Intercellular transfer of shed tumor cell gangliosides

AbstractThree distinct steps underlie immunosuppression by tumor gangliosides: (i) their shedding by the tumor cell, (ii) binding to target leukocytes in the tumor microenvironment, and (iii) action upon the target cell. While shedding is well documented, cell to cell transfer of shed gangliosides is not. To address this, we employed a dual chamber culture system. In this system, metabolically radiolabeled lymphoma cells shed gangliosides into the conditioned medium of the contralateral chamber, which contained normal fibroblasts as the target cell. The shed lymphoma cell gangliosides bound avidly to the target fibroblasts in a trypsin-resistant manner (1−2×106 and 7×106 molecules/fibroblast in 24 and 48 h). Significantly higher than binding rates of purified lymphoma gangliosides added exogenously, these binding rates in a system which models the in vivo microenvironment suggest that cell to cell ganglioside transfer is a highly efficient process

Detection of complex gangliosides in human amniotic fluid

AbstractGangliosides are possibly very potent immunosuppressive molecules. Here we show that human amniotic fluid contains high concentrations of a number of previously unnoted, structurally complex and highly polar gangliosides. These unusual molecules are present early in pregnancy (first trimester), increase in concentration with gestational age, and reach maximum levels (0.8 μM) at term. Since similar gangliosides have been detected in human placenta, trophoblast, and amnion, we suggest that these molecules are shed into the amniotic fluid bathing these tissues

Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study

We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged ,18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P 5 .035). For children with verified FHL (family history/genetically verified, n 5 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n 5 53) was significantly lower (52%; 95% CI, 38-65) (P 5 .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival.Fil: Bergsten, Elisabet. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Horne, AnnaCarin. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Hed Myrberg, Ida. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Aricó, Maurizio. Children Hospital Giovanni XXIII; ItaliaFil: Astigarraga, Itziar. Universidad del País Vasco; EspañaFil: Ishii, Eiichi. Ehime University; JapónFil: Janka, Gritta. Universitat Hamburg; AlemaniaFil: Ladisch, Stephan. Children’s National Medical Center; Estados UnidosFil: Lehmberg, Kai. Universitat Hamburg; AlemaniaFil: McClain, Kenneth L.. Baylor College of Medicine; Estados UnidosFil: Minkov, Milen. Universidad de Viena; AustriaFil: Nanduri, Vasanta. Watford General Hospital; Reino UnidoFil: Rosso, Diego. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sieni, Elena. Universitaria A. Meyer Children Hospital; ItaliaFil: Winiarski, Jacek. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Henter, Jan Inge. Karolinska Huddinge Hospital. Karolinska Institutet; Sueci

How I treat Langerhans cell histiocytosis.

“Langerhans cell histiocytosis” (LCH) describes a spectrum of clinical presentations ranging from a single bone lesion or trivial skin rash to an explosive disseminated disease. Regardless of clinical severity, LCH lesions share the common histology of CD1a(+)/CD207(+) dendritic cells with characteristic morphology among an inflammatory infiltrate. Despite historical uncertainty defining LCH as inflammatory vs neoplastic and incomplete understanding of mechanisms of pathogenesis, clinical outcomes have improved markedly over the past decades through cooperative randomized clinical trials based on empiric therapeutic strategies. Significant advances include recognition of high- and low-risk clinical groups defined by hematopoietic and/or hepatic involvement, and of the importance of optimal intensity and of duration of chemotherapy. Nevertheless, mortality of high-risk patients, disease recurrence, lack of robustly tested salvage strategies, and significant disease morbidity of both high- and low-risk patients remain challenges. Recent discovery of recurrent somatic mutations in mitogen-activated protein kinase pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy