The objective of this research is to use neoplastic and normal accessory cells in a novel model system to study the regulation of B cell triggering and tolerance. We have shown that haptenated-immunoglobulin molecules can be presented directly to B cells by normal peritoneal macrophages and certain macrophage-like tumor lines to induce specific unresponsiveness. The role of the B cell FcR and the mechanisms of macrophage elicited tolerance will be investigated. Variant clones derived from the J774 macrophage-like tumor line have been isolated which possess a differential ability to induce B cell unresponsiveness. These clones will be studied to determine characteristics which confer the ability to tolerize B cells. In contrast to the action of macrophages, a lymphoid dendritic cell-like tumor line can convert a tolerogenic signal into an immunogenic one and elicit augmented antibody responses. The mechanism and role of T cells in this conversion will be studied using these tumor cells, as well as the normal splenic lymphoid dendritic cells. The ability of macrophages and lymphoid dendritic cells to present immunoglobulin tolerogen in vivo will be determined. In addition, the ability of these accessory cells to present immune complexes in a tolerogenic or immunogenic fashion will be assessed. Since relatively little is known about how accessory cells modulate B cell responsiveness, this research proposal would help fill that gap. Furthermore, an understanding of macrophage and lymphoid dendritic cell modulation of B cell signalling could lead to more rational approaches when attempting immunological modulation of cancer and autoimmunity.
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