Muromonab-CD3 therapy for refractory rejections after liver transplantation: a single-center experience during two decades in Japan

Background/purpose

Refractory rejections still occur in the liver transplantation (LT) field. The aim of this study was to investigate significant factors for the introduction of therapy with muromonab-CD3 (MCD3) after LT.

Methods

A total of 1415 LT patients were retrospectively evaluated, and 11 of the recipients received MCD3 therapy because of steroid-resistant rejections. The clinical factors before LT and before MCD3 therapy were investigated.

Results

The recipients were retrospectively divided into two groups based on responses to MCD3 therapy, including their clinical courses after MCD3 therapy and their outcomes. The MCD3 therapy had positive effects in LT recipients with the following four factors: low score of model for end-stage liver disease or pediatric end-stage liver disease; earlier time point of the first incidence of rejection; more frequent steroid pulse therapy (SPT) within 2 weeks after LT; and the expression of CD3 in the peripheral blood before MCD3 introduction.

Conclusion

Optimal induction of MCD3 triggered recovery from refractory rejections, especially in LT recipients in a stable condition, but not in those in a critical or compromised condition.     

Suspected distinct activation pathways of human lymphocytes induced by antilymphocyte globulin and anti-CD3 monoclonal antibody result in different secretion of hematopoietic colony-stimulating activities.

We evaluated the activation sequence of peripheral blood lymphocytes from healthy donors using different mitogens, including antilymphocyte globulin (ALG), anti-CD3 monoclonal antibody (OKT3), and phytohemagglutinin (PHA). Blood mononuclear cells stimulated by ALG, OKT3 and PHA incorporated 3H-thymidine in the same way. When enriched T cells were tested in the presence of interleukin-1 alpha (0 to 100 U/ml, incorporation of 3H-thymidine was greater in those cells stimulated by ALG than by PHA. OKT3 did not activate enriched T cells. Thymidine incorporation was reduced to less than 50% of maximum concentrations by the addition of 10(-7) mol/1,25-dihydroxyvitamin D3 (vit D3) in PHA- or OKT3-activated cells. However, the inhibitory effect of vit D3 was not apparent in ALG-activated cells. Production of granulocyte-macrophage colony-stimulating factor and interleukin-3 by lymphocytes upon activation was consistently higher when cells were treated with ALG or PHA than with OKT3. Taken together, the data indicate that there appear to be distinct functional mechanisms between ALG- and OKT3-induced lymphocyte activation that lead to characteristic immunohematologic events.     

Interleukin 2 activity in peripheral blood mononuclear cells of patients with gynecologic malignancies

We studied production of, absorption of and response to interleukin 2 (IL-2) by peripheral blood mononuclear cells (PBMC) from 66 patients with gynecologic malignancies, in addition to measurement of the OKT 4/OKT 8 cell ratio. Patients with benign tumor served as controls. The OKT 4/OKT 8 cell ratio in patients with advanced (but not early) gynecologic malignancies was significantly lower than that in patients with benign tumor. PBMC from advanced cancer patients activated with phytohemagglutinin (PHA) had significantly lower IL-2 production compared to that from patients with benign tumors, while significant changes in their ability to respond to IL-2 and to absorb IL-2 were not observed. Absolute numbers of OKT 8 positive cells in PBMC of patients with good prognosis were significantly decreased after surgery and chemotherapy, while those of OKT 4 positive cells remained unchanged. Although IL-2 production in PBMC of patients with good prognosis was significantly elevated after chemotherapy, that in PBMC of patients with poor prognosis declined to about a half of pre-operative levels. The ability of PBMC to respond to IL-2 was significantly elevated not only in patients with good prognosis but also in patients with poor prognosis after termination of chemotherapy. On the other hand, the ability of PBMC to absorb IL-2 remained unchanged during the course of treatment. These findings may contribute to the understanding of tumor-induced immune suppression.     

舌鳞癌患者手术前后免疫状态的检测

本文应用免疫扩散法及 C_3单扩散板测定舌鳞癌患者手术前后血清 Ig 及 C_3含量,与正常对照组比较及手术前后相比差异均不显著(P>0.05),提示舌鳞癌患者的体液免疫功能影响不明显。而应用 OKT 系列单克隆抗体以间接免疫荧光法对舌鳞癌患者手术前后的外周血 T 细胞亚群进行检测,结果表明,OKT_4/OKT_(?)细胞比值由1.28±0.19升至1.42±0.03(P<0.01)可较为客观地反映患者体内的细胞免疫功能状态,可作为判断舌鳞癌患者免疫状态的指标。     

Connection of atopic disease in Japanese patients with juvenile dermatomyositis based on serum IgE levels

Summary Serum IgE levels of 22 patients with juvenile dermatomyositis (JDMS), 44 normal children, and 43 patients with adult dermatomyositis were compared. The geometric mean of serum IgE levels was significantly higher in the juvenile patients when compared with normal children (p<0.01) and adult patients (p<0.01). Of the 22 patients with JDMS, 11 (50%) had elevated serum IgE levels accompanied by atopic disease. Dermatomyositis was accompanied by atopic dermatitis (AD) in 9 (41%) of these 22 patients, a high prevalence when compared with reports among the general population. Following the appearance of muscular symptoms in JDMS patients with AD, the ratio of OKT4 to OKT8 cells rose due to a reduction in the percentage of OKT8-positive cells, along with further elevations in serum IgE levels and intractable cutaneous manifestations of dermatomyositis. All this may be a result of an interaction between the immuno-mechanism of this disease and that of AD. We suspect that, in general, children with impaired cell-mediated immunity, presenting with such symptoms as AD, may have a higher tendency for developing JDMS.     

Transplantation of Cultured Islets from Two-Layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4+ T-cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.     

The use of OKT3 in steroid-resistant rejections following cadaveric kidney transplantation

OKT3 has been proved to be effective in the treatment of steroid-resistant rejection after renal allograft transplantation [1]. We investigated the clinical course of OKT3 recipients to find out in which cases of steroid resistance OKT3 therapy might be ineffective.     

Evaluation of OKT3 monoclonal antibody and anti-thymocyte globulin in the treatment of steroid-resistant acute allograft rejection in pediatric renal transplants

We reviewed the effectiveness of Muromonab-CD₃ (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P=NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P<0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P=NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P=NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.     

人的活化T细胞出现的T_4~+T_6~+双标记现象

OKT系列单克隆抗体的产生,促进了人T细胞亚类的划分。最初的报道认为,人的外周血T细胞可分为OKT_4~+(T_4~+)和OKT_8~+(T_8~+)细胞两个亚类,分别占T细胞总数的55～65%和30～40%。最近有报道指出,人的末梢血中存在少量的T_4~+T_8~+双标记细胞,在体外活化的T细胞,可以暂时     

47例急性白血病患者T细胞及其亚群免疫应答能力测析

本文报道了对47例急性白血病患者(急淋18例、急粒29例)外周血T细胞对PHA刺激反应及OKT单克隆抗体玫瑰花试验T细胞亚群的检测。其结果为急淋、急粒患者的细胞免疫功能均低于健康人,其中急淋患者的T细胞对PHA刺激反应(用SI表示)及T细胞亚群降低的程度均大于急粒患者。急性白血病缓解期患者诸项检测均与健康成人接近,而未经治疗者,治疗中期及预后极差:临床表现上则有出不同程度的免疫抑制。