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Cyclosporin A prevents the histologic damage of antigen arthritis without inducing fibrosis

ARTHRITIS AND RHEUMATISM 2000年第2期43卷 311-319页

作者： Benito, MJ Sánchez-Pernaute, O López-Armada, MJ Hernández, P Palacios, I Egido, J Herrero-Beaumont, G Fdn Jimenez Diaz E-28040 Madrid Spain Univ Autonoma Madrid Madrid Spain

Objective. To study the effects of cyclosporin A (CSA) in a model of rheumatoid arthritis (RA) and the activation of growth factors related to pannus development at the site of injury. Methods. Antigen arthritis was induced in the knees of 14 New Zealand rabbits, and the animals were randomized into 2 therapeutic groups: CSA at 10 mg/kg/day and CSA solvent. After 3 weeks of treatment, the rabbits were killed, and synovial tissues were obtained and compared with healthy specimens with regard to histopathologic lesions, deposition of transforming growth factor beta (TGF beta) and collagens, and messenger RNA expression of platelet-derived growth factor B (PDGF-B) and TGF beta, The effect of CSA on the expression of TGF beta and PDGF-B was also examined in cultured synovial cells. Results. CSA administration alleviated the histologic damage and avoided the overdeposition of matrix elements in the injured tissue. It was also able to normalize the enhanced expression of TGF beta and PDGF-B observed in the untreated rabbits, Despite this modulation found in vivo, CSA up-regulated in a dose-dependent manner the gene expression of both trophic factors by healthy cultured synovial cells. Conclusion. The present study shows that continuous administration of CSA prevents the development of chronic synovitis in an experimental model of RA, As reported in other cell types, CSA promoted TGF beta transcription by synovial cells in vitro, but failed to display a profibrogenic effect in the inflamed environment.

关键词：关节炎实验性/病理学关节炎实验性/预防和控制细胞培养的胶原/代谢环孢菌素/血液环孢菌素/药理学环孢菌素/治疗应用疾病模型动物纤维化基因表达关节/病理学巨噬细胞血小板源性生长因子/遗传学 RNA 信使/代谢染色与标记滑膜/化学滑膜/细胞学滑膜/病理学转化生长因子β/生物合成转化生长因子β/遗传学转化生长因子β/代谢动物兔

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Further evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis (FHLH)

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PEDIATRIC RESEARCH 2000年第2期48卷 227-232页

作者： Graham, GE Graham, LM Bridge, PJ Maclaren, LD Wolff, JEA Coppes, MJ Egeler, RM Alberta Childrens Prov Gen Hosp Dept Med Genet Calgary AB T2T 5C7 Canada Alberta Childrens Prov Gen Hosp Dept Oncol Calgary AB T2T 5C7 Canada Alberta Childrens Prov Gen Hosp Dept Pediat Calgary AB T2T 5C7 Canada Univ Calgary Calgary AB T2T 5C7 Canada

Familial hemophagocytic lymphohistiocytosis (FKLH;MIM #267700) is an autosomal recessive disorder of immune regulation characterized by fever, hepatosplenomegaly, and cytopenia that is fatal without bone marrow transplantation. Recent studies have suggested the existence of FHLH loci at 9q21.3-22 and 10q21-22 in Asian and European/African/Australian families, respectively. We studied two unrelated Canadian families in which first cousins were affected with FHLH. In an effort to localize the causative gene, we completed a genome-wide screen for homozygosity by descent by using an automated system to genotype 400 highly polymorphic dinucleotide repeat markers covering the genome with an average resolution of 10 centiMorgans (cM). We identified a total of three candidate loci that met the combined criteria for homozygosity by descent in one family and shared maternal alleles in the other family. One of these, D9S1690, had a cytogenetic localization (9q22.33) proximal to a previously reported inversion of chromosome 9 in an FHLH patient. However, additional closely linked flanking markers within 1-2 cM of all three candidates did not conform to the criteria for linkage in either family. Similarly, we excluded the linked 9q21.3-q22 and 10q21-22 regions recently reported in Asian and European/African/Australian families, respectively. The two families were then analyzed independently to encompass the possibility that they were segregating separate genes. Six additional candidate loci were identified on the basis of homozygosity for the same allele in all affected members of one family, but further analysis of closely linked flanking markers did not demonstrate similar homozygosity. Our data provide further evidence of genetic heterogeneity in FHLH and suggest the existence of at least a third locus for this disease.

关键词：肾上腺皮质激素类/治疗应用骨髓/病理学骨髓移植染色体图染色体人 10对染色体人 14对染色体人 19对染色体人 9对环孢菌素/治疗应用遗传标记组织细胞增多症非郎格尔汉斯细胞/遗传学组织细胞增多症非郎格尔汉斯细胞/病理学组织细胞增多症非郎格尔汉斯细胞/治疗甲氨蝶呤/治疗应用新斯科舍系谱青少年儿童女(雌)性人类男(雄)性

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Inhibition of stimulated interleukin-2 production in whole blood: A practical measure of cyclosporine effect

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CLINICAL CHEMISTRY 1999年第9期45卷 1477-1484页

作者： Stein, CM Murray, JJ Wood, AJJ Vanderbilt Univ Div Clin Pharmacol Sch Med Dept Med Nashville TN 37232 USA Vanderbilt Univ Dept Pharmacol Sch Med Nashville TN 37232 USA

Background: Prediction of cyclosporine (CSA) efficacy and toxicity in individual patients is difficult. There is no practical, biologically relevant, pharmacodynamic measure of CSA effect. A major effect of CSA is to decrease interleukin-2 (IL-2) production;however, measurement of this effect in isolated lymphocytes as a marker of response to CSA has been problematic. Methods: CSA inhibition of phytohemagglutinin-P (PHA)-stimulated IL-2 production, measured by ELISA, was studied ex vivo in whole blood drawn before, and after subjects received 4 mg/kg oral CSA. Results: Four hours after CSA was administered, the mean (+/- SD) CSA concentration was 702 +/- 196 mu g/L and PHA-stimulated IL-2 production decreased by 68.7% +/- 17.2% (P < 0.0001;n = 17). Twenty-four hours after CSA was administered, concentrations were low (64 +/- 24 mu g/L), with no inhibition of IL-2 production. A rapid, concentration-dependent response occurred. Maximum CSA concentrations (944 +/- 187 mu g/L) and maximum inhibition of IL-2 production (86.9% +/- 13.7%) occurred 90 min after subjects received CSA. In vitro, 32.5-1200 mu g/L CSA also inhibited PHA-stimulated IL-2 production in whole blood in a dose-dependent fashion with a similar IC50 (similar to 300-400 mu g/L) ex vivo and in vitro. Conclusion: In the search for a pharmacodynamic marker to better guide immunosuppressive therapy, the relationship between this simple, biologically relevant measure of CSA effect and clinical outcome should be determined. (C) 1999 American Association for Clinical Chemistry.

关键词：环孢菌素/治疗应用药物监测/方法酶联免疫吸附测定免疫抑制剂/治疗应用白细胞介素2/拮抗剂和抑制剂白细胞介素2/生物合成白细胞介素2/血液植物血凝素类时间因素人类男(雄)性

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Microneurovascular allotransplantation of the canine tongue

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LARYNGOSCOPE 1999年第9期109卷 1461-1470页

作者： Haughey, BH Beggs, JC Bong, J Genden, EM Buckner, A Washington Univ Sch Med Dept Otolaryngol Head & Neck Surg Div Head & Neck Surg Oncol St Louis MO 63110 USA Univ S Florida Dept Otolaryngol Head & Neck Surg Tampa FL 33620 USA YonSai Univ Dept Otolaryngol Head & Neck Surg Seoul South Korea Mt Sinai Sch Med Dept Otolaryngol Head & Neck Surg New York NY USA Johns Hopkins Univ Sch Med Dept Otolaryngol Head & Neck Surg Baltimore MD 21205 USA

Introduction: Reconstruction of the tongue with existing methods of tissue transfer often leaves glossectomy patients with significant deficits in speech and swallowing. The critical role of the tongue is implied by its unique structure and function. This paper reports the development of an animal model of hemitongue allotransplantation and documents functional and anatomic outcomes of this procedure. Methods: Ten pairs of unmatched clogs underwent reciprocal exchange of the left hemitongue with microneurovascular replantation. The unoperated hemitongue acted as the control. Under cyclosporine immunosuppression, animals surviving long term underwent clinical observation, before electromyography, force transduction studies, and histological evaluation being euthanized. Results: Five animals survived between 6 and 13 months for long-term evaluation. The remaining group were euthanized because of or died of overwhelming infection or uncontrollable transplant rejection. The latter sometimes resulted from difficulty in the delivery of the cyclosporine. Clinical recovery of tongue function was observed, as well as resumption of motor unit potential activity on electromyography. Contractile force recovery of the transplanted tongue averaged 68% of control (range, 47%-97%), and histological study of the hypoglossal and lingual nerves demonstrated anatomic evidence of reinnervation. Preservation of muscle, mucosal, and stromal ultrastructure was seen with light microscopy of the transplanted tongue. Conclusions: Allotransplantation of the hemitongue and associated neurovascular apparatus is possible in a large mammalian model, with long-term survival of tissue being accompanied by partial recovery of contractile properties. Anatomical and clinical evidence also points to sensory recovery. These data support the future possibility of employing a similar technique in glossectomy patients.

关键词：环孢菌素/治疗应用肌电描记术移植物排斥移植物存活舌下神经/生理学舌下神经/外科学免疫抑制剂/治疗应用舌神经/生理学舌神经/外科学神经再生/生理学舌/病理生理学舌/移植移植同种动物狗女(雌)性男(雄)性

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Mycophenolate mofetil-based immunosuppressive therapy: Induction, maintenance, and conversion protocols in renal transplantation

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TRANSPLANTATION PROCEEDINGS 1999年第8A期31卷 27S-32S页

作者： Land, W Univ Munich Klinikum Grosshadern Div Transplant Surg D-81377 Munich Germany

This work supports the paradigm of patient category-oriented immunosuppressive regimens in using MMF. The MMF-based induction protocol in elderly recipients of renal llografts from elderly donors was free of the risk of drug-induced neprhotoxicity, hyperlipidemia, and hypertension and was safe and efficacious in a selected group of elderly patients. By avoiding all neprhotoxic drugs, this group of patients experienced excellent early graft function and a low incidence of delayed graft function. A preliminary report of this study has been published. Further long-term follow-up will define the success of this regimen. Only preliminary conclusions can be drawn from the conversion studies. However, for the majority of patients, conversion of long-term transplant recipients with stable graft functin to a calcineurin inhibitor-free, MMF-based monotherapy produced an immediate and stable improvement of renal function. All cases of biopsy-proven acute rejection episodes (11%) were reversed after the reinstitution of calcineurin inhibitor and pulse steroids as rescue therapy. At the time this article is being written (November 1999), all patients enjoy completely stable renal function without any signs of acute/chronic allograft rejection. An earlier report that includes some of these patients has already appeared. The practice of reducing the dosage of CsA in immunosuppressive regimens is controversial. However, the search for long-term, low-toxicity regimens has meant that experimentation with these pharmacologic maneurvers continues. Two studies have reported the successful removal of CsA and its replacement with azathioprine. Both studies reported an increase in the incidence of acute rejection after CsA withdrawal, but these events did not negatively affect long-term outcome. MMF has demonstrated immunosuppressive superiority over azathioprine, is not nephrotoxic or neurotoxic, and does not cause hyperlipidemia or hypertension. Furthermore, it has not been found to dist

关键词：环孢菌素/治疗应用移植物存活免疫抑制剂/治疗应用肾移植/免疫学肾移植/死亡率肾移植/生理学霉酚酸/类似物和衍生物霉酚酸/治疗应用存活率分析他罗利姆/治疗应用移植同种老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Intravenous cyclosporin in ulcerative colitis: A five-year experience

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AMERICAN JOURNAL OF GASTROENTEROLOGY 1999年第6期94卷 1587-1592页

作者： Cohen, RD Stein, R Hanauer, SB Univ Chicago Hosp & Clin Dept Med Gastroenterol Sect Chicago IL 60637 USA

OBJECTIVE: Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago's 5-yr CSA experience in these patients. METHODS: All steroid-refractory severe ulcerative colitis (UC) patients treated with TV CSA from 1991 to 1995 were identified by using the university's IBD database, with additional information from patient charts and physician files. RESULTS: A total of 42 patients with severe UC unresponsive to IV steroids were treated with TV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded;31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of "noncolectomy survival" of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery. CONCLUSIONS: CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for "elective" colectomy in others, especially if 6MP/ aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol. (Am J Gastroenterol 1999;94:1587-1592. (C) 1999 by Am. Cell. of Gastroenterology).

关键词： 6-巯嘌呤/治疗应用硫唑嘌呤/治疗应用结肠切除术结肠炎溃疡性/药物疗法结肠炎溃疡性/外科学环孢菌素/治疗应用抗药性药物疗法联合注射静脉内纵向研究再治疗甾类/治疗应用治疗结果青少年成年人老年人儿童女(雌)性人类男(雄)性中年人

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Monitoring of Epstein-Barr virus serology in children after liver transplant: Lack of clinical correlation

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TRANSPLANTATION PROCEEDINGS 2000年第4期32卷 706-707页

作者： Granot, E Doron, D Morag, R Hadassah Univ Hosp Dept Pediat IL-91120 Jerusalem Israel Hadassah Univ Hosp Dept Clin Virol IL-91120 Jerusalem Israel Hebrew Univ Jerusalem Hadassah Med Sch IL-91010 Jerusalem Israel

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Rapamycin on trial

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NEPHROLOGY DIALYSIS TRANSPLANTATION 1999年第9期14卷 2087-2089页

作者： Sacks, SH Guys Hosp Guys Kings Coll & St Thomas Hosp Med Sch London SE1 9RT England

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Neoral dose monitoring with cyclosporine 2-hour postdose levels in heart transplant patients receiving anti-thymocyte globulin induction

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TRANSPLANTATION PROCEEDINGS 2000年第2期32卷 446-448页

作者： Cantarovich, M Quantz, M Elstein, E Ergina, P Magnan, C de Varennes, B McGill Univ Royal Victoria Hosp Dept Med Ctr HlthDiv Transplantat Montreal PQ H3A 1A1 Canada

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Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial

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BLOOD 2000年第5期96卷 1690-1697页

作者： Locatelli, F Bruno, B Zecca, M Van-Lint, MT McCann, S Arcese, W Dallorso, S Di Bartolomeo, P Fagioli, F Locasciulli, A Lawler, M Bacigalupo, A Univ Pavia IRCCS Policlin San Matteo Dipartimento Sci Pediat I-27100 Pavia Italy Univ Roma La Sapienza Cattedra Ematol Rome Italy Osped San Martino Genova Div Ematol 2 Genoa Italy Ist Giannina Gaslini Dipartimento Ematol & Oncol Pediat I-16148 Genoa Italy Osped Civile Dipartimento Ematol Unita Terapia Intensiva Ematol Trapianto Emopoiet Pescara Italy Univ Turin Osped Regina Margherita Pediat Clin Turin Italy Univ Milan Osped Nuovo San Gerardo Pediat Clin Milan Italy St James Trinity Coll Dept Hematol Dublin Ireland

A randomized trial was carried out comparing cyclosporin A (CsA) and shortterm methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years;range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT, Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT, Patients randomized in both arms had comparable characteristics and received the same preparative regimen tie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P = .01), No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P = .07). With a median follow-up of 48 months from BMT, the B-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P = .05), These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings, (C) 2000 by The American Society of Hematology.

关键词：贫血再生障碍性/死亡率贫血再生障碍性/治疗骨髓移植环孢菌素/治疗应用药物疗法联合随访研究移植物排斥移植物抗宿主病/预防和控制组织相容性试验免疫抑制剂/治疗应用甲氨蝶呤/治疗应用核型家庭存活率分析时间因素移植同种治疗结果青少年成年人儿童儿童学龄前女(雌)性人类男(雄)性中年人

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