MHC GENE PRODUCTS IN PROTECTING CELLS AGAINST NK LYSIS

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The aim of this research project is to further document that the major histocompatibility complex (MHC) gene products can protect tumor and normal cells against cytolysis by natural killer cells (NK) and by lymphokine (interleukin2) activated killer cells (LAK). Studies will also be aimed at (i) elucidating the mechanism by which MHC gene products afford such protection, and (ii) determining the relative importance of class I vs Class II HLA molecules (and their polymorphic determinants) in affording protection to normal or tumor cells. In these in-vitro studies human tumor cells obtained form lymphoid and solid-tumor malignancies will be interacted with autologous and or allogeneic human NK and LAK cells. Similar studies will be performed on normal human cells, i.e. lymphocytes and freshly obtained (and cultured) endothelial cells. The protective role of MHC gene products on cell membranes will be primarily determined by "blocking" or "masking" these antigens with monoclonal or (Fab) '2 antibodies using techniques that we have recently published. Normal cells (e.g. B lymphocytes) will be activated with lymphokines, antigens, and with viruses (e.g. EBV). The role of MHC products in protecting such activated and antigen exposed cells against autologous or allogeneic NK or LAK lysis will then be determined. Tumor cells will also be activated with gamma-interferon prior to using them as targets in NK or LAK lysis. The effect of altering tumor cell MHC products with interferon will then be assayed in these cytolytic experiments. In separate studies involving NK and LAK lysis, we will use as targets mutant tumor cell lines that vary in their expression of Class I or II MHC molecules and also tumor cells transfected with MHC genomes. Correlating lytic data (before and after masking of MHC molecules) with level of MHC antigen expression and conjugate formation should yield more conclusive data on the role of MHC in tumor cell protection. These studies will increase our understanding on cancer immunity (and perhaps therapy with biological agents) and with autoimmune mechanisms.