Brief DetTnitive Report

The selective elimination of subpopulations of cells on the basis of their capacity to specifically bind various toxin conjugates has been the focus of recent intensive interest and study (1, 2). The regulatory mechanisms that control the specificity and size of discrete B lymphocyte clones occasionally break down and results in the production of deleterious antibodies directed against self determinants. In such cases, it would be desirable to suppress specific B cell clones without inhibiting the normal functions of the remainder of the immune system. Using an in vitro model system of antigenspecific antibody synthesis (3, 4) and an antigen-toxin conjugate, we demonstrate that selective abrogation of antigen-specific human B cell responses can be achieved. The rationale for the procedure of using a toxin-conjugate to reduce the population of specific cells has been previously outlined (1). Toxins such as ricin and diphtheria consist of two chains, each having different functions (5, 6). The A chain is an enzyme capable of inactivating protein synthesis once it is transported to the cytosol compartment. The B chain initiates the entry process by binding the toxin to cell surface receptors present on most cell types. By replacing the normal toxin B chain with a new binding chain having receptor specificity for a distinct cell type, a structural analogue of the toxin is created (1). The specificity of cell killing is now determined by the new binding chain. A variety of such toxin analogues have been constructed with varying degrees of potency and cell type specificity (7, 8). The antigen-toxin conjugate used in these studies is a thioether conjugate of tetanus toxoid (TT) and intact ricin containing both the A and B chains. This was done for the initial studies because of recent evidence showing that the toxin-binding B chain plays a role in facilitating A chain entry (9). This role appears to be independent of surface membrane receptor binding (2, 10). Certain conjugates containing toxin B chains have been shown to have faster rates of specific cell killing (2, 9). Conjugates of ricin containing the B chain are used in the presence of lactose, which largely (20200-fold) blocks the ricin entry route via its receptor and thereby reduces nontarget cell killing (9). Conjugates constructed along these lines, such as mannose-6-PO4-ricin and monoclonal anti-Thy-l.2-ricin, have been useful in selecting mutant cell lines deficient in mannose-6-PO4 receptors (11) and in eliminating T cells from murine bone marrow allografts as a means of preventing experimental graft-vs.-host disease (12), respectively. In both of these cases, the selectivity of the conjugate between target and nontarget cells is between 100:1 and 1000:1, and the desired objective is achievable without complete elimination of the target cell population (11, 12).