BackgroundDespite Natural Killer (NK) cells were originally defined as effectors of spontaneous cytotoxicity against tumors, extremely limited information is so far available in humans on their capability of killing cancer cells in an autologous setting.Methodology/Principal FindingsWe have established a series of primary melanoma cell lines from surgically resected specimens and here showed that human melanoma cells were highly susceptible to lysis by activated autologous NK cells. A variety of NK cell activating receptors were involved in killing: particularly, DNAM-1 and NKp46 were the most frequently involved. Since self HLA class I molecules normally play a protective role from NK cell-mediated attack, we analyzed HLA class I expression on melanomas in comparison to autologous lymphocytes. We found that melanoma cells presented specific allelic losses in 50% of the patients analyzed. In addition, CD107a degranulation assays applied to NK cells expressing a single inhibitory receptor, revealed that, even when expressed, specific HLA class I molecules are present on melanoma cell surface in amount often insufficient to inhibit NK cell cytotoxicity. Remarkably, upon activation, also the so called “unlicensed” NK cells, i.e. NK cells not expressing inhibitory receptor specific for self HLA class I molecules, acquired the capability of efficiently killing autologous melanoma cells, thus additionally contributing to the lysis by a mechanism independent of HLA class I expression on melanoma cells.Conclusions/SignificanceWe have investigated in details the mechanisms controlling the recognition and lysis of melanoma cells by autologous NK cells. In these autologous settings, we demonstrated an efficient in vitro killing upon NK cell activation by mechanisms that may be related or not to abnormalities of HLA class I expression on melanoma cells. These findings should be taken into account in the design of novel immunotherapy approaches against melanoma.

This is the first study to describe the frequency of distribution of HLAs in a population from a restricted geographic area. The findings suggest a possible correlation between HLA allele distribution and the occurrence of newly diagnosed malignant astroglial brain tumors.

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Since previous data have provided conflicting results on immunoresponsiveness in senile dementia, Alzheimer type (SDAT), we evaluated the immune function in groups of SDAT patients and aged and young donors. In comparison to the younger subjects, SDAT and aged subjects did not exhibit significant differences in lymphocyte surface markers. Both groups of aged donors showed decreased B cell polyclonal responsiveness in a nonspecific T cell-driven B lymphocyte differentiation system. The use of an antigen-specific induction assay revealed an imbalance of T helper (Th) or T suppressor function in the elderly, while SDAT individuals were characterized by decreased Th activity. At the same time, aged individuals manifested an impairment of leukocyte-inhibiting factor (LIF) and lymphocyte-derived chemotactic factor production; a selective deficit of LIF release was seen in SDAT. Finally, elderly individuals displayed a decline of polymorphonuclear cell (PMN)-mediated functions and monocyte phagocytosis; only a decrease in PMN response was observed in SDAT. These results reveal discrepancies in impaired immune responses between SDAT and aging.

The analogue of phenylalanine, (-3-thienylalanine ((-3-TA), inhibits the primary and secondary immune responses to sheep red blood cells in CBA mice fed with phenylalanine-free diet. The optimal dose of (-3-TA needed to obtain maximum immunosuppression with minimal toxicity is 250 mg per kg per day. The drug is maximally effective when administered for 7 days, beginning 2 days prior to primary immunization. With these experimental conditions, the antibody titers and the numbers of direct and indirect plaque-forming cells are greatly reduced during the primary and the secondary immune response.