? This R03 application is associated with the K08 award entitled, """"""""Tolerance Induction Using Modified Dendritic Cells."""""""" Despite tremendous progress over the past 50 years of clinical organ transplantation, patients continue to suffer from immune rejection as well as complications of generalized immunosuppression. The development of tolerance induction methods would revolutionize transplantation and may have potential for the treatment of autoimmune diseases. A growing understanding of the biology of dendritic cells (DC) has lead to the concept that donor-derived DC might be useful for the induction of donor-specific tolerance. During the first two years of the K08 award, we have validated our hypotheses that targeted lymphoid migration of DC is critical to tolerance induction, and that genetically modified DC can produce striking prolongation of cardiac allograft survival. However, a precise understanding of how modified DC affect donor-specific T cell responses is lacking, inhibiting the development of robust DC-based therapies required for clinical translation. During the K08 period, we have developed a powerful T Cell receptor transgenic mouse model of alloreactivity that allows simultaneous tracking of the three dominant pathways of T cell reactivity to allografts (CD4-direct, CD4-indirect, and CD8-direct). Using this model, we propose to expand upon the mechanistic studies originally proposed in the K08 award. We will study the T cell response to heart allografts using recently developed techniques and reagents in order to develop a precise definition of T cell alloreactivity that will have broad ranging implications for transplant immunology. These studies will also provide a foundation to analyze the effect of targeted lymphoid migration of DC, as well as the effect of immunomodulatory gene expression by DC on the three pathways of alloreactivity. We believe that these studies will provide an important framework for developing clinically applicable approaches to DC-based tolerance induction. The funds made available through this grant will make these studies possible by helping to fund a full-time technician and to offset experimental costs. Thus, these funds will facilitate the PI's development of this novel approach, helping to establish independent investigator status and forming the basis for a competitive R01 application. Specialized immune cells called dendritic cells are promising agents to prevent transplant rejection and autoimmune disorders. We have shown that delivery of genetically modified, tolerogenic dendritic cells to the specialized lymph organs is important for preventing transplant rejection in a mouse model. In this application, we propose to use state-of-the art techniques and tools to understand the mechanisms underlying our findings in order to help understand the rejection response, as well as to guide further improvement of dendritic cell therapy. ? ?
| Brennan, T V; Jaigirdar, A; Hoang, V et al. (2009) Preferential priming of alloreactive T cells with indirect reactivity. Am J Transplant 9:709-18 |
