摘要:

Spontaneous orthotopic liver allograft acceptance associated with microchimerism in mice induces tolerance to subsequent skin or heart transplants from the donor but not third-party animals. Despite in vivo hyporesponsiveness, in vitro MLC and CTL assays showed continuing antidonor reactivity. Cells isolated from recipients' spleens and grafted livers, when tested in MLC and CTL assays, were antidonor reactive out to 3 months to the same degree as splenocytes obtained from either naive or presensitized (with skin or heart) mice. Nevertheless, passive transfer of splenocytes or liver lymphocytes from liver tolerant mice, but not naive or sensitized donor strain mice, were able to prolong skin graft survival significantly in naive irradiated recipients. By using a strain combination in which the donor but not the recipient expressed the stimulatory endogenous super-Ag (Mlsf), it was possible to determine whether super-Ag-reactive T cells bearing Vβ5 and Vβ11 were deleted or anergic. Phenotypic analysis of cells isolated from recipients' spleens and grafted livers (up to 90 days after transplant), when compared with naive animals, showed no significant difference in Vβ5 and Vβ11 TCR expression. Additionally, when these isolated spleen cells were tested for antibody-mediated stimulation, both anti-Vβ5 and Vβ11 TCR mAb led to marked proliferation of cells obtained from naive and liver-transplanted recipients, but as expected, proliferation was very low in cells from naive donors. These results suggest that liver transplantation induces donor-specific tolerance in vivo, which may not be reflected in in vitro proliferative and cytotoxicity assays (split tolerance). Furthermore, this tolerance does not seem to be induced by clonal deletion or anergy of minor-lymphocyte-stimulating-antigen-reactive T cells in the recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To reveal the kinetics of infiltrating cells in the hepatic parenchyma after the liver transplantation, we identified the cell type (macrophages, monocytes, agranular lymphocytes, large granular lymphocytes, and neutrophils) and localization on toluidine blue-stained sections of perfusion-fixed liver grafts in rejecting and tolerant combinations and performed quantitative analysis of the density of each cell species infiltrating inside and outside the sinusoid at days 4 and 7. The number of total infiltrating cells per unit square became 9 times as high as that of an untreated liver at day 4 and 30 times as high at day 7. Macrophages accounted for a large part of the infiltrating cells both in and around the sinusoid: 72% of intrasinusoidal infiltrating cells and 88% of extrasinusoidal ones at day 4; 73% of intrasinusoidal ones and 93% of extrasinusoidal ones at day 7. The ratio of extrasinusoidal cell to intrasinusoidal cell of macrophages was 9:91 at day 4 and 34:66 at day 7, much higher than ratios of other infiltrating cells. This fact means that macrophages show a marked tendency to migrate out of the sinusoid in the liver graft. The proportion of macrophages to total infiltrating cells dropped at day 4 and went up again at day 7, while that of monocytes showed a reverse pattern. Histologically, immature macrophages, possibly derived from recipient monocytes, coexisted with vacuolated donor macrophages in the sinusoid at day 4, but the latter cells were diminished at day 7. These data indicate that transfor

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A new strategy based on a clonal reduction hypothesis has been developed for prolonging concordant cardiac xenograft survival. Splenocytes from Golden Syrian hamsters were transfused intravenously into Lewis rats 14 days before the time of a donor-specific heart transplant into the recipient. Cyclophosphamide was administered from days −11 to −7 to reduce or eliminate proliferating xenoreactive clones. Low dose CsA was administered after the cyclophosphamide to prevent emergence and expression of xenoreactive cells. Finally, rapamycin 1.0 mg/kg was given for 5 days after transplant as further immunosuppression since it acts synergistically with CsA. In the group that received no immunosuppression after day +8, mean graft survival was 33.2pm7.0 days with 10 of 17 xenografts surviving > 28 days. Extending either CsA therapy or rapamycin therapy after day +8 did not prolong graft survival. Each component of the therapy was found to be necessary for the effect.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation. With the median effect analysis of Chou and Kahan for quantitative drug interactions, substantial therapeutic synergism was demonstrated between FK506 and non-toxic doses of MIZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg/day), which was particularly evident with the lowest dose MIZ (2.5 mg/kg/day). When FK506 was used in combination with MIZ or AZA but not with RS, the maximum effect (peak median graft survival) was enhanced significantly from 15 days (MIZ alone) to 26 days (P<0.05), and from 19 days (AZA alone) to 32 days (P<0.01). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful single antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase the percent mortality and LD50of the antimetabolites.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This study investigates the hypothesis that inhibition of nucleoside transport during hypothermic storage elevates tissue adenosine (ADO) content and improves the function of the isolated rat heart. The hearts, flushed with a cardioplegic solution containing varying concentrations (0–100 nM) of a nucleoside transport inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI), were immersion-stored at 0$dGC for 9 hr. Function was assessed after 30 min of working reperfusion. Function of unstored fresh hearts served as controls and poststorage recovery is reported as percentage of control function. Poststorage heart rate in all groups returned to control level after reperfusion. Recovery of other functional parameters in the no-NBTI group was as follows: aortic flow (AF), 56.2pm4.6%; coronary flow (CF), 53.9pm3.2%; cardiac output (CO), 55.5pm4.0%; systolic pressure, 81.6pm2.5%; work, 47.0pm4.2%; and coronary vascular resistance (CVR), 157.1pm7.8% of control. NBTI improved functional recovery in a dose-dependent fashion; the maximal improvement was seen at a dose of 5 nM, in which the recovery was; AF, 78.1pm3.4%; CF, 73.5pm4.4%; CO, 76.7pm3.6%; work, 70.7pm5.0%; and CVR, 127.5pm4.5% of control (P<0.05 vs. no-NBTI). The ADO A1receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (0.1 μUM) blocked the effects of 5 nM NBTI; the recovery of AF, CF, CO, work, and CVR decreased to 62.8pm8.0%, 58.3pm5.0%, 61.5pm3.9%, 54.4pm4.5%, and 163.8pm12.7% of control, respectively (P<0.05 vs. 5 nM NBTI). Tissue ADO content in 5 nM NBTI hearts at the end of storage was 0.075pm0.025 μUmol/g dry wt, which was significantly elevated from 0.016pm0.004 μUmol/g dry wt in no-NBTI hearts. Purine release during initial reperfusion was delayed in 5 nM NBTI hearts, indicating the inhibition of nucleoside transport by NBTI. But NBTI treatment did not improve end-storage or end-reperfusion myocardial ATP. In conclusion, the addition of NBTI to cardioplegic solution enhanced tissue ADO and improved poststorage function of the hypothermically stored rat heart. The effect is ADO A1-receptor mediated without invoking energy conservation.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Episodes of acute rejection can occur in functional renal grafts even at a very late stage after transplantation. They are not necessarily due to patient non-compliance. The incidence of late acute rejection is commonly underestimated because the diagnosis generally requires histopathology in order to rule out other origins of declining graft function, even more so, as the typical signs of acute rejection as seen in the early posttransplantation period (sudden and rapid increase of creatinine serum level, inflammatory signs) are missing. Histology revealed acute rejection in 157 of 412 renal allograft recipients suffering from progressive graft deterioration between the 2nd and 18th year after Tx.Late acute rejection was clearly associated with elevated levels of activated HLA-DR+T cells in the peripheral blood. These cells were characterized by flow cytometry to be postmitotic activated effector-T cells belonging to the CD4+and CD8+“memory” T cell pool. The high sensitivity (97%) and specificity (88%) of flow cytometric analysis allows for the discrimination between late acute rejection and other causes of deteriorating graft function (infection, toxicity, arteriopathy, chronic rejection). Additionally, this immune monitoring can predict the success of antirejection therapy as early as a few days after initiation of treatment while conventional parameters do not reflect the therapeutic result until 1–3 weeks later. In addition to this, peripheral T cell activation also seems to identify a subgroup of patients with chronic rejection who would respond, at least partially, to steroid bolus therapy. As a result, this parameter is very useful for the clinical management of patients suffering from late deterioration of renal graft function.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Hyperlipidemia is common in heart transplant patients. Lipid-lowering therapy poses special problems, yet may be important because accelerated graft atherosclerosis is the major factor limiting long-term survival.Simvastatin 5 mg/day was started > 6 months after surgery in 26 consecutive cardiac transplant recipients with a total serum cholesterol level of > 250 mg/dl. The dose of simvastatin was increased in 5-mg increments until total serum cholesterol fell below 220 mg/dl or until side effects developed or up to a maximal dose of 20 mg/day. The final average daily dose was 10 mg. Changes in serum lipid levels after 6 months of therapy were compared with data from a matched and concurrent control group of heart transplant patients not taking simvastatin. Immunosuppression for both groups consisted of CsA, AZA, and corticosteroids. In the simvastatin-treated group, the serum level of total cholesterol decreased by 27% from 315pm53 to 230pm38 mg/dl (P<0.0001), low density lipoprotein cholesterol decreased by 40% from 205pm30 to 123pm32 mg/dl (P<0.0001), and triglycerides decreased by 21% from 177pm89 to 140pm49 mg/dl (P<0.01). There was no significant change in high density lipoprotein cholesterol level. Body weight and CsA blood levels remained stable. Steroid intake decreased during the study period to a similar extent in both the treated and the control groups. In the control group, no significant changes in serum lipid levels were observed. Two patients experienced a mild form of myotoxicity. In one other patient simvastatin treatment was stopped after an acute pancreatitis of uncertain etiology developed.Low dose simvastatin effectively lowers total serum cholesterol, low density lipoprotein cholesterol, and triglycerides in heart transplant patients. With due precautions, the safety profile of the drug in this patient population seems reasonable.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

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.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

C3H/HeH or C57BL/6 mice were injected with resting orEscherichia colilipopolysaccharide (LPS)-stimulated splenic B cells from adult B10.BR mice. Animals were grafted with tail skin grafts from B10.BR mice 36 hr later. Spleen cells were removed from these mice 7 days after grafting and challenged in tissue culture with irradiated B10.BR spleen cells or BALB/c cells. LPS blasts, but not naive B cells, induced an antigen-specific reduction in proliferation and IL-2 production from stimulated C3H/HeJ cells. The response obtained from C57BL/6 spleen responder cells was increased by this treatment. IL-4 production was either unchanged (C57BL/6) or enhanced (C3H/HeJ). Modification of the C3H/HeJ anti-B10.BR response by B blasts was not blocked by CTLA-4 Ig, although the increased response seen using MHC-incompatible (C57BL/6) spleen cells was inhibited by CTLA-4 Ig. B10.BR, but not BALB/c, skin graft survival in vivo was enhanced in C3H/HeJ recipients of B10.BR B blasts. In addition, in lymph nodes draining the graft site of C3H/HeJ mice injected with B10.BR LPS blasts, mRNA for IL-4 was detected by polymerase chain reaction.When similar studies were performed with B10.BR immune C3H/HeJ or C57BL/6 mice, no enhancement of graft survival in vivo, or decrease in proliferation/IL-2 production in vitro, was seen following prechallenge with B10.BR LPS blasts.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID