I. Analysis of human lymphocyte mediated cytotoxicity. Effectors. Spontaneously cytotoxic polyclonally activated and antigen stimulated killer cells will be compared for lineage, stage of maturation, and release of cytotoxic factors. Do donors with different killing efficiencies to BEBV differ in the number of specific precursors? Can IFNs participate in BEBV inhibition? What is the relative importance of EBV-determined and EBV-independent B-blast structures in BEBV induced autologous T-cell responses? Target cell involved in the triggering of lytic interactions will be compared for membrane properties and antigenic expression. Is it possible to modulate the NK sensitivity of the B2M/class I antigen defective Daudi and K562 lines by B2M transfection? The role of C3 and split products in mediating complement dependent cytotoxicity (CDCC) will be studied with particular emphasis on its possible role as a surveillance mechanism. II. Genetic analysis of natural effector mechanism in the mouse. 13 congenic resistant strains are being developed, to carry a single gene that influences natural resistance to small grafts from an NK-sensitive Moloney lymphoma (YAC). In the previously identified 2 H-2 linked genes, NKD and NKT, that influence NK-mediated lysis, will be studied for interactions with each other and with the genetic background. The genetics of natural and immune resistance will be compared in selected tumor-host combinations. III. Studies on natural resistance against tumor cell variants with MHC class I losses or gains. Stable variants will be tested for susceptibility to NK lysis and natural resistance, with particular focus on i) the role of defined class I tumor/host mismatching: ii) the effector of changed class I antigen expression on growth properties in the syngeneic host and iii) the influence of changed H-2 expression on tumor cell immunogenicity and immunosensitivity. The H-2 loss and gain variants will also be compared for early elimination, pulmonary colonization and effector sensitivity in syngeneic and in specifically mismatched hosts. We shall also explore whether NK cells can protect the primary host of an autochthonous tumor that is non-immunogenic in the usual preimmunization-rejection test, from metastasis.
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