Bone marrow derived cells, especially B lymphocytes, have been shown to function as tolerogenic antigen-presenting cells (APC's) both in vivo and in vitro. In addition, it is well established that immunoglobulins can function as potent tolerogenic carriers for associated epitopes. We have taken advantage of these properties to develop a gene therapy approach to induce unresponsiveness in a number of animal models for clinical diseases. In our system, we engineered target peptide-IgG constructs into retroviral vectors and transduced hematopoietic cells to create tolerogenic antigen-presenting cells. In this review, we discuss the strategies and mechanism of our gene therapy approach mediated by B cells, as well as by bone marrow cells, for tolerance acquisition in various mouse models for autoimmune disease and hemophilia A. Our results show that MHC class II and co-stimulatory molecules must be expressed on the tolerogenic antigen presenting cells for efficacy. This therapy requires regulatory T cells for both the induction and maintenance of tolerance. The putative role of epitopes provided by the IgG carrier in this process is emphasized. Studies in non-human primates and with human T cell clones in vitro are in progress to transition this approach to the clinic. The use of stem cells and B cell-delivered gene therapy in human clinical diseases may soon become a reality.
- B cells
- Immune tolerance
- Immunoglobulin fusion proteins
- Regulatory t cells