-induced protein and mRNA levels of VCAM-1, and suppressed cell adherence between tumor necrosis factor-α-stimulated ECs and mononuclear leukocytes or Molt-4 cells. These results suggest that verapamil may suppress immune response partly via inhibition of VCAM-1 expression on ECs and a certain subset of lymphocytes adherent to ECs.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Central to the specificity of the immune system is the interaction between the T cell receptor and the major histocompatibility complex (MHC)-peptide ligand complex. To better understand the nature of this interaction, and to investigate possible avenues for specific therapeutic intervention, we have produced soluble recombinant molecules that can modulate antigen-specific T cells. Our approach involved the construction of recombinant murine genes composed of the MHC class I geneH-2Ldand the Fc portion of immunoglobulin (Ig) heavy chain genes μ or γ1. Stable transfectants of theseLd/Fcγ1andLd/Fcμ genes generated correctly spliced transcripts and were capable of secreting chimeric protein. Immunoprecipitation analyses demonstrated the presence of chimeric Ld/Fcγ1 and Ld/Fcμ monomers of approximately 69 kDa and 90 kDa, respectively, as well as chimeric dimers under nonreducing conditions. The capacity of Ld/Ig molecules to bind specific peptide ligands was demonstrated using radiolabeled peptides or with monoclonal reagents that specifically identify peptide-induced conformational changes in the Ldligand binding site. Soluble divalent Ld/Fcγ1 molecules were loaded with the murine cytomegalovirus-derived peptide and other Ld-specific peptide ligands and subsequently isolated and purified. Peptide-loaded Ld/Fcγ1 molecules were capable of inhibiting the response of class I-restricted T cells in vitro in a peptide-specific fashion. The development of soluble multivalent chimeric proteins that possess unique properties of both the MHC class I and Ig molecules provides a valuable reagent for the study of potential mechanisms of in vitro and in vivo immune modulation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.Hepatitis B virus infection originating from hepatitis B surface antigen-negative, hepatitis B core antibody (anti-HBc)-positive organ donors has been documented, and anti-HBc-positive donors have been excluded as liver donors. We assessed the prevalence of anti-HBc in UK organ donors and followed up recipients of organs from anti-HBc-positive donors for serological evidence of posttransplantation hepatitis B virus infection.Methods.Serum samples from 400 hepatitis B surface antigen-negative organ donors were tested for anti-HBc.Results.Only five (1.25%) of 20 sera in which anti-HBc was initially detected were confirmed as anti-HBc positive on further testing. Posttransplantation serum samples from four recipients of confirmed anti-HBc-positive organs showed no evidence of de novo hepatitis B infection.Conclusions.The poor specificity of some anti-HBc immunoassays was confirmed and suggests that donor exclusion on the basis of a single anti-HBc-positive result may result in the inappropriate loss of organs.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Background.The new microemulsion formulation of cyclosporine (CsA-ME) is more bioavailable than cyclosporine (CsA) in de novo renal transplant patients. Therefore, it was of interest to compare the safety profile of each formulation in such patients.Methods.In a multicenter, double-blind, parallelgroup study, 101 renal transplant recipients were randomized after transplantation to receive either CsA (n=50) or CsA-ME (n=51) capsules twice daily for 2 years. Of these patients, 54 (CsA, n=26; CsA-ME, n=28) completed 1 year of the study and entered the second-year, double-blind extension. Initial dose at the time of transplantation was 5 mg/kg b.i.d.; doses were titrated to target trough levels.Results.The mean (±SD) doses at the end of 2 years were 4.6±1.8 and 3.8±1.1 mg/kg per day for CsA- and CsA-ME-treated patients, respectively. The mean (±SD) CsA trough levels at end point were 187±63 and 210±95 ng/ml for CsA- and CsA-ME-treated patients, respectively. At least one adverse event was reported by 25/26 (96%) of CsA- and 27/28 (96%) of CsA-ME-treated patients. No patient discontinued the study because of adverse events. No deaths occurred during the study. Renal function, as measured by serum creatinine levels, and blood pressure were comparable over time in both treatment groups.Conclusions.There was no significant difference in safety and tolerability between CsA- and CsA-ME-treated kidney recipients for 2 years after transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We report a case in which a living donor kidney that contained a large benign cyst was successfully transplanted between a mother and her daughter. The donor, a 53-year-old woman, had good renal function, but her right kidney contained a large 4-cm cyst that had a benign appearance on computed tomography. At operation the cyst was proven to be benign by frozen-section histological examination and the transplant was performed. Both donor and recipient continue to enjoy satisfactory renal function 3 years after transplantation. A review of the literature regarding renal cysts and management strategies for use of cystic kidneys in transplantation are presented.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Most recipients of simultaneous pancreas-kidney transplants experience acute rejection in the early postoperative course. We report our experience with four recipients of simultaneous pancreas-kidney transplants with acute rejection who were effectively treated with the combination of intravenous and oral FK506 therapy. This spared these patients an extra course of monoclonal or polyclonal antibody.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The value of urine flow cytometry (UFC) in diagnosing acute renal allograft rejection (AR) was recently established in a prospective double-blind study.In this study, we report the 1-year follow-up of three groups of patients identified during the previous study: group 1-stable patients (no ARs) with persistently negative UFCs (n=7); group II-patients who had early ARs (<3 months after transplantation), with positive UFCs that completely normalized with antirejection therapy (n=8); group III-stable patients (no ARs) with positive UFCs (n=7). By definition, group III consists of patients previously considered to have “false positive” UFCs. All patients received standard immunosuppressive therapy, with regimens that included cyclosporine at doses adjusted to maintain target levels.Serum creatinine (SCr) levels (mg/dl) were similar in all three groups at 1 month after transplantation. However, at 1 year after transplantation, SCr was 1.4±0.2 in group I, 2.0±0.9 in group II, and 1.9±0.3 in group III (P=0.004 group I vs. group III). There were no ARs clinically diagnosed during this follow-up period in any of the three groups of patients, but there were significantly higher SCr increments among group III patients after the 1 year of follow-up.The detection of an active urine sediment by flow cytometry in “clinically stable” allograft recipients may indicate ongoing, subclinical acute rejection activity, which in this study was found to be associated with worse renal function at the end of the first post-transplant year as compared with patients with persistently negative UFCs. Increased immunosuppression may be indicated for these patients with persistently positive UFCs.

ISSN:0041-1337    

出版商:OVID    

年代:1997

数据来源: OVID