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Enhanced lymphocyte proliferation in patients with adrenoleukodystrophy treated with erucic acid (22:1)-rich triglycerides

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JOURNAL OF INHERITED METABOLIC DISEASE 2000年第2期23卷 113-119页

作者： Barmaki Pour, R Stöckler-Ipsiroglu, S Hunneman, DH Gahr, M Korenke, GC Pabst, W Hanefeld, F Peters, A Univ Gottingen Childrens Hosp Dept Neuropediat D-3400 Gottingen Germany Univ Vienna Dept Pediat A-1010 Vienna Austria Univ Hosp Giessen Dept Med Informat Giessen Germany Univ Dresden Dept Pediat Dresden Germany Univ Freiburg Dept Pediat D-7800 Freiburg Germany

Lymphocytopenia and depression of natural killer cells have been observed in patients with adrenoleukodystrophy (ALD) treated with glycerol trioleate and glycerol trierucate ('Lorenzo's oil'). To investigate possible alterations of cellular immunoreactivity, we measured lymphocyte proliferation in response to mitogens (PHA, Con A, PWM, OKT3) in 27 patients on treatment and in 14 patients without treatment. In patients on treatment, lymphocyte proliferation in response to the mitogens PHA and Con A was significantly higher than in patients without treatment. Lymphocyte proliferation in patients without treatment was comparable to that of normal control lymphocytes. Additionally, we found increased concentrations of erucic acid, C-22:1, in lymphocytes from patients with treatment. The enhanced proliferation of lymphocytes in response to mitogens is an indication of increased reactivity of cellular immunity to unspecific immunological stimuli. Long-term side-effects on cellular immunoreactivity have to be considered in ALD patients treated with Lorenzo's oil.

关键词：肾上腺脑白质营养不良/血液肾上腺脑白质营养不良/药物疗法细胞分裂/药物作用膳食膳食脂肪类不饱和/治疗应用复方合剂芥酸类/代谢芥酸类/治疗应用淋巴细胞计数/药物作用淋巴细胞/药物作用淋巴细胞/代谢有丝分裂原/药理学三油酸脂/治疗应用青少年成年人儿童女(雌)性人类男(雄)性中年人

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In vivo rapid reduction of alloantigen-activated CD8⁺ mature cytotoxic T cells by inhibitors of acidification of intracellular organelles, prodigiosin 25-C and concanamycin B

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IMMUNOLOGY 2000年第2期99卷 243-248页

作者： Lee, MH Kataoka, T Honjo, N Magae, J Nagai, K Tokyo Inst Technol Dept Bioengn Midori Ku Yokohama Kanagawa 2268501 Japan Inst Res & Innovat Kashiwa Chiba Japan

Prodigiosin (PrG) 25-C and concanamycin B (CMB) are immunosuppressants that specifically inhibit the induction of cytotoxic T cells (CTL) without affecting the function of B cells and helper T cells in vivo. Both compounds inhibit acidification of intracellular organelles and induce destruction of cytotoxic granules and degradation of perforin in vitro. Here we show that a single intraperitoneal (i.p.) injection of PrG 25-C, and of CMB, into mice eliminates cytotoxic activity 7 days after alloantigen stimulation (when mature CTL activity has been detected in control mice), with minimal effect on the alloantigen-specific antibody titre in serum. FK506 did not suppress the cytotoxic activity with this administration schedule. Suppression was accompanied by a decrease in the CD8(+) population and in perforin expression of spleen cells induced by alloantigen stimulation. The suppression of CTL activity and decrease in CD8(+) cell number was detected as early as 7 hr after the injection of compounds. These results suggest that inhibitors of acidification of intracellular organelles suppress CTL activity in vivo by reducing the number of mature CD8(+) CTL.

关键词：抗菌药/药理学 CD8阳性T淋巴细胞/药物作用细胞毒性免疫/药物作用氢离子浓度/药物作用免疫耐受/药物作用免疫抑制剂/药理学同种抗原/免疫学淋巴细胞计数/药物作用大环内酯类小鼠近交C57BL 细胞器/药物作用细胞器/代谢灵菌红素/类似物和衍生物灵菌红素/药理学动物女(雌)性小鼠

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Thymic function, aging, and AIDS

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HOSPITAL PRACTICE 1999年第3期34卷 59-+页

作者： Haynes, BF Hale, LP Duke Univ Med Ctr Dept Med Durham NC 27710 USA Duke Univ Med Ctr Dept Pathol Durham NC 27710 USA

For the first time, physicians are challenged by clinical states in which the T-cell pool is destroyed postnatally in large numbers of patients. One such state is AIDS;another is the immune damage of cancer chemotherapy. Accordingly, study of postnatal thymic function is now a matter of clinical urgency, Ongoing work may point toward new strategies for repairing a damaged T-cell repertoire.

关键词：获得性免疫缺陷综合征/免疫学获得性免疫缺陷综合征/病理学年龄因素抗HIV药/投药和剂量抗肿瘤药/投药和剂量淋巴细胞活化/药物作用淋巴细胞活化/免疫学淋巴细胞计数/药物作用淋巴细胞减少/化学诱导淋巴细胞减少/免疫学淋巴细胞减少/病理学 T淋巴细胞/药物作用 T淋巴细胞/免疫学 T淋巴细胞/病理学胸腺切除术胸腺/药物作用胸腺/免疫学胸腺/病理学青少年成年人老年人儿童儿童学龄前女(雌)性人类婴儿婴儿新生中年人妊娠

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Clinical and immunologic response without decrease in virus load in patients with AIDS after 24 months of highly active antiretroviral therapy

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CLINICAL INFECTIOUS DISEASES 1999年第6期29卷 1423-1430页

作者： Mezzaroma, I Carlesimo, M Pinter, E Muratori, DS Di Sora, F Chiarotti, F Cunsolo, MG Sacco, G Aiuti, F Univ Roma La Sapienza Dept Allergy & Clin Immunol I-00185 Rome Italy Natl Inst Hlth Lab Organ & Syst Pathophysiol Rome Italy

This study reports an analysis of clinical, virological, and immunologic outcomes in a cohort of 77 multidrug-experienced AIDS patients during 24 months of highly active antiretroviral therapy (HAART). Our results have shown a reduced risk of AIDS complications, prolonged survival, and immunologic benefit even in the absence of sustained virus suppression. The degree of immunodepression, the risk factors for HIV-1 infection, the use of 2 drugs instead of 3, and a change in protease inhibitor were independently correlated with virological failure. In the majority of studied patients, an increase in CD4(+) T cells was observed after HAART However, the increase was more pronounced in patients who showed a decrease in virus load than in those who did not. Moreover, we observed an absence of relapses among patients who permanently discontinued prophylaxis for Cytomegalovirus retinitis and atypical mycobacterial infections. Peripheral lipodystrophy developed in the majority of patients, regardless of treatment used and virological outcome.

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Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus

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INTERNATIONAL JOURNAL OF DERMATOLOGY 2000年第5期39卷 383-388页

作者： Walchner, M Meurer, M Plewig, G Messer, G Univ Munich Dept Dermatol & Allergol D-80337 Munich Germany Tech Univ Dresden Dept Dermatol D-8027 Dresden Germany

Background Thalidomide is used as an experimental drug for the treatment of chronic inflammatory diseases with an autoimmune or infectious background. The pharmacologic action involves the downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis;however, not much is known about thalidomide's effect on immunologic parameters in lupus erythematosus (LE). Method This is an open study of a group of five consecutive systemic lupus erythematosus (SLE) patients treated with thalidomide (100 mg/day) and five consecutive cutaneous LE patients not responsive to conventional therapy. The clinical and immunologic parameters (C-reactive protein, immunoglobulin, and complement serum levels, lymphocyte counts) were investigated during thalidomide treatment for up to 2 years in both patient groups. Results An increase in the absolute peripheral lymphocyte count was observed beginning after 2 weeks of systemic thalidomide treatment in nine out of 10 LE patients, and remained stable throughout thalidomide treatment. Elevated serum levels of C-reactive protein and titers of autoantibodies to double-stranded (ds) DNA decreased in SLE patients. No significant changes were detected in the serum levels of the complement components C3 and C4 and immunoglobulins in all LE patients. Regression of inflammatory skin lesions and regrowth of hair were recorded. As a side-effect, polyneuropathy was observed in four out of 10 patients, with the earliest onset at 3 weeks of thalidomide treatment. Conclusions Thalidomide is a potent anti-inflammatory drug in patients with SLE and cutaneous LE, possibly interacting with the recruitment of lymphocytes. It leads to the regrowth of hair in LE-related alopecia and effluvium. Early symptoms of polyneuropathy should be registered and the drug should be withdrawn. Thalidomide should be restricted to patients who show no response to standard therapeuti

关键词：抗体抗核/药物作用 C反应蛋白质/药物作用补体系统蛋白质类/药物作用酶联免疫吸附测定免疫球蛋白类/药物作用免疫抑制剂/药理学免疫抑制剂/治疗应用红斑狼疮皮肤/药物疗法红斑狼疮皮肤/免疫学红斑狼疮系统性/药物疗法红斑狼疮系统性/免疫学淋巴细胞计数/药物作用沙立度胺/药理学沙立度胺/治疗应用成年人女(雌)性人类男(雄)性中年人

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Pharmacodynamics of immunosuppression by mycophenolic acid: Inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期291卷 1100-1112页

作者： Gummert, JF Barten, MJ Sherwood, SW Van Gelder, T Morris, RE Stanford Univ Sch Med Dept Cardiothorac Surg Stanford CA 94305 USA

Mechanisms of immunosuppressive action of mycophenolic acid (MPA) on rat lymphocytes and correlations among MPA plasma concentrations (pharmacokinetics) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lymphocyte proliferation in blood [tritium-labeled thymidine ([H-3]TdR) incorporation, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G(2)M by flow cytometry] and activation (percentage of lymphocytes expressing CD25 or CD134). Maximum percent inhibitions (I-max) of lymphocyte functions and concentrations of MPA (mg/l in blood) inhibiting 50% of I-max (IC50) were 99%/0.14 mg/l for [H-3]TdR, 93%/0.28 mg/l for S-G(2)M, 74%/0.29 mg/l for CD25, and 83%/0.24 mg/l for CD134. Blood sampled at different times after single or multiple oral MPA administrations at four dose levels was assayed for lymphocyte functions and MPA plasma concentrations. I-max (%) and IC50 (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [H-3]TdR, 88 to 98%/0.70 to 0.83 mg/l for S-G(2)M, 60 to 63%/0.65 to 0.81 mg/l for CD25, and 72 to 77%/0.61 to 0.74 mg/l for CD134. IC50 values for S-G(2)M, CD25, and CD134 were higher after multiple daily treatments than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of lymphocyte functions. MPA treatment in vitro and in vivo inhibits not only mitogen-stimulated lymphocyte proliferation in whole blood but also lymphocyte expression of cell surface cytokine receptors. These two different mechanisms of action may contribute to the therapeutic efficacy of MPA in vivo.

关键词：抗生素类抗肿瘤/血液抗生素类抗肿瘤/药代动力学抗生素类抗肿瘤/药理学抗原 CD27/生物合成抗原 CD27/免疫学细胞分裂/药物作用 DNA/生物合成流式细胞术血细胞比容免疫抑制剂/血液免疫抑制剂/药代动力学免疫抑制剂/药理学白细胞计数淋巴细胞活化/药物作用淋巴细胞计数/药物作用淋巴细胞/药物作用淋巴细胞/免疫学霉酚酸/血液霉酚酸/药代动力学霉酚酸/药理学大鼠近交Lew 受体免疫/生物合成受体免疫/免疫学受体白细胞介素2/生物合成受体白细胞介素2/免疫学受体 OX40 受体肿瘤坏死因子动物男(雄)性大鼠

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Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期293卷 33-41页

作者： Sharma, A Davis, CB Tobia, LAP Kwok, DC Tucci, MG Gore, ER Herzyk, DJ Hart, TK SmithKline Beecham Pharmaceut Dept Drug Metab & Pharmacokinet King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Safety Assessment King Of Prussia PA 19406 USA

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments, The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R-max ) of PD effects was increased, and the time to reach R-max shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

关键词：抗体单克隆/诊断应用抗体单克隆/药代动力学抗体单克隆/药理学抗原 CD4/遗传学抗原 CD4/代谢 CD4阳性T淋巴细胞/药物作用剂量效应关系药物流式细胞术淋巴细胞计数/药物作用小鼠转基因模型生物学动物人类男(雄)性小鼠

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Low-dose methotrexate for the treatment of patients with large granular lymphocyte leukemia associated with rheumatoid arthritis

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AMERICAN JOURNAL OF MEDICINE 2000年第9期108卷 730-732页

作者： Hamidou, MA Sadr, FB Lamy, T Raffi, F Grolleau, JY Barrier, JH CHU Nantes Dept Internal Med F-44093 Nantes France CHU Rennes Dept Hematol Rennes France

Large granular T lymphocytes are a morphologically distinct subset of normal peripheral blood mononuclear cells. They can be classified into two major lineages based on the presence of the CD3 receptor: CD3+ lymphocytes and CD3- natural killer cells (1–3). The Revised European-American Lymphoma Classification considers clonal proliferation of these cells, or large granular lymphocyte leukemia, as a distinct type of peripheral T-cell neoplasm (4). The great majority of these leukemias have a CD3+, α-γ+, CD4-, CD8+, CD16+, CD57+, CD56- phenotype and an indolent course. In contrast, the CD3-/CD56+ (natural killer) subtype is an aggressive disease with a poor clinical outcome.

关键词：抗代谢药抗肿瘤/投药和剂量抗代谢药抗肿瘤/治疗应用抗风湿药/投药和剂量抗风湿药/治疗应用关节炎类风湿/并发症关节炎类风湿/药物疗法白血病髓样/并发症白血病髓样/药物疗法白细胞计数/药物作用淋巴细胞计数/药物作用甲氨蝶呤/投药和剂量甲氨蝶呤/治疗应用中性白细胞/药物作用回顾性研究治疗结果老年人女(雌)性人类中年人

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