UBC Theses and Dissertations
Cell surface antigens in normal and neoplastic human B lymphocyte differentiation : cellular distribution and functional implications Howard, Donald Raymond
Differentiation within the lymphoid system produces effector cells which are involved in a variety of immune functions. For T cells these include the provision of help, suppression, cytolytic activity and the regulation of cooperative cellular interactions. The primary function of B lineage cells is the production of specific antibody. Understanding the regulation of normal lymphocyte proliferation and differentiation may lead to a better appreciation of those factors which result in the development of malignancy. The non-Hodgkin's lymphomas are neoplasms of the immune system, the majority of which are B cell in origin. Despite advances in immunology and molecular biology, little is known about the mechanisms involved in B cell activation, proliferation and differentiation or about those events leading to their malignant transformation. The advent of monoclonal antibody technology a decade ago has revolutionized our ability to identify and characterize cell surface antigens. Because the activation and control of proliferation of B cells was already known to involve structures at the cell surface, it was logical to utilize monoclonal antibodies to identify additional cell surface molecules that might be important in the function of normal B lymphocytes and that might allow normal and various types of neoplastic B cells to be distinguished. To achieve this goal, we developed monoclonal antibodies that showed differential reactivity between large actively dividing lymphoma cells and small inactive (quiescent) lymphocytes. These were tested for their ability to inhibit various T and B lymphocyte functions (i.e. responses to anti-µ, lipopolysaccharide, phytohemagglutinin and the mixed lymphocyte response) as well as for their reactivity with cell suspensions from a variety of malignant and nonmalignant hematopoietic tissues. From these studies emerged the following: 1) Cell surface molecules other than Immunoglobulin are involved in regulating the activation of normal B cells. This was shown by the discovery that monoclonal antibodies to both lymphocyte function associated antigen (LFA-1) and certain HLA class II determinants were able to inhibit the activation of peripheral blood mononuclear cells by the B cell mitogens anti-p and LPS. This inhibition was shown to be mediated via effects of these antibodies on T cells and/or monocytes. 2) B lymphoma cells appear to express unique cell surface antigens (defined by monoclonal antibodies LM-26 and LM-155) not detectable on cells of other lineages, and absent from normal resting or activated B lymphocytes. Future investigations will attempt to define the mechanisms by which the indirect involvement of LFA-1 and HLA class II molecules in B cell activation in vitro suggests new regulatory interactions not previously identified. Further studies will be required to define the mechanisms underlying these interactions and their significance in vivo. Similarly, the structure and function of the antigens detected by LM-26 and LM-155 remains to be determined. Nevertheless, the expression of apparently unique molecules on B lymphoma cells holds new promise for the diagnosis, classification and treatment of this group of diseases.