Evidence of donor-specific cellular suppressor activity in donor-specific cell-mediated lympholysis unresponsiveness in renal transplant patients.

Twenty patients with well-functioning kidney grafts from one-haplotype-mismatched related donors, were studied 1-10 years after transplantation (A). Another group of six patients were studied at various times after transplantation (B). The presence of donor-specific transplantation tolerance, using mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) tests was investigated, as well as the possible existence of cells with suppressive activity. All recipients were transfused prior to transplantation and treated with conventional immunosuppression. The patients in group A showed MLC reactivity against donor and third-party cells, indicating a allogeneic response capacity. The CML activity against the donor was low, however, and remained low also following removal of adherent cells. The CML activity toward third-party cells was within the normal range of unmatched individuals. In group B, two of six recipients and high postoperative CML activity against the donor. Both recipients showed clinical signs of rejection. In the remaining four recipients, the antidonor CML reactivity one week after transplantation was lower than the preoperative level. The decrease was even more pronounced at 12 months, although the reactivity against third-party cells was unaltered. The CML reactivity from unrelated fourth-party individuals toward donors was suppressed when cells from recipients with long-term functioning kidneys were added to the cell cultures. The results suggest the presence of a donor-specific cellular suppressor mechanism underlying the donor-specific CML unresponsiveness in recipients with long-term-functioning kidney allografts.

Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.

BACKGROUND: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS: At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.

BACKGROUND: T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS: A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS: There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION: Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.

Bicêtre hospital experience with sirolimus-based therapy in human renal transplantation: the Sirolimus European Renal Transplant Study.

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P

[The immune system of the hunter-gatherer meets poverty and excess]. / Jägarens-samlarens immunsystem möter fattigdom och överflöd.

The immune system is closely integrated with the neuroendocrine system, and infection-induced increases in cytokines such as IL-1, IL-6 and TNF have numerous effects on the central nervous system. These include stimulation of the hypothalamus-pituitary-adrenal (HPA) axis, as well as of leptin production. The increase in leptin causes loss of appetite, which may be deleterious for children who are living under conditions of poverty, have frequent infections and are often already undernourished. These cytokines may also be involved in problems of obesity, since they activate the HPA-axis and since TNF is produced by fat cells and can cause insulin resistance. The immune system originally developed for hunter-gatherers may not be well adapted to the pathology of poverty or that of excess.

A comparative, randomized trial of concentration-controlled sirolimus combined with reduced-dose tacrolimus or standard-dose tacrolimus in renal allograft recipients.

BACKGROUND: The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. METHODS: One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. RESULTS: Demographic variables were similar between groups. At 6 months, mean (± standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P = .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P = .095). CONCLUSIONS: The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.

Renal function in renal or liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus.

Two Six-month pilot studies were conducted in renal (n = 17) or liver (n = 15) transplant recipients to evaluate renal function after conversion from calcineurin inhibitor (CI)- to sirolimus (SRL)-based immunosuppression. After an SRL loading dose, doses were individualized to achieve whole blood trough levels of 10-22 ng/mL. Overall, serum creatinine did not change from baseline to six months post-conversion but an improvement from 219.9 to 201.4 micromol/L at three months was noted in renal transplant recipients (p < 0.05). Another finding was a numerical increase in the mean glomerular filtration rate (GFR) from 26.8 to 33.2 mL/min/1.73 m(2) at six months among liver transplant recipients (NS). All patients survived and all grafts were functioning at the end of the study. In conclusion, renal function remained stable, with a tendency towards improvement, after abrupt conversion from CI- to SRL-based therapy in renal or liver transplant recipients with moderate renal insufficiency.

Effect of captopril treatment on allograft survival and induction of unresponsiveness in heart-transplanted, ATG-treated rats.

The angiotensin-converting enzyme inhibitor captopril has been suggested to have an immunomodulatory effect both in clinical and experimental studies. To further investigate this possible effect in organ transplantation, captopril was given to inbred rats before transplantation of an allogeneic heart. Captopril was found to prolong graft survival significantly compared to untreated controls. In rats treated with a tolerogenic dose of ATG, additional captopril administration tended to increase the proportion of rats with long-term functioning grafts, but this did not reach statistical significance. It is concluded that captopril displays an immunosuppressive effect that seems to be weak, since no augmentation of ATG-induced transplantation unresponsiveness was seen.

Cell-mediated immune responses in renal transplant recipients treated with cyclosporin and prednisolone with or without azathioprine.

The cell-mediated immune response was studied, using mixed lymphocyte reactivity (MLR) and cell-mediated lympholysis (CML) tests, in patients with well-functioning kidney grafts from living donors at 6 and 12 months and at 2-5 years after transplantation. The patients were allocated to treatment with cyclosporin A (CyA) and prednisolone (group A) or with CyA, prednisolone and azathioprine (group B). The MLR towards a third party were in the range of that of untreated controls while the anti-donor activities were reduced after 6 months in both groups. The CML activities in group A towards a third party were in the range of that of untreated controls at all times, while the anti-donor activities were decreased. By contrast, the CML activities in group B towards a third party were decreased during the first year and were in the range of that of normal controls at 2-5 years. The anti-donor CML activities were low at all times in group B. In summary, the two CyA protocols allowed the induction of donor-specific unresponsiveness within the first post-transplant year. The anti-third party activities were low during the first post-transplant year in recipients with triple therapy but not in those without azathioprine.