Background. OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of tumor necrosis factor and sequestration of neutrophils in the lungs. We have previously shown that inhibition of tumor necrosis factor does not completely eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. The current studies analyzed complement activation in vivo during the first hour after OKT3 administration. Methods. Renal (n=4) and lung (n=4) transplant recipients received OKT3 as treatment for rejection and induction therapy, respectively. Complement activation products C4d, Bb, iC3b, and SC5b-9 were also monitored in the lung transplant recipients. Neutrophil expression of CD11a, CD11b, and CD18 was monitored by flow cytometry. Controls included patients receiving methylprednisolone for rejection (n=4), two adults with adult respiratory distress syndrome who received extracorporeal membrane oxygenation, and normal volunteers (n=5). P values less than 0.05 (*) were considered significant. Results. Increases in the plasma levels of C4d, Bb, iC3b, and SC5b-9 were observed in seven of eight patients after OKT3 administration. Mean values (n=8) at 0, 15, and 60 min (in µg/ml) were as follows-C4d: 1.865, 2.644*, and 2.607*; Bb: 0.245, 0.411, and 0.385; iC3b: 10.881, 17.242*, and 15.145*; and SC5b-9: 0.232, 0.269, and 0.302*. An increase in CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with complement activation was observed. In lung transplant recipients, C3 activation correlated with increases in mean pulmonary and central venous pressures (P<0.05). As compared with extracorporeal membrane oxygenation, which activated classical and alternative pathways, OKT3 predominantly activated complement by the classical pathway. Methylprednisolone pulses did not activate complement. Conclusions. Complement activation is an early event after OKT3 administration and is associated with the increased expression of adhesion molecules on neutrophils and with pulmonary hemodynamic changes. Effective therapeutic approaches to the control of early monoclonal antibody side effects may require measures that limit complement activation in addition to reducing cytokine activity.
The renal allograft biopsy is generally accepted as the gold standard for clarifying the cause of renal dysfunction. However, the clinical usefulness of this procedure has rarely been studied prospectively, nor have most studies included follow-up of patients to delineate the influence of the biopsy on clinical outcome. In this study, we evaluated prospectively the clinical usefulness of the allograft biopsy in renal transplant recipients receiving cyclosporine (CyA).During a 21-month period, 82 biopsies were performed. In 54 instances (47 patients), we outlined a presumed diagnosis and tentative treatment plan before the procedure. After the biopsy, a definitive diagnosis was made and an appropriate patient management approach was instituted. We analyzed the incidence of change in patient management that resulted from histological findings. All patients were followed to monitor their response to treatment and allograft survival. In cases of biopsy-proven acute cellular rejection (ACR) or cyclosporine (CyA) toxicity, clinical and laboratory data from the day of the biopsy were reviewed to determine their diagnostic value.One biopsy specimen was inadequate for definitive interpretation. The biopsy findings resulted in a change in patient management in 22 (41.5%) of the remaining 53 cases (change group). The incidence of altered patient management was 38.7% in biopsy specimens taken in the first month, 55.6% between 1 and 12 months, and 38.5% after 1 year posttransplantation. A change in management was required in 2 of 2 patients with chronic allograft dysfunction, in 44.4% of the 45 patients with acute allograft dysfunction, and in none of the patients with delayed graft function (n=6). Within the first week of treatment 19 of 22 (86.4%) in the change group and 25 of 31 (80.6%) in the no change group had a positive response to therapy. The 1-year allograft survival rate was also similar between the two groups. None of the clinical and laboratory data was useful in distinguishing ACR from CyA toxicity.Renal allograft biopsy findings alter patient management recommendations in approximately 40% of patients in whom a presumptive diagnosis had been made on the basis of clinical and laboratory findings. Patients who had a change in patient management because of biopsy findings demonstrated a response to therapy and allograft survival similar to those of patients who had no alteration in management plan after the biopsy.
Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with severe respiratory distress syndromes. However, an inflammatory response has been observed with the use of this therapy. We measured complement activation in vivo in two adults receiving ECMO for acute respiratory distress syndrome (AROS). Production of complement activation fragments C4d, Bb, iC3b, and SC5b-9 was determined using commercial ELISA kits. In both patients there was intense activation of complement that peaked 1 hour (mean SC5b-9 increase to 1135% of baseline) after the start of ECMO and occurred predominantly via the alternative pathway (Bb production). Early and acute complement activation may be responsible for the initiation of the inflammatory response that has been observed in patients treated with ECMO. ASAIO Journal 1999; 45:113–114.
Background. Complement activation has recently been implicated as a contributing factor to early and late allograft dysfunction in cardiac transplantation. The current study was designed to determine whether measurement of plasma complement fragments C4d and SC5b-9 would be useful in detecting acute rejection or accelerated graft atherosclerosis (AGA) in cardiac allograft recipients. Methods. We measured complement activation products, C4d (classical pathway) and SC5b-9 (terminal pathway), at the time of routine endomyocardial biopsy in heart transplant recipients. Ten patients in the immediate posttransplantation period (0–100 days) and 19 patients more than 6 months after transplantation were studied. Results. No correlation was found between plasma levels of complement activation fragments and the presence of biopsy-proven acute allograft rejection or AGA (assessed by coronary angiography). However, plasma C4d and SC5b-9 were significantly elevated in 9 of 10 and 7 of 10 patients, respectively, in the immediate posttransplantation period. This was followed by progressive decrease in the levels of C4d and SC5b-9 fragments during the first 4–6 weeks after transplantation. Conclusion. We conclude that measuring plasma levels of fragments C4d and SC5b-9 is not a useful noninvasive method for detecting acute rejection or AGA after heart transplantation. However, this study provides further evidence that early complement activation after heart transplantation may play a pathogenic role in allograft injury.
155 Background: OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of cytokines such as tumor necrosis factor (TNF) and sequestration of neutrophils in the lungs. We have previously shown that inhibition of TNF does not eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. We analyzed the mechanisms of complement (C) activation in vivo, during the first hour following OKT3 administration. Methods: Renal transplant (Tx) recipients (n=4) with steroid-resistant rejection and lung Tx recipients (n=4) received OKT3 as treatment for rejection and induction therapy, respectively. Blood samples were obtained in Nafamostat-EDTA tubes. C activation products C4d (classical pathway), Bb (alternative pathway), iC3b (C3 cleavage product) and SC5b-9 (terminal pathway) were measured using ELISA kits (QUIDEL Corporation, San Diego, CA). Hemodynamic parameters were monitored using a Swan-Ganz catheter in lung Tx recipients in the ICU. Neutrophil CD11a, CD11b, and CD18 were monitored in two patients by flow cytometry. Controls included patients receiving 500mg i.v. methylprenisolone (MP) pulses for rejection, adults with acute respiratory distress syndrome who received extracorporeal membrane oxygenation (ECMO) in the ICU and normal individuals. Data were analyzed using the student's t-test and correlated by regression analysis. Results: An increase in the levels of C4d, Bb, iC3b, and SC5b-9 was observed in 7/8 OKT3-treated patients. No significant differences in C activation were found between lung and Table kidney Tx recipients. Total WBC and neutrophil counts at 60 minutes were 65% and 70% of their pre-OKT3 values. A marked increase in the expression of CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with C activation was observed. In lung Tx recipients C4d and iC3b production correlated with increases in central venous pressure (p = 0.023, p = 0.003) and iC3b production correlated with increases in mean pulmonary arterial pressure (p = 0.024). As compared to ECMO (silicone membrane), OKT3 induced activation of C occurred predominantly by the classical pathway, whereas ECMO activated C by the alternative pathway and MP pulses did not activate C.TableConclusions: C activation is an early event after OKT3 administration and is associated with activation of neutrophils and pulmonary hemodynamic changes. In addition to cytokine production, C activation should be studied to delineate potential side-effects of new monoclonal antibodies used in organ transplantation.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)