Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer

Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell–cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma

Toxic epidermal necrolysis and Stevens-Johnson syndrome

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease

7th Drug hypersensitivity meeting: part two

No abstract availabl

Comparison study of intraocular pressure reduction efficacy and safety between latanoprost and tafluprost in Japanese with normal-tension glaucoma

Yoko Ikeda,1,2,* Kazuhiko Mori,1,* Kaori Tada,3 Morio Ueno,1 Shigeru Kinoshita,4 Chie Sotozono1 1Department of Ophthalmology, Kyoto Prefectural University of Medicine, 2Oike-Ganka Ikeda Clinic, 3Department of Ophthalmology, Japanese Red Cross Society Kyoto Daini Hospital, 4Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan *These authors contributed equally to this work Purpose: To evaluate and compare the intraocular pressure (IOP) reduction efficacy and safety between the ophthalmic solutions 0.005% latanoprost (Lat) and 0.0015% tafluprost (Taf) in Japanese patients with normal-tension glaucoma (NTG).Methods: In this randomized nonmasked study, we prospectively enrolled 30 Japanese NTG patients who had used Lat monotherapy for more than 4 weeks, and randomly divided them into the following two groups: 1) Lat-to-Taf group (LT group) and 2) Taf-to-Lat group (TL group). At the beginning of the study, both groups were switched from initial Lat to Lat or Taf for 12 weeks, and then switched over to the other drug (crossover) for 12 additional weeks. At 0, 4, 12, 16, and 24 weeks, we evaluated each patient’s IOP, conjunctival injection, and corneal epitheliopathy score, and at 0, 12, and 24 weeks, we evaluated their eyelash changes and pigmentation of the eyelids and irises.Results: The mean IOP of the LT group (15 eyes) was 10.5, 10.6, and 11.1 mmHg, at 0, 12, and 24 weeks, respectively, whereas that of the TL group (15 eyes) was 11.7, 11.1, and 10.5 mmHg at 0, 12, and 24 weeks, respectively. No significant differences were found between the two groups and in the intragroup comparisons. Moreover, no significant differences were found between Lat and Taf in regard to the conjunctival injection score and corneal epitheliopathy score. Eyelash changes and eyelid and iris pigmentation were similar in both groups.Conclusion: The findings of this study show that Lat and Taf have equivalent efficacy and safety in Japanese patients with NTG. Keywords: latanoprost, tafluprost, normal-tension glaucoma, crossove

Characteristics of the human ocular surface epithelium

An appreciation of the biological characteristics of the human ocular surface epithelium affords us a great insight into the physiology of the human ocular surface in health and disease. Here, we review five important aspects of the human ocular surface epithelium. First, we recognize the discovery of corneal epithelial stem cells, and note how the palisades of Vogt have been suggested as a clinical marker of their presence. Second, we introduce the concept of the gene expression profile of the ocular surface epithelium as arrived at using a new strategy for the systematic analysis of active genes. We also provide a summary of several genes abundantly or uniquely expressed in the human corneal epithelium, namely clusterin, keratin 3, keratin 12, aldehyde dehydrogenase 3 (ALDH3), troponin-I fast-twitch isoform, ßig-h3, cathepsin L2 (cathepsin V), uroplakin Ib, and Ca2+-activated chloride channel. Genes related to limbal and conjunctival epithelia are also described. Third, we touch upon the genetic abnormalities thought to be involved with epithelial dysfunction in Meesmann's dystrophy, gelatinous drop-like corneal dystrophy, and the ßig-h3-mutated corneal dystrophies. Fourth, we provide an update regarding the current state of knowledge of the role of cytokines, growth factors and apoptosis in relation to ocular surface homeostasis and tissue reconstruction; the main factors being epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), transforming growth factor-ß (TGF-ß), and some inflammatory cytokines. Fifth, corneal epithelial barrier function and dysfunction as measured by fluorophotometry is remarked upon, with an explanation of the FL-500 fluorophotometer and its ability to detect corneal epithelial dysfunction at a subclinical level. The research described in this review has undoubtedly generated a complete understanding of corneal epithelial pathophysiology—an understanding that, directly or indirectly, has helped advance the development of new therapeutic modalities for ocular surface reconstruction