Transient disappearance of immunologic disorders and remission after intercurrent measles infections in children with chronic idiopathic thrombocytopenic purpura

In two children with chronic idiopathic thrombocytopenic purpura (ITP) a transient remission of thrombocytopenia was observed after intercurrent measles infection. Both cases were girls who had a long history of thrombocytopenia. During acute measles infection, the delayed hypersensitivity response was suppressed. Total T lymphocytes, T-cell subsets, especially OKT4 cells, the lymphoproliferative response, and interleukin-2 (IL-2) and -interferon production were decreased accompanying normalization of the OKT4/OKT8 ratio. However, OKT4 cells remained at a reasonably low level and the lymphoproliferative response stimulated with pokeweed mitogen was still in the lower normal range. Direct immunofluorescent study demonstrated that the measles antigen was present in the mononuclear cells, especially OKT4 cells. The levels of platelet-associated IgG antibody (PAIgG) and IgG circulating immune complex (CIC) were undetectable. One month later, the OKT4/OKT8 ratio lymphoproliferative response significantly increased, IL-2 and -interferon production increased, and PAIgG and IgG CIC reappeared with the relapse of thrombocytopenia. There was also a significant increase inin vitro IgG production due to the presence of patient OKT8 cells and/or OKT4 cells. However, there was no enhancement in the presence of patient B cells. This suggests that the presence of specific OKT4 helper T cells and a defect in the suppressor function of suppressor OKT8 cells contribute to an overproduction of IgG and the appearance of PAIgG accompanied by thrombocytopenia. The transient remission associated with measles infection is probably related to the effect of the virus on the helper T cells, resulting in a decrease in specific OKT4 helper T cells and normalization of the OKT4/OKT8 ratio, suppression of IL-2 and -interferon production, and platelet-associated IgG production.     

抗人CD3单链抗体基因的构建及序列分析

本文在已克隆抗人ＣＤ３抗体ＶＨ和ＶＫ基因的基础上，设计并合成了ＰＣＲ引物。两个外侧引物分别含有ＥｃｏＲＩ和ＳａｌＩ酶切位点及起始码和终止码序列，４个内侧引物各含部分连肽基因序列，回收后混合退火。     

Levels of HBV-DNA and HBsAg after acute liver allograft rejection treatment by corticoids and OKT3

The aim of this work was to analyze whether the treatment of acute rejection of orthotopic liver transplants (OLT), either with corticoids or OKT3, has any effect on the levels of hepatitis B virus (HBV)-DNA and HBsAg in individuals which were originally affected by cirrhosis or fulminant hepatic failure as a result of B virus. We have found that HBV-DNA is present in macrophages, B cells and both CD4+ and CD8+ T cells after OLT in all cases studied. Interestingly, the levels of HBV-DNA and HBsAg in the serum analyzed were increased extremely rapidly in the patients treated with OKT3 in an acute rejection episode. However, the serum levels of HBV-DNA and HBsAg found were lower when the patients were treated with steroids, and were not found in non-treated patients. As the serum levels of HBV-DNA increase, the process of liver reinfection could be accelerated; therefore, these results may help to understand how OKT3 and corticoids immunosuppressive therapy may accelerate the reinfection of OLT by HBV. In conclusion, our results suggest that special care must be taken in the use of OKT3 in the treatment of acute liver rejection episodes in chronic or fulminant HBV transplanted patients.     

肾移植术后应用单克隆抗体OKT3的护理观察

目的总结使用OKT3出现并发症的处理方法,探讨有效的预防措施.方法回顾性分析2004年9月～2005年2月8例使用OKT3患者的临床资料,总结出现的并发症.结果本组8例患者均有效控制因OKT3使用出现的并发症.结论选择相应的处理方法和预防措施,可有效减少OKT3使用后的并发症.     

Muronomab-CD3 for Pediatric Acute Myocarditis

The treatment of pediatric acute myocarditis that is hemodynamically significant often includes immune modulation with intravenous immunoglobulin (IVIG) and steroids, and supportive measures. In this population, published outcomes include recovery of ventricular function from 6 months to years, transplantation, or death. We studied the effect of the immunosuppressive agent muronomab-CD3 (OKT3) on recovery of heart failure in the treatment of pediatric myocarditis. A retrospective chart review was performed identifying 15 pediatric patients diagnosed with acute myocarditis and depressed left ventricular ejection fraction (LVEF) or arrhythmias to which OKT3 was added to the immunosuppressive regimen. All patients were treated with supportive care, intravenous immunoglobulin, and steroids. LVEF by echocardiogram was plotted for each patient versus time. Outcomes included recovery of left ventricular function (as defined by an LVEF ≥ 45%), death, or listing for transplant. The diagnosis of acute myocarditis was made by a positive endomyocardial biopsy in 8 patients. Nine patients required extracorporeal membrane oxygenation (ECMO) or LV assist device. After treatment with OKT3, 9 patients made a significant recovery of LVEF within 17 days, and 1 recovered by 60 days. Six of the patients requiring mechanical assistance recovered within this time period. There were 4 deaths––3 due to ECMO complications and 1 due to underlying gastrointestinal illness. One patient diagnosed with chronic myocarditis on biopsy underwent transplantation. No significant side effects attributable to OKT3 occurred. By decreasing the autoimmune inflammatory response, OKT3 may hasten recovery of ventricular function and be a useful adjunct therapy for hemodynamically significant acute pediatric myocarditis.     

High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation

OBJECTIVE: To determine the prevalence and identify variables associated with renal dysfunction in long-term survivors of pediatric liver transplantation. STUDY DESIGN: Data from 117 patients who survived>or=3 years after liver transplantation were analyzed. Demographic and clinical information was obtained from chart review and from a clinical care database. The dependent variable was renal function as determined by measured glomerular filtration rate (mGFR). Univariate and multivariate analyses were performed to identify independent variables associated with renal dysfunction (mGFR<70 mL/min per 1.73 m2). RESULTS: The average time since liver transplant was 7.6+/-3.4 years (range, 3 to 14.6 years). When the last available mGFR for all patients was analyzed, renal dysfunction was present in 32%. In the univariate analysis, mGFR at 1 year after transplant, cyclosporine immunosuppression, and time since transplant were significant; the second two were strongly collinear. Using multiple logistic regression modeling excluding time since transplant, cyclosporine and mGFR at 1 year after transplant were strongly associated with renal dysfunction. CONCLUSIONS: Renal dysfunction is a common complication in children who survive liver transplantation. Our observations are of critical importance because children may live long enough to move from a stage of renal insufficiency characterized by asymptomatic decreased GFR to symptomatic end-stage renal disease.     

A randomized prospective trial of OKT3 induction in the current immunosuppression era

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.     

Living related liver transplantation across ABO blood groups with FK506 and OKT3

In living related liver transplantation (LRLT), the use of graft livers across ABO blood groups is unavoidable since the organ donor is usually one of the recipient's parents. This report presents our initial experiences with LRLT, focusing on ABO-incompatible cases. From June 1990 to May 1992, we successfully performed a series of 34 LRLT on children (15 males and 19 females) ranging in age from 7 months to 15 years. Overall recipient survival rates were 90% (25/28) in elective LRLT and 50% (3/6) in emergency LRLT. These cases were classified into three groups: ABO blood group-identical (n=21), compatible (n=10), and incompatible (n=3). The immunosuppressive regimen consisted of FK506 and low-dose steroids in the first two groups. In the incompatible cases, exchange transfusion was performed to decrease anti-A and/or-B antibody titers before LRLT, and prophylactic OKT3 was added to FK506 and steroids after LRLT. No significant difference in recipient and graft survifal was observed among the groups. In the identical group, no rejection episodes have been observed thus far. Rejection occurred in two out of the ten compatible cases. Among the incompatible cases, one recipient had mild rejection and was treated. The remaining two recipients have had no rejection episodes thus far. Although all three recipients had cytomegalovitus (CMV) infection, they were successfully treated with gancyclovir, and no lethal infection has developed in any of these cases. The present results suggest that graft livers from living related donors across ABO blood groups can function well with FK506, low-dose steroids, and prophylactic OKT3 without causing lethal complications.     

Broad reactivity and enhanced potency of recombinant anti-EGFR × anti-CD3 bispecific antibody-armed activated T cells against solid tumours

Introduction: Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation. Clinical trials in breast, prostate, and pancreatic cancer using BATs armed with chemically heteroconjugated BiAbs demonstrated safety, feasibility, induction of anti-tumour immune responses and potential increases in overall survival (OS).Objectives: The primary objective of this study was to develop a recombinant BiAb that confers enhanced anti-tumour activity of BATs against a broad range of solid tumours.Methods: A recombinant anti-epidermal growth factor receptor (EGFR) x anti-CD3 (OKT3) BiAb (rEGFRBi) was designed and expressed in CHO cells, used to arm ATC (rEGFR-BATs), and tested for specific cytotoxicity against breast, pancreatic and prostate cancers and glioblastoma.Results: rEGFR-BATs exhibit remarkably enhanced specific cytotoxicity and T1 cytokine secretion against a wide range of solid tumour cell lines vs. their respective chemically-heteroconjugated BATs.Conclusion: rEGFR-BATs may provide a “universal” T cell therapy for treating a wide range of solid tumours.

KEY MESSAGE

• A (Gly4Ser)6 linker between the variable light and heavy chains of an scFv fused to the N-terminus of a heavy chain antibody confers unexpected stability to the heavy chain fusion protein and supports the efficient expression of the bispecific antibody.
• Arming of activated T cells with the rEGFRBi greatly enhances the relative cytotoxicity and Th1 cytokine secretion of theT cells relative to a chemically heteroconjugated BiAbs.
• rEGFR-BATs are promising candidates for the treatment of a broad range of solid tumours.

     

巴利昔单抗联合鼠抗人CD3单克隆抗体在高致敏受者肾移植中的临床应用

目的:探讨巴利昔单抗与鼠抗人CD3单克隆抗体(OKT3)联合诱导在高致敏受者肾移植临床应用中的有效性及安全性。方法:术前2个月内群体反应性抗体(PRA)检测值均>50%的尸体供肾肾移植受者20例,其中9例受者接受巴利昔单抗联合OKT3免疫诱导(联合诱导组),11例受者接受OKT3常规免疫诱导(OKT3诱导组),均以他克莫司(Tac)+吗替麦考酚酯(MMF)+泼尼松(Pred)为基础免疫抑制方案,评估术后移植肾功能恢复情况、3个月内急性排斥反应发生率、1年内肺部感染发生率、1年人/肾存活率及移植肾功能。结果:联合诱导组、OKT3诱导组肾移植术后3个月内急性排斥反应发生率及术后1年内肺部感染发生率分别为11.1%vs.36.4%(P=0.319),11.1%vs.63.6%(P=0.028);联合诱导组患者术后1周内移植肾功能恢复正常比例明显高于OKT3诱导组(88.9%vs.27.3%,P=0.010);联合诱导组术后1年人/肾存活率均为100%,与OKT3诱导组(分别为90.9%、81.8%)比较,差异不显著(P=1.00和P=0.100);术后1年联合诱导组、OKT3诱导组血肌酐值分别为(105±24)、(97±22)μmol·L-1(P=0.437)。结论:巴利昔单抗联合OKT3进行免疫诱导,在预防高致敏受者术后早期排斥反应的同时,缩短了移植肾功能的恢复时间,是一种安全、有效的防治策略。