The in vitro restoring effects of a thymic hormone preparation, TP-1, on defective monocyte and dendritic cell function in patients with head and neck squamous cell carcinoma (HNSCC) have been examined. The N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced polarization of monocytes isolated from the peripheral blood was significantly lower (a mean of 19%) than the polarization of monocytes isolated from healthy controls (a mean of 33%). After the in vitro addition of TP-1 this defective polarization was improved to the normal value of 33% polarized monocytes. The capability of dendritic cells prepared from the blood to form cellular clusters with allogeneic cells was impaired in 26/44 patients. In vitro addition of TP-1 again had restoring effects. The original defective dendritic cell clustering of 97 clusters/six microscopic fields (mean) was improved to a value of 121 clusters. The defects in monocyte polarization and clustering of dendritic cells could be ascribed to the presence in serum of a tumor-derived low-molecular-mass factor low-M(r) factor; < 25 kDa) sharing structural homology with p15E, the capsular protein of murine and feline leukemogenic retroviruses. The incubation of low-M(r) factor from the serum of HNSCC patients with healthy donor monocytes resulted in a significantly higher inhibition of fMLF-induced monocyte polarization than did incubation with control low-M(r) factor (a mean of 42 versus 16% inhibition). This suppressive effect of patient low-M(r) factor was abrogated with a mixture of two monoclonal antibodies against p15E as well as with TP-1. The observations here reported on the in vitro effects of TP-1 on depressed monocyte and dendritic cell function in HNSCC have provided one of the rationales for a TP-1 therapeutic pilot trial recently started in HNSCC patients.

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Endothelial-monocyte activating polypeptide (EMAP)-II is a novel molecule with cytokine-like pro-inflammatory properties, inducing procoagulant activity on the surface of endothelial cells and monocyte/macrophages in vitro, as well as up-regulating E-and Pselectin expression. EMAP-II is chemotactic for monocytes/macrophages and neutrophils, and stimulates myeloperoxidase release from neutrophils. Injection of EMAP-II into the mouse footpad induces an acute inflammatory response, although some regression occurs in response to direct injection of EMAP-II into murine tumors. Very little is known about the expression of EMAP-II in normal tissues of mice or humans, or about its function in vivo. We developed polyclonal antibodies against EMAP-II using recombinant protein produced in Escherichia coli, and used these antibodies to carry out an immunohistochemical study of the occurrence and distribution of EMAP-II in human tissues. The distribution of EMAP-II protein is relatively restricted, occurring primarily in endocrine organs, in cells of neuroendocrine origin, but also in tissues with high turnover. EMAP-II is strongly expressed in secretory epithelial cells of the thyroid, pancreas, adrenal and salivary glands, among others, as well as in neurons and subsets of monocytes/macrophages. It is also found in the epithelium of the small and large intestines. We conclude that EMAP-II expression is usually, but not always, associated with tissues that display high turnover and high levels of protein synthesis. EMAP-II is a novel molecule with pleiotropic activities toward endothelial cells, monocytes/macrophages, and neutrophils.

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