GENETICALLY TRANSFERRED CENTRAL AND PERIPHERAL IMMUNE TOLERANCE VIA RETROVIRAL-MEDIATED EXPRESSION OF IMMUNOGENIC EPITOPES IN HEMATOPOIETICPROGENITORS OR PERIPHERAL B-LYMPHOCYTES

Background: Based on the hypothesis that IgGs are potent tolerogens an d that immature lymphohematopoietic antigen-presenting cells (APC), an d even mature peripheral B cells, may be effective APC for tolerance i nduction, we designed an immunoglobulin fusion protein retroviral expr ession vector to test the role of B cells in a novel gene therapy stra tegy for the transfer of immune tolerance. Methods: An immunodominant epitope (residues 12-26 of the lambda repressor cI protein) was fused in Game to an IgG heavy chain in a retroviral vector, which was used t o infect either bone marrow cells or activated peripheral B lymphocyte s. These cells were transferred into syngeneic recipients, who were su bsequently challenged with the 12-26 peptide in adjuvant. Results: Bon e marrow (BM) chimeras generated with retrovirally transduced bone mar row were shown to be profoundly unresponsive to the 12-26 peptide at b oth the humoral and cellular levels, but were competent to respond to an unrelated protein (lysozyme or PPD). Importantly, we also show that immunocompetent adult recipients infused with transduced mature, acti vated B lymphocytes, are rendered unresponsive by this treatment. Surp risingly, lymphoid-deficient BM progenitors from syngeneic SCID donors could also be transduced to produce tolerogenic APC. Conclusions: Our data suggest that activated B cells are sufficient to be effective to lerogenic APC in immunocompetent adult mice, but that nonlymphoid cell s may also induce tolerance in reconstituted hosts. This approach for gene-transferred tolerogenesis has the potential to be maintained inde finitely, and it requires only knowledge of cDNA sequences of target a ntigens.