The role of LPS and CpG in the farm ef- fect against allergies, and beyond

The prevalence of allergic disease has increased significantly over the past decades. Although allergies are inherently multifactorial and heterogenous; environmental, maternal, and early life microbial exposures could strongly modify disease risk. The effects of environmental microbiota are illustrated by the "farm effect", showing protection against asthma when growing up on traditional farms. Recent studies have further revealed an important role for early-life exposure to a microbe-rich environment imposing lung and gut microbiome maturation and immune education, preventing allergic disease in childhood. Advances are made in the field of immunology and microbiome research, which identified entire microbial taxa, as well as specific microbial metabolites and bacterial products associated with reducing disease risk. Here we discuss the cross-talk between the microbiota and allergic disease pathogenesis, including bacterial products as lipopolysaccharide and CpG in the farm effect

The feasibility of radioimmunotherapy of head and neck cancer

Since the introduction of the hybridoma technology by Kohler and Milstein (Nature 1975, 256, 495-497), tremendous effort has been put in the realisation of Ehrlich's concept of the magic bullet, which was proposed as early as the beginning of the century. The first clinical studies for radioimmunoscintigraphy (RIS) and radioimmunotherapy (RIT) with radiolabelled antibodies were undertaken in the early 1980s. Since then, RIS has been performed on thousands of patients with various types of malignancies, like colon carcinoma, lung carcinoma, breast carcinoma, neuroblastoma, T-cell lymphoma and ovarian carcinoma. In addition, a substantial number of therapy trials with radiolabelled antibodies have been performed. The developments for head and neck squamous cell carcinoma (HNSCC) have only recently been able to catch up with these events to some extent. One of the main reasons for this slow progress has been the lack of monoclonal antibodies (mab) with specificity for HNSCC. Although there are as yet no real tumour specific antigens known for HNSCC, which also holds true for the majority of malignancies arising from other tissues, we now have the availability of a number of Mab with high specificity for HNSCC and with a very restricted reaction pattern with normal tissues. Labelled with 131I, these Mab have been shown to be highly capable to localise in HNSCC xenografts in nude mice. Based on these promising data, patient studies with one of these Mab, sesignated Mab E48, labelled with 99mTc, were started to evaluate the feasibility of RIS in patients with head and neck cancer. The first results of these studies indicated the capacity of 99mTc-labelled Mab E48 F(ab′)2, as well as IgG to detect metastatic and recurrent disease in these patients. These data justified further studies investigating the possibilities for RIT with this Mab. In preclinical experiments, the capacity of 131I-labelled Mab E48 IgG to eradicate established HNSCC tumours in nude mice was shown. Following the latest developments in the field of radioimmunoconjugate chemistry and anticipating the need for more appropriate radionuclides for clinical applications, a technical protocol for the labelling of Mab with 186Re was developed. Labelled with 186Re, Mab E48 appears to be even better suited to eradicate established tumours than when labelled with 131I. Based on these encouraging observations we are now making preparations for the first RIT studies with 186Re-labelled Mab E48 in patients with head and neck cancer

Complete ablation of small squamous cell carcinoma xenografts with186Re-labeled monoclonal antibody E48

In previous studies we have shown that in mice bearing head and neck squamous cell carcinoma (HNSCC) xenografts, radioimmunotherapy (RIT) with186Re-labeled MAb E48 resulted in complete regressions in one-third of the tumors (followup >150 d). MAb E48 was labeled with186Re following a novel labeling procedure developed at our institute. The injected dose was 600 μCi, which was the maximum tolerated dose (MTD; 150 d). In all mice, weight loss did not exceed 10%. to obtain biodistribution data, mice bearing two xenografts with a vol of 58±31 mm3 were injected with 100 μCi of186Re-labeled MAb E48 IgG. The maximum uptake in blood was 26.4% injected dose/g (%ID·g-1) at 2 h pi and was 53.1%ID·g-1 in the tumor at d 7 pi. In normal tissues, no nonspecific accumulation was observed. Based on these biodistribution data, the absorbed cumulative radiation dose was calculated. The accumulated dose in blood and tumor was 2004 cGy and 8580 cGy, respectively. In other tissues, the dose was less than 8.1% of the dose delivered to tumor. These data implicate that RIT with186Re-labeled MAb E48 may be especially suited to be used as adjuvant therapy for the treatment of head and neck cancer patients with minimal residual disease

Monoclonal antibodies for diagnosis and therapy of squamous cell carcimona of the head and neck

O grupo de carcinomas espinocelulares da cabeça e pescoço em pacientes com alto risco de desenvolver metástases à distância, tem sido bem definidos do ponto de vista prognóstico em nossa instituição. Com intuito de selecionar fatores de risco preditivos no desenvolvimento de metástases à distância, Leemans e col analisaram um grupo de 281 pacientes com carcinoma epidermóide que não desenvolveram doença recorrente acima da clavícula (79). Todos os pacientes foram primariamente operados e submetidos à radioterapia complementar diante de 3 ou mais linfonodos histológicos metastáticos na avaliação da peça operatória, sendo que neste grupo, a incidência de metástases à distância a 5 anos foi de 10,7%. 0 número de metástases em Iinfonodos em n4 de 3 ou mais, foi determinante do desenvolvimento de metástases à distância em 50% dos casos, fato este não detectado quando esta cifra estava abaixo de 3 linfonodopatias. Em contrapartida, a presença de ruptura extra-capsular foi um fator dramático de mudança de prognóstico no que diz respeito à presença de metástases à distância (3 vezes mais que nos casos onde a ruptura extra-capsular estava ausente). Outro aspecto que mereceu a atenção dos autores, foi aquele relacionado com os pacientes recidivados loco-regionalmente ocorrendo nestes pacientes duas vezes mais metástases sistêmicas (80,81). A opção proposta no sentido de introduzir uma terapia adjuvante para os pacientes com alto risco de desenvolver metástases à distância, é o emprego de anticorpos monoclonais marcados. Recentemente, apresentamos um primeiro estudo experimental em carcinoma epidermóide da cabeça e pescoço tratados por radio-imunoterapia. Foi demonstrado que a IgG E48 de anticorpos monoclonais marcados com 1131 foi capaz de eliminar implantes humanos de carcinoma escamocelular em tumores transplantados para ratos(82). Em 20% dos experimentos desenvolvidos (2 em 10 tumores), foi observada uma regressão em ratos tratados com 400iCi de IgG E48 de anticorpos monoclonais marcados com lodo 131 tratados com 800 µCi, 2 em 7 tumores(29%) mostraram completa remissão sem recidiva durante o seguimento (> 3 meses). Nos mesmos casos, a utilização de quimioterapia com doxorubicina, 5 fluor-uracil, cisplatinum e methotrexate exibiram uma resposta menor, demonstrando um efeito antitumoral mais fugaz, não ocorrendo nenhuma cura com o emprego de antiblásticos. Este dados sugerem que o emprego da radio-imunoterapia no tratamento do câncer da cabeça e pescoço, pode se transformar numa nova alternativa no tratamento das lesões com altas capacidade de recidiva e disseminação

The human E48 antigen, highly homologous to the murine Ly-6 antigen ThB, is a GPI-anchored molecule apparently involved in keratinocyte cell-cell adhesion

Abstract. The E48 antigen, a putative human homologue of the 20-kD protein present in desmosomal preparations of bovine muzzle, and formerly called desmoglein III (dg4), is a promising target antigen for antibody-based therapy of squamous cell carcinoma in man. To anticipate the effect of high antibody dose treatment, and to evaluate the possible biological involvement of the antigen in carcinogenesis, we set out to molecularly characterize the antigen. A cDNA clone encoding the E48 antigen was isolated by expression cloning in COS cells. Sequence analysis revealed that the clone contained an open reading frame of 128 amino acids, encoding a core protein of 13,286 kD. Database searching showed that the E48 antigen has a high level of sequence similarity with the mouse Th