Specific aims: The first part of this application aims at understanding the biological significance of the NK system as a mechanism to maintain homeostasis in the hematopoietic system and to avoid extra medullary hematopoiesis. Given the ability of NK cells to inhibit normal progenitor cells in the bone marrow, possible consequences of an over-activated NK system may be dysfunction of the bone marrow, and example of this in man and mouse experimental systems will be analyzed. A better understanding of the ability of NK cells to inhibit growth and metastatic spread of tumor cells is the aim of part 2 in this application. The possibility that quantitative variations of MHC-1 expression affects tumorogenicity and metastatic spread of tumor cells will be investigated. With increased knowledge about how lymphokines affect tumor sensitivity and how NK cells can be used in adoptive transfer models, the study aim at helping to improve immunotherapy protocols. Methodology: Chronic suppression of NK activity by in vivo administration of NK - specific antibodies, or activation of NK cells by acute virus infection, will be performed in mouse experimental system. The consequences of these treatments on the frequency of pluripotent, myeloid and erythroid progenitor cells will be analyzed by in vivo spleen colony assays or in vitro agar assays. Aplastic anemia and leukopenia in man will be analyzed as possible examples of conditions where the immune system, including NK cells may play a role. Factors produced by lymphocytes of these patients will be characterized purified and cloned. The consequences on tumor NK sensitivity, tumorogenicity and metastatic spread of modulation of MHC-1 expression by interferons or in vivo passage of tumor cells will be analyzed. The proteins and genes responsible for confering NK protection to tumor cells as a consequence of IFN-gamma treatment will be investigated by 2-D gels and by cDNA subtraction methods. Long-term objectives: A deeper understanding of the biological significance of the NK system as a regulator of hematopoiesis and as a tumor surveillance mechanism will make it possible to in a controlled manner up- or down-regulate host NK activity. This may have positive consequences in the therapy of patients suffering from malignant tumors or from dysfunction of the bone marrow caused by the immune system.
Showing the most recent 10 out of 33 publications
