摘要:

Although cyclosporine (CsA) displays high immunosuppressive efficacy due to potent selective inhibition of T cell, but not nonspecific, immune functions, the pleiotropic toxicities of the drug result in a low therapeutic index. Thus for a given individual there is at best only a narrow dosage range producing immunosuppression not beclouded by toxicity. Selection of the appropriate CsA dose to achieve this state is complicated by marked inter- and intraindividual variability in drug pharmacokinetics and pharmacodynamics (1). Even considering renal transplant recipients solely, pharmacokinetic variations in drug absorption, volume of distribution, and metabolism as estimated by clearance rates are so great that strategies based on median population values are not useful for a great proportion of patients. Thus it is necessary to devise a CsA strategy that tailors therapy to compensate for interindividual variations. Implementation of such a strategy not only standardizes drug therapy, but also reveals the clinical impact of interindividual differences in the profile of CsA metabolites and in pharmacodynamic effects of a given quantity of CsA, reflecting both the therapeutic actions on the immune system and toxic effects on target organs. Thus a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variation is essential for the eventual dissection of a rational CsA regimen.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The effect of cyclosporine on the alloantibody response to blood transfusion was investigated in inbred strains of rats by IHA and CELISA; recipient animals differed from the donors at the class I (RT1A) or both class I and class II (RT1B) antigens of the major histocompatibility complex. Alloantibody titers stimulated in high responder PVG animals by blood transfusions were attenuated by cyclosporine; this effect was not demonstrated in low responder PVG rats, as alloantibody titers decreased after further blood transfusions whether or not cyclosporine was given. Cyclosporine not only reduced the initial IgM response but suppressed the subsequent production of IgG.Splenocytes from rats receiving cyclosporine and blood transfusions from donors that differed from the recipients at the class I antigen were effective in suppressing the subsequent antibody response to blood transfusion. When blood transfusions from donors which differed from the recipients at both class I and class II antigenic loci were given after splenocyte transfer, a greater degree of immunosuppression was detected than if the transfusion donor differed only at the class I locus.These data suggest that the sensitization produced by blood transfusions and the persistence or decline of the alloantibody response depend upon the responder status of the recipient. Blood transfusions given with cyclosporine are capable of inducing suppressor activity that is transferable in spleen homogenates. Subsequent alloantibody responses are influenced by the class I and class II disparities of the donor and recipient animals. If these results can be extrapolated to clinical practice, cyclosporine should be given with pretransplant blood transfusions to prevent sensitization, and the transfusion donor should differ from the recipient at both class I and class II antigenic loci.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

We investigated (1), whether long-term (more than 6 months) streptozotocin-induced diabetes in mice had a detrimental effect on the function of pancreatic islet isografts; and (2), whether there was an effect on graft function in chronically diabetic mice of continuous pretransplant insulin infusion.BALB/c female mice that had been diabetic for more than 6 months were each transplanted with 1/2 of a 17-day fetal mouse pancreas that had been in organ culture for 14 days. All animals were grafted with same batch of tissue. One group of animals received continuous intraperitoneal infusion of regular insulin via an Alzet 2002 osmotic pump at the rate of 0.5 U/day for 14 days prior to grafting. Matched, chronically diabetic animals with pumps containing diluent alone, acutely diabetic animals of the same age, and acutely diabetic younger animals were used as controls. At 20 weeks after transplantation the grafts were removed and their insulin content measured.Following transplantation and removal of the pumps, all acutely diabetic animals returned to euglycemia within 6 weeks. The chronically diabetic animals which received diluent alone took 11 weeks to reach euglycemia compared to 7 weeks for their littermates that had received insulin. Graft insulin content was decreased from 16,300±4100 ng in the acutely diabetic animals to 9600±5200 ng in the chronically diabetic, non—insulin-treated group. The chronically diabetic insulin-treated group, however, had grafts with 16,400±5100 ng.Our studies suggest that there is a detrimental effect of chronic diabetes on graft insulin content that is ameliorated by pretransplant insulin therapy.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Incubation of canine marrow and peripheral blood mononuclear cells with L-leucyl-L-leucine methyl ester resulted in the inhibition of mitogen- and alloantigen-induced blastogenesis, the elimination of allosensitized CTL and NK activity, and prevented the development of CTL from pCTL. The effects of these incubations were similar to those described in mice and humans. Additionally, in vitro CFU-GM growth from treated canine marrow was reduced, but could be regained when the Leu-Leu-OMe—treated marrow was cocultured with either untreated autologous peripheral blood mononuclear cells or monocyte-enriched PBMC but not with untreated monocyte-depleted PBMC. Six of seven dogs conditioned with 920 cGy total-body irradiation engrafted successfully after receiving autologous marrow that was incubated with Leu-Leu-OMe prior to infusion. These cumulative results indicate that incubation with Leu-Leu-OMe is a feasible method to deplete canine marrows of alloreactive and cytotoxic T cells prior to transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Haploidentical fetal rabbit islets were transplanted into the renal subcapsular space of outbred maternal hosts. Islets were prepared by a mild collagenase digestion and were cultured in air and a high oxygen environment for 10 days prior to implantation. Grafts were examined at 14 days and later.No grafts survived in the absence of host immunosuppression, even when treatment of the donor tissue included both culture and ultraviolet-B irradiation (groups 1 and 3). With a high dose of oral cyclosporine, 30 mg/kg/day on days 0–3, viable but disrupted islets were present in 1/7 recipients of islets treated by culture alone. Only with high-dose peritransplant cyclosporine or chronic low-dose immunosuppression, and islet treatment with UVB and culture, was regular graft survival achieved (groups 4A and 5).These results demonstrate that haploidentical outbred hosts can be made to accept fetal islet allografts pre-treated by UVB irradiation and culture in a high oxygen environment only if the recipient is given a high peritransplant dose of oral cyclosporine (30 mg/kg/day) or chronic low-dose cyclosporine, (10 mg/kg/day).

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

We studied morphologic features of small bowel transplants in 25 dogs immunosuppressed by cyclosporine, and preoperative graft irradiation. Graft and host bowel were compared with respect to multiple histologic parameters in a blinded analysis. A lymphoplasmacytic infiltrate in nerves and vessels in submucosa and muscle was present in 18 graft bowels and only 3 host bowels, suggesting that these findings represent a cellular rejection reaction. The other histologic parameters were the same in graft and host bowel. Although the dogs did not exhibit clinical signs of rejection, end-stage scarring of the bowel and death occurred in 6 dogs. The animals did not develop systemic graft-verus-host reaction. These findings indicate that under cyclosporine therapy, a sub-clinical rejection reaction persists deep in the wall and may remain undetectable in mucosal biopsies, but may progress to destroy the graft.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

We investigated the effect of 15-deoxyspergualin (DSG) on graft rejection, starting administration at the onset of rejection and on the induction of immunologic unresponsiveness. Hearts from WKAH rats were transplanted into the neck of ACI rats. The energy metabolism of the grafted hearts was followed by P nuclear magnetic resonance spectroscopy. The day that energy metabolism started to fall was defined as the onset of rejection, and intraperitoneal administration of DSG was initiated at 5 mg/kg/day for 15 days from this day. The grafted heart arrested in 2 of 10 rats 9 and 11 days after transplantation, respectively, but the remaining 8 recovered from rejection and 5 of them showed evidence of immunologie unresponsiveness. Of 10 rats treated with DSG from the day of transplantation, only 1 rat showed evidence of unresponsiveness. The initiation of DSG treatment from the onset of rejection resulted in a higher percentage of induction of unresponsiveness. Therefore, DSG was considered to specifically inhibit lymphocyte clone expansion at the onset of rejection. Spleen cells obtained from recipients 7–10 days after the end of DSG treatment were administered to syngeneic ACI rats grafted with WKAH hearts. Graft survival was significantly prolonged, but long-term unresponsiveness could not be transferred. However, immunologie unresponsiveness could be adoptively transferred in 3 of 5 rats receiving spleen cells from syngeneic rats that had recovered from rejection after DSG treatment and had acquired long-term unresponsiveness. These results suggest that suppressor cells are resistant to DSG and are spared and participate in the maintenance of immunologic unresponsiveness.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Orthotopic bowel transplantation continues to be a “difficult” procedure, both experimentally and clinically, despite the advent of cyclosporine. Even with high-dosage CsA administration, long-term survival has been sporadic and short-term mortality high. In the present study, a low-dosage CsA regimen (5 mg/kg/day for 2 weeks postoperatively) produced prolonged sur- vival in BN-Lewis donor/recipient combinations utilizing an orthotopic bowel transplantation model with portal venous anastomosis. The transplanted bowel continued to survive despite the lack of maintenance dosage after initial induction. The recipient animals evinced donor-specific hyporesponsiveness as donor skin grafts were rejected in a slow, indolent fashion. Third-party skin grafts acutely rejected in normal fashion. It was remarkable that the bowel grafts continued to survive in good condition despite the rejection of donor-specific and nonspecific challenging skin grafts placed on the animals. The precise mechanism of this donor-specific hyporesponsiveness is not known.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The long-term results of conversion of cyclosporine to azathioprine and those of continuous CsA therapy were evaluated in a prospective study of 66 renal transplant patients who had been randomly assigned to each treatment group at 3 months following transplantation. The start point of the study was thus at 3 months posttransplant; no differences in the three-year patient and graft survival were found; these consisted of 97% and 94% in the converted group and 100% and 94% in the nonconverted group, respectively. The incidence of one or more antirejection treatments did not differ between the two groups at 3–12 months (16% vs. 17%) or after 12 months (12% vs. 9%). The incidence of hypertension at different intervals ranged from 79% to 100% in the group on continuous CsA therapy versus 50 to 58% in the converted patients. The degree of proteinuria in the 2 groups was not different at at 12 months. At 24 and 36 months the proteinuria (g/24 hr) was higher in the converted group (0.51±0.18 and 0.53±0.13; mean ± SEM) versus the CsA group (0.15±0.04 and 0.21±0.09). At 3 years, the mean creatinine clearance for the patients converted to Aza was higher than that found for the continuously CsA-treated patients (67±8 and 59±6 ml/min; mean ± SEM). This study shows that early CsA conversion to Aza gives a slightly better 3-year graft function, although not significantly different, compared with continuous CsA therapy without differences in patient or graft survival.

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Cyclosporine blood levels were measured in 225 blood samples taken 14 days to 3 years after transplantation from 8 adult and 7 pediatric liver graft recipients. Results by high-performance liquid chromatography, radioimmunoassay with a polyclonal antibody (PARIA) or with a selective monoclonal antibody (MARIA) were compared in the context of major clinical events and alterations in serum bilirubin, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, urea, and creatinine. Cyclosporine blood levels by MARIA were significantly higher than HPLC values, but only by mean values of 11 μg/L in adult and 20 μg/L in pediatric patients. These differences were unaffected by alterations in liver or renal function and seem unlikely to affect clinical management. Minimum PARIA:HPLC ratios of 2–4 were noted in patients with good graft function, with higher ratios (up to 18) associated with hepatic dysfunction. Multiple regression analysis demonstrated that elevations in serum bilirubin and alkaline phosphatase significantly contributed toward the correlation with raised PARIA:HPLC ratios in adults and that γ-glutamyl transpeptidase and aspartate aminotransferase were additionally important in children. There was no significant contribution from either serum urea or creatinine levels to raised PARIA:HPLC ratios, but in children a positive correlation existed between these indicators of renal function and trough cyclosporine concentrations determined by selective methods (HPLC and MARIA).

ISSN:0041-1337    

出版商:OVID    

年代:1988

数据来源: OVID