ROLE OF NATURAL CYCTOTOXIC CELLS IN LYMPHOMAS

Transplantable reticulum cell sarcomas (RCS) of SJL/J mice exhibit several unique interactions with the host immune system that illustrate important concepts regarding host-tumor cell interactions. By virtue of their surface I-As determinants, RCS tumor cells stimulate proliferation of syngeneic Ly-1+2-T cells and activate NK cells, as a result of which a variety of lymphokines are also produced, including IL-2, and IFN-gamma. I-As-specific monoclonal antibodies (McAb) inhibit these in vitro host responses. Growth of RCS tumor cells in vivo appears dependent on the host's immune system to generate these responses, since tumor cells do not grow progressively in immunocompromised SJL recipients or in SJL F1 hybrids which, because of Ir-genetic restrictions, cannot respond to RCS cells. Since many of these hypotheses have been formulated on the basis of in vitro correlates, it is necessary to demonstrate that such interactions also occur in vivo. The proposed investigation will address this question in two ways. First, experiments will be performed to define the repertoire of RCS-reactive cells, using contemporary lymphocyte cloning methodology. Cloned cell lines with defined functional attributes and/or their soluble products will be assessed in immunocompromised SJL mice for the capacity to reconstitute the microenvironment necessary for optimal tumor growth. SJL "beige" mice will also be used in this study to determine whether the selective pressure of an NK-deficient environment will influence the growth, maturation/differentiation and functional characteristics of primary RCS and transplantable RCS lines. As a secondary aspect of this investigation, McAb will be produced against cloned RCS-reactive cells. These McAb will be tested for therapeutic efficacy in inhibiting tumor growth in vivo by regulating the lymphocyte populations that are necessary to support the growth of RCS cells. Immunotherapy with I-As-reactive McAb will also be used to regulate the growth of these I-A+ lymphoma cells. Once the efficacy of immunotherapy with these McAb has been demonstrated against the transplantable RCS cell lines, immune intervention in aging SJL mice will be performed in order to arrest the development of primary RCS tumors, which occur with high frequency (greater than 90%) in this strain. Since the RCS tumors of SJL mice have properties in common with some human B cell malignancies, the proposed investigation will yield a clearer understanding of host-tumor cell interactions in man and may define new approaches for the diagnosis and treatment of cancer patients.