Antigen-specific drug-targeting used to manipulate an immune response in vivo.
The administration of dextran-conjugated cytosine arabinonucleoside (araC) to BALB/c mice at various times prior to but not subsequent to immunization with native dextran renders mice unresponsive to this thymic-independent antigen. These results demonstrate that the primary immune response to an antigen can be selectively and efficiently suppressed or eliminated in vivo by the delivery of a single dose of an appropriate antigen-cytotoxic drug conjugate. Evidence presented here indicates that the dextran-araC conjugate (toxogen) acts directly and selectively upon unprimed dextran-specific antibody-forming cell precursors, presumably by binding to their receptors and subsequent internalization of the resultant receptor-toxogen complexes. The resistance of antigen-primed mice to the cytotoxic effect of the toxogen could result from the failure of dextran-primed cells to reexpress antigen-specific receptors, from an alternative processing of the toxogen, or from the inability of the antigen-primed cells to internalize a second round of receptor-ligand complexes. We also determined that B cells responding to thymic-dependent antigens were not affected by the prior exposure to a toxogen. The inability to eliminate or suppress the primary response to a thymic-dependent antigen via the administration of a cytotoxic drug-antigen conjugate distinguishes the thymic-independent set of B cells from the thymic-dependent B-cell repertoire. The difference between these two B-cell compartments could be due either to differences in the amount of ligand bound to receptors or to differences in the trafficking patterns of receptor-ligand complexes within each cell type.
D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology*; D001402:B-Lymphocytes / Q000145:classification / Q000187:drug effects* / Q000276:immunology; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D003911:Dextrans / Q000008:administration & dosage / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects*; D007114:Immunization; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C
D000955:Antigens, T-Independent; D003911:Dextrans; D007166:Immunosuppressive Agents; D003561:Cytarabine