SELECTIVE CYTOTOXICITY IN THE LYMPHATICS

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Following subcutaneous injection, radiolabeled monoclonal antibodies bind efficiently to normal and tumor target cells in the lymph nodes (Project et Z01 CB 08359-03 LTB). This finding prompted us to attempt specific therapy using monoclonal antibody conjugates. An immunotoxin made from the A-chain of ricin coupled to an anti-mouse MHC antibody has proved to be highly toxic for lymphoid cells and similar results have been found with ricin A-chain conjugated to monoclonal antibodies against subsets of mouse lymphocytes in vitro. We have also been able to augment the effects of these toxins by the action of certain drugs which are known to affect cell biological processes. These studies have led to a new hypothesis for the cell biological pathway (the "neutral bypass") by which toxin molecules enter the cytoplasm from antibody conjugates to kill a cell. A further type of immunoconjugate for specific cell killing in vivo consists of a radioactive compound chelated to an antibody. We have demonstrated selective ablation of lymph node B lymphocytes in mice injected subcutaneously with an anti-murine B cell antibody labeled with the alpha particle emitter 212 Bismuth. The relative potency of this conjugate for B cells in vivo was 10-fold higher than for T cells taken from the same nodes. In order to assess the effects of antibodies and antibody conjugates in vivo we have established two models of lymph node T cell activation. In one, the stimulus is the plant lectin concanavalin A administered into the footpad; the other stimulus is allogeneic cells. Both of these stimuli induce T cells to express receptors for IL-2. The concanavalin A model is susceptible to the inhibitory effects of cyclosporin A whereas the allogeneic model is not.