摘要:

Graft-versus-host disease and graft rejection remain the two principal causes of morbidity and mortality after major - histocompatibility - complex - mismatched bone marrow transplantation. Human and animal models suggest that both CD4+and CD8+T cell subsets present in the donor inoculum are responsible for their initiation. Since the human mixed lymphocyte culture (MLC) and the HLA-restricted cytotoxicity may reflect cellular interactions occurring during GVHD and graft rejection, inhibitions of these responses may represent useful approaches for screening functional T cell depletion in experimental bone marrow transplantation studies. For this purpose, we have tested the possibility of removing the host-specific allogeneic T cells present in the marrow. After a two-day MLC, the specifically activated host alloreactive blood or bone marrow T cells were incubated with the ricin A-chain toxin conjugated with the antibody 33B3.1 directed against the human receptor of interleukin 2 (33B3.1-IT). A complete inhibition of a primary MLC and of cytotoxic activities was observed as well as a disappearance of IL-2R(+) (p55) T cells. This method had limited consequence upon the alloreactivity of blood or marrow T cells toward a third unrelated party. The limiting-dilution analysis of residual alloantigen-reactive T lymphocytes has shown that this depletion results in a twentyfold to fiftyfold reduction of antihost reactivity. The procedure was also shown not to inhibit the growth of marrow precursors for granulocytes and macrophages.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

A potent platelet-activating factor (PAF) antagonist, RP 48740, was tested for its ability to delay acute and accelerated rejection in experimental kidney transplantation. Lewis rats (RT11) either nonimmunized or preimmunized against Brown Norway (BN) antigens, received allogeneic kidney transplants from BN rats (RT1n) and were bilaterally nephrectomized. Survival of transplanted animals was observed following oral treatment with RP 48740 (100 mg/kg/day). Control animals received orally methylcellulose 5% (placebo), cy-closporine (10 mg/kg/day), or CsA (10 mg/kg/day) plus RP 48740 (100 mg/kg/day). CsA prolonged rat survival in both rejection models. RP 48740 induced prolongation of survival in preimmunized rats and, to a lesser but significant degree, in nonimmunized animals. Although treatment with CsA plus RP 48740 was efficient in acute rejection, it induced no significant increase of survival in preimmunized rats as compared with placebo, indicating a lack of potentiating activities between the two compounds. The pharmacokinetic study of CsA showed that this lack of efficacy of combined treatment may be interpreted as the decreased CsA bioavailability observed when the animals also received RP 48740. The demonstration that a PAF antagonist delays accelerated rejection sheds some light on the biological effects of hyperimmunization in transplantation and on the possible therapeutic approaches.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Kupffer cells are activated by calcium and release a variety of toxic mediators, including proteases. The purpose of these studies, therefore, was to determine if protease inhibitors and a calcium channel blocker could increase survival time in the rat model of orthotopic liver transplantation. Survival for 30 days was greater than 90% in this model when livers were stored for 1 hr in Ringer's solution (survival conditions)—however, grafts stored for 4 hr in Euro-Collins solution or 8 hr in University of Wisconsin (UW) solution survived post-operatively only 1.2 and 0.7 days, respectively (nonsurvival conditions). When livers were stored for 4 hr in Euro-Collins containing a cocktail of protease inhibitors (leupeptin, pepstatin A, phenylmethylsulfonyl fluoride, 20 ng/ml each; diisopropyl fluorophosphate, 100 μM) and subsequently transplanted, however, survival time was increased significantly to 11.5 days. Inclusion of a calcium channel blocker, nisoldipine (1.4 μM), in the protease inhibitor cocktail increased survival time to 23 days. Actually, nisoldipine alone increased survival time to 25 days. Nisoldipine alone also increased survival time in livers stored for 8 or 16 hr in UW solution to between 15 and 20 days. Serum transaminase levels reached peak values greater than 2400 U/L one day postoperatively in the nonsurvival groups, and liver injury assessed histologically was apparent. Under these conditions, pulmonary infiltration of inflammatory cells was observed in about 60% of the lungs examined and was associated with massive bleeding. Inclusion of the protease cocktail, nisoldipine, or both in the storage solutions decreased maximal SGOT levels and injury to both liver and lung significantly by about 50% postoperatively. Nisoldipine also decreased phagocytosis of carbon particles by the perfused liver 2− to 3-fold following storage under nonsurvival conditions (half-maximal effect = 0.3–0.4 μM nisoldipine). Moreover, nisoldipine improved hepatic microcirculation. It accelerated blood flow into the liver, as indexed by hemoglobin reflectance from the liver surface. These data support the hypothesis that Kupffer cells are activated early in the sequence of events that causes graft failure leading to endothelial cell-mediated alterations in the microcirculation. This work demonstrates clearly that dihydropyridine-type calcium channel blockers such as nisoldipine may be clinically useful in storage solutions for liver prior to transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Treatment of type I diabetes by early pancreas transplantation requires the availability of a safe and effective transplantation technique. With the currently available immunosuppressive drugs it is difficult to obtain long-term pancreatic allograft survival. In this respect pancreas grafts compare unfavorably with heart or kidney grafts. Using a relatively simple and safe subcutaneous transplantation technique we investigated the effect of blood transfusions combined with low-dose immunosuppressive drugs in rats and dogs in order to attain an immunosuppressive schedule of low toxicity. Subcutaneous pancreas transplantation appeared to be a feasible technique, with long-term graft survival in syngeneically transplanted rats and autotransplanted dogs. Only a moderate prolongation of pancreatic allograft survival by blood transfusions was demonstrated in both models. In rats one or three preoperative donor-specific blood transfusions significantly prolonged pancreas graft survival to 23±15 and 29±15 days, respectively, compared with 12±2 days in untreated controls. Low-dose cyclosporine (15 mg/kg on the day of operation) led to improved graft survival in nontransfused recipients (17±4 days), however, this treatment could not further prolong graft survival in transfused animals (34±20 days). In dogs, treated postoperatively with azathioprine and prednisolone, three preoperative third-party blood transfusions led to 29±19 days of pancreas graft survival, which was not significantly different from nontransfused controls (17±5 days). These results indicate that, in rats as well in dogs, pancreatic allografts are less sensitive to the immunomodulating effect of blood transfusions than heart and kidney grafts.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The attitudes, religious issues, and participation level of 110 practicing hospital chaplains concerning cadaver-organ donation are considered. Chaplains are identifying with the emotional aspects of organ donation, in particular the grief and emotional trauma of the grieving family. Donor rates of minority groups are discussed from the perspective of religious traditions and myths. Religious questions of next of kin are investigated, and recommendations are made for a comprehensive approach to cadaver-organ procurement.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The frequency of donor-reactive cytolytic T lymphocytes was measured in the peripheral blood mononuclear cell population of a group of 12 cardiac allograft recipients immediately before and at various time points after transplantation. At each of the time points after transplantation the donor heart was biopsied and the rejection status of the graft was determined by applying standard histological criteria.The results of this study showed that the preoperative frequency of donor-reactive cytolytic T lymphocytes in the blood was not predictive of a future tendency toward graft rejection. However, when all the data were examined it was apparent that the frequency of donor-reactive cytolytic T lymphocytes was significantly higher (P<0.05) in blood samples from patients whose simultaneous biopsy showed histological evidence of acute cardiac allograft rejection than in blood samples from transplant patients showing no evidence of rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

We evaluated the efficacy of the addition of the lymphoblasticidal agent vincristine to standard immunosuppression in heart transplantation in a prospective randomized study of 92 patients (46 to receive and 46 to not receive vincristine) with a follow-up period of 12 months. Patients received either equine antithymocyte globulin for the first week or OKT3 monoclonal antibody (OKT3) for the first 10 or 14 days after transplantation. Six to eight doses of vincristine were given over 9–12 weeks, beginning 2 days after completion of ATG or OKT3. The number of rejection episodes in the first six months posttransplantation, the percentage of patients corticosteroid maintenance-free at one year, cumulative immunosuppressive drug doses, deaths, infections, and neuropathy were followed.The addition of vincristine resulted in more patients achieving corticosteroid maintenance-free status at one year (vincristine 68%, no vincristine 38%,P= 0.01). In comparing patients at relatively high risk for rejection (those younger than 55 years and all females) with those at relatively low risk (males older than 55 years), only the high-risk vincristine-treated patients showed significantly fewer rejection episodes and a higher corticosteroid maintenance status at one year (66% vs. 32%,P= 0.01). There were no significant differences in survival (vincristine 96%, no vincristine 98%), infection, or amounts of other immunosuppressive agents used. The major side effect was neuropathy, which occurred more frequently in the vincristine-treated group (43% vs. 18%,P<.001).We conclude that vincristine acts as an immunosuppressive agent in cardiac transplantation, particularly in patients at higher risk for rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Forty-five patients were prospectively studied during the first 100 days after allogeneic marrow transplant to determine the relationship between cytomegalovirus-specific gamma-interferon and interleukin 2 production by peripheral blood mononuclear cells and CMV infection. IL-2 production was significantly lower than normal throughout the study period (P=0.0001). In contrast, mitogen-induced gamma-interferon production was in the normal range by days 41–60 while CMV antigen induced gamma-interferon production by PBMC was normal by 81–100 days after transplant. Antibody- and complement-depletion studies showed that T4 helper cells were capable of gamma-interferon production in response to CMV antigen despite deficient IL-2 production. Neither gamma-interferon nor IL-2 production distinguished CMV-infected from uninfected patients. However, CMV-infected patients had significantly more T8 cytotoxic/suppressor cells than did uninfected patients by 81–100 days after transplant (P=0.001). In vitro addition of IL-2 significantly increased gamma-interferon production by PBMC from patients with reduced production, suggesting that decreased gamma-interferon production may be related to deficient IL-2 production. Deficiencies in both CMV-specific IL-2 and gamma-interferon production may contribute to the high frequency and severity of CMV infection after marrow transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1–36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months post-transplant in the triple-therapy group (p<0,05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor β chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7–53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3–44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 μg/ml were achieved in patients treated with 0.5 or 1.0 mg/ kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID