CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.

Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.

Adverse Childhood Experiences and Trauma-Informed Care: An Online Module for Pediatricians.

Introduction: The epidemic of adverse childhood experiences (ACEs) has many known health consequences. Robust research has linked ACEs to increased morbidity and mortality. Because of their frequent interaction with children and their families, pediatricians should be educated to recognize ACEs and practice trauma-informed care (TIC). There is a lack of education for pediatric residents on ACEs despite their significance. Our goals were to identify residents' baseline perceived importance, confidence, and frequency of discussion of ACEs, TIC, toxic stress, and resiliency and evaluate the efficacy of an educational module addressing these topics. Methods: A 25-minute self-directed module was created for pediatric residents. The module was accessible online and independently completed by residents during the child advocacy rotation. Pre- and postmodule surveys using a 5-point Likert scale (1 = low, 5 = high) were administered, and median scores of 11 participants who completed both surveys were compared using the Wilcoxon signed rank test. Results: Presurvey results demonstrated that residents were not confident discussing ACEs, TIC, or resiliency (median = 2). Residents reported that it was very important to discuss ACEs, toxic stress, and resiliency with families (median = 5), although they were rarely discussed in clinic (median = 1 or 2). Matched pre/post data showed significant increases in knowledge, confidence, and discussion frequency. Discussion: The results demonstrated a need for ACE education for pediatric residents. The matched survey results showed the module's success in knowledge and behavior change. The module can be adapted to other learners to enhance understanding of ACEs.

Pharmacokinetics, pharmacodynamics, and immunodynamics of daclizumab in a two-dose regimen in liver transplantation.

BACKGROUND: The humanized anti-interleukin 2 receptor (IL-2R) monoclonal antibody daclizumab (Zenapax) has been shown to be safe and effective for preventing acute allograft rejection in renal transplantation. The aim of this study was to evaluate pharmacokinetics and pharmacodynamics of daclizumab in a two-dose regimen (1.5 mg/kg total) after liver transplantation. METHODS: Twenty-eight patients were enrolled in this study. Patients were evaluated for outcome, postoperative blood and ascites loss, serum levels of daclizumab, and corresponding changes in peripheral blood. Patients were also checked for development of anti-daclizumab antibodies. RESULTS: CD25+ cells in patients' blood were significantly reduced for 28 days after daclizumab application. Elimination half-life of the antibody was 99 hr with a total body clearance of 57 ml/hr. Blood loss was not statistically significant and loss of ascites was weakly correlated to the monoclonal antibody clearance. One episode of mild acute rejection occurred. Although there was no significant decrease in absolute counts of CD3+, CD4+, and CD8+ lymphocytes, we were not able to show constant coating of IL-2Ralpha with daclizumab. IL-2Ralpha was not detectable on cell surface with two different antibodies and IL-2Rbeta was clearly reduced. Low titers of neutralizing anti-daclizumab antibodies in 3 of 13 patients were not of clinical significance and without influence on the pharmacokinetics. CONCLUSIONS: A two-dose regimen with daclizumab in liver transplantation leads to effective blockade of the IL-2Ralpha for at least 14 days after transplantation. Daclizumab seems to affect not only IL-2Ralpha but also IL-2Rbeta and may lead to an impairment of other cytokine pathways, such as the IL-15 pathway.

Long-term safety, tolerability and efficacy of daclizumab (Zenapax) in a two-dose regimen in liver transplant recipients.

A major thrust of transplantation research is to find more effective and less broadly toxic immunosuppressive agents. One potential way is the use of monoclonal antibodies directed to IL-2R alpha. Immunoprophylaxis with daclizumab, a humanized anti-IL-2R alpha monoclonal antibody, has been shown to be effective in the prevention of acute rejection in kidney transplant patients. These results encouraged us to initiate a pilot study in 28 liver transplant patients in 1997. Daclizumab was administered intravenously approximately 6 h after reperfusion (1 mg/kg) and on day 4 post-transplant (0.5 mg/kg). Additional immunosuppression consisted of cyclosporine A as well as of corticosteroids. Administration of daclizumab was not associated with any side-effects. We only experienced one acute rejection in a patient on day 17 post-transplant. It resolved immediately under therapy with prednisolone. The rate of opportunistic infections did not differ from results with conventional immunosuppressive regimens. At 4 years post-transplant no lymphoproliferative disease was observed. Patient survival at 12, 24, 36 and 48 months post-transplant was 88.5, 84.6, 80.8 and 73.1%, respectively. Immunoprophylaxis with a two-dose daclizumab regimen is safe, effective and well tolerated, and does not lead to increased opportunistic infections.

Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation.

Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2:1 to receive either daclizumab 1 mg/kg or placebo pre-transplantation and every other week, for a total of five doses. All patients received cyclosporine, steroids, and MMF. Levels of mycophenolic acid (MPA), its glucuronide metabolite, and daclizumab were measured after dosing on days 28 and 56. Safety parameters evaluated included: adverse events, laboratory abnormalities, infections, patient/graft survival, incidence of lymphoproliferative disorders, and incidence of acute rejection at 12 months. The concomitant administration of daclizumab and MMF had no effect on the pharmacokinetics of MPA: AUC(0-8) values (microg h/mL +/- SD) on day 28 were 30.1 +/- 13.3 for daclizumab-treat patients vs. 31.1 +/- 12.4 for placebo and on day 56, 37.7 +/- 18.2 for daclizumab-treated patients vs. 35.7 +/- 14.0 for placebo. Adverse events were similar between the two groups. Acute rejection at 12 months occurred in 14% of patients receiving daclizumab and 20% of patients receiving placebo. The coadministration of daclizumab did not result in a pharmacokinetic interaction with MPA, the active metabolite of MMF.