Showing papers by "Diego Cantarovich published in 1989"

Anti-interleukin 2 receptor monoclonal antibody in the treatment of ongoing acute rejection episodes of human kidney graft--a pilot study.

Abstract: Monoclonal antibodies (MoAbs) against human interleukin 2 receptor (IL-2-R) have been shown to prevent early kidney rejection in animals and humans. We report here the effect of an anti-IL-2-R MoAb (33B3.1) inhibiting IL-2 binding high-affinity sites on activated lymphocytes in 10 declared acute rejection episodes of first cadaveric kidney grafts. Six patients were under cyclosporine treatment only at the time of diagnosis of the rejection. All rejection episodes but one were biopsy-proved cellular rejections. Treatment consisted of intravenous infusions of 33B3.1 at 20 mg/day x 2 days, followed by 10 mg/day for 8 additional days. In case of MoAb ineffectiveness at day 5, anti-IL-2-R MoAb was discontinued and a rescue treatment of corticosteroid boluses (CSb) was given. If not, in all cases corticosteroids (CS) were given (1 mg/kg) at the end of MoAb treatment (day 10) and tapered off thereafter. Two rejection episodes immediately responded to 33B3.1 treatment. During 33B3.1 treatment four other patients had only a stabilization of their blood creatinine concentration, which nevertheless returned to prerejection levels after day 10 when anti-IL-2-R was discontinued and CS administered at 1 mg/kg (no rescue treatment). The four remaining patients had an increase of their blood creatinin levels at day 5 despite 33B3.1 treatment, and their renal function only improved with CSb rescue treatment. One of these patients lost the graft despite rescue treatment, as well as a 9-day course of antithymocyte globulin. Trough levels of MoAb reached a plateau as early as day 2 (approximately 6 micrograms/ml). All patients developed antibodies (IgM and IgG) after day 14. In no instance could unresponsiveness be related to low circulating 33B3.1 trough levels or to early host anti-MoAb immune response (IgM or IgG). We conclude that 33B3.1, known to be effective in preventing early rejection, has only inconsistent and/or incomplete effects on the ongoing rejection process. Our data suggest that once IL-2-dependent clones are expanded in the rejected graft, interference with IL-2/IL-2-R signals does not block the effector mechanisms sustaining acute rejection.

Polyclonal rabbit gamma globulins against a human cytotoxic CD4 T cell clone. II: Use in prevention of rejection in kidney transplantation: a pilot study

Abstract: Antiblast globulins (GAB) were prepared by immunization of rabbits with activated T lymphocytes (AT) derived from a rejected kidney allograft. AT consisted of a CD4+ (CD3+, CD2+ TCR alpha+ beta+) clone cytotoxic for HLA DR8-positive targets. The immunizing cells were adapted to industrial growth conditions by repetitive stimulations with an EBV-transformed line from the kidney donor and recombinant IL-2. In the pilot study, GAB (1.0-1.5 mg/kg/day) was given in 12-hr infusions, in association with prednisone (Pred) 1 mg/kg/day and azathioprine (Aza) 2 mg/kg/day, as prophylactic treatment of rejection in 12 kidney-transplanted patients during the first 2 weeks postgrafting. GAB dosage was further adapted according to the level of circulating E-rosette-forming T cells (ERFT). Cyclosporine A (8 mg/kg/day) was given at day 14 as a monotherapy after Pred and Aza were progressively tapered. No patient died, but one kidney was lost from surgical complication. No rejection occurred under GAB treatment; 41% of patients had at least one episode in the first 3 months and 16% from 3 to 9 months. GAB side effects were minor (skin rash: 2, low grade fever: 4) except for one acute serum sickness. Platelet and white blood cell counts were unchanged, but there was a significant decrease in hemoglobin during the 2 weeks of GAB infusions. Few infectious episodes occurred (3 bacterial, 2 viral). GAB monitoring showed a dramatic drop in T11+, T3+, T4+, and T8+ circulating T cells (less than 10% of normal values between days 3 and 14), whereas EFRT cells had a delayed and somewhat lower decrease (less than 10% after day 6 only). Consequently, mean GAB doses had to be raised to 1.3 mg/kg/day at day 4 and 1.6 at days 8 and 14. This pilot study suggests that this new bioreagent should be of major interest in the prophylaxis and treatment of rejection in allograft recipients. A controlled study is in progress.

Azathioprine-cyclosporin A (CyA) double therapy versus CyA alone after the first rejection episode in kidney-transplanted patients under CyA. A randomized study.

Abstract: A controlled trial was carried out in 78 kidney transplant recipients under cyclosporin A (CyA) monotherapy who had experienced a first rejection episode. Thirty-nine were randomly selected to receive azathioprine (AZA; 2 mg/kg per day) in combination with CyA (group AZA+), while the others continued to receive CyA alone (group AZA-). Four of the patients in the study died; three were in group AZA+ and the cause of their deaths was cardiovascular. Graft survival rates were 97% at 6, 12, and 24 months postrejection in group AZA+ as compared to 97%, 90%, and 81%, respectively, in group AZA- (P less than 0.05 at 12 and 24 months). Significantly more patients were free of rejection with the double therapy than with CyA monotherapy (75% vs 51% at 12 months; P less than 0.05). In spite of the addition of a second immunosuppressive drug, the CyA dosages given and the CyA trough blood levels maintained were similar in the two groups. Serum creatinine was similar in patients with and without AZA. Infectious complications were also similar in both groups. A significant macrocytosis was the only side effect of AZA therapy. On the whole, these data show the benefit of CyA-AZA double therapy in the prevention of rejection recurrence without exposing patients to either increased risk of infection or serious side effects of AZA. Whether this double therapy should be systematically administered to all recipients or only after a first rejection episode is discussed.

Azathioprine-cyclosporin A (CyA) double therapy versus CyA alone after the first rejection episode in kidney-transplanted patients under CyA

Abstract: A controlled trial was carried out in 78 kidney transplant recipients under cyclosporin A (CyA) monotherapy who had experienced a first rejection episode. Thirty-nine were randomly selected to receive azathioprine (AZA; 2 mg/kg per day) in combination with CyA (group AZA+), while the others continued to receive CyA alone (group AZA−). Four of the patients in the study died; three were in group AZA+ and the cause of their deaths was cardiovascular. Graft survival rates were 97% at 6, 12, and 24 months postrejection in group AZA+ as compared to 97%, 90%, and 81%, respectively, in group AZA− (P<0.05 at 12 and 24 months). Significantly more patients were free of rejection with the double therapy than with CyA monotherapy (75% vs 51% at 12 months;P<0.05). In spite of the addition of a second immunosuppressive drug, the CyA dosages given and the CyA trough blood levels maintained were similar in the two groups. Serum creatinine was similar in patients with and without AZA. Infectious complications were also similar in both groups. A significant macrocytosis was the only side effect of AZA therapy. On the whole, these data show the benefit of CyA-AZA double therapy in the prevention of rejection recurrence without exposing patients to either increased risk of infection or serious side effects of AZA. Whether this double therapy should be systematically administered to all recipients or only after a first rejection episode is discussed.

Anti-IL-2-R Monoclonal Antibody in Allograft Recipients

Abstract: A rat IgG2a monoclonal antibody (33B3.1) directed at the human Tac antigen and interacting with the high affinity binding site of IL-2 on its receptor was tested for treatment of kidney allograft recipients. This antibody is efficient in preventing graft rejection in the weeks following transplantation. Its activity compares to polyclonal rabbit anti-thymocyte globulin but it has fewer side effects. The dose of 33B3.1 given is critical for its preventive effect. A majority of the recipients developed IgM and/or IgG against rat Ig. Rejection episodes occurring during 33B3.1 therapy were associated with an early rise in host anti-33B3.1 antibodies and a drop in their monoclonal antibody (MoAb) circulating levels. When 33B3.1 was given to treat ongoing rejection, it had only an inconsistent and/or delayed effect. Various factors are discussed, such as circulating free 33B3.1 levels, host anti-33B3.1 immune response and the presence of inhibiting concentrations of soluble Tac chain, which can interplay with the protective effect of the anti-interleukin-2-receptor monoclonal antibody. The use of bioreagents which interfere only with determinants present on host activated lymphocytes may represent a new step toward selective immunosuppression in allograft recipients.