In transplantation, the ability to induce donor specific tolerance has the potential to overcome rejection without the need for life-long immunosuppression that is associated with significant morbidity and economic cost. Studies in irradiation chimeras have shown that bone marrow derived hematopoietic cells are potent inducers of transplantation tolerance. However, the use of allogeneic bone marrow transplantation to induce tolerance suffers from many complications that include the need for toxic host conditioning to allow donor hematopoietic stem cell engraftment, graft versus host disease, and the possibility of leaving the host immunocompromised. We hypothesized that if hematopoietic lineages could be identified that are capable of inducing tolerance, it may be possible to harvest autologous tolerance inducing lineages, modify them ex vivo to express donor type alloantigens and re-infuse them back into the patient following appropriate conditioning to induce tolerance without the possibility of inducing GvHD or the need for an allogeneic bone marrow transplant. Data from our laboratory obtained using bone marrow chimeras, molecular chimeras, and adoptive cell transfer approaches have led to the novel observation that alloantigen expressing T cells are capable of inducing tolerance to MHC class I and MHC class II mismatched skin grafts. Our central hypothesis is that delivery of alloantigen on mature T cells can be used to induce long-term stable tolerance to transplantation antigens effectively re-shaping the immunological repertoire.
The specific aims of this proposal are therefore to: Determine the extent to which delivery of antigen by T cells can be used to induce tolerance and prevent chronic rejection;Determine the mechanisms by which expression of alloantigen on mature T cells leads to tolerance;and Develop clinically relevant strategies to induce tolerance by delivery of alloantigen on mature T cells. These studies may make it possible to develop novel approaches to inducing transplantation tolerance that eliminate many of the problems associated with using allogeneic bone marrow transplantation for this purpose, as well as eliminate or reduce the requirement for life-long immunosuppression in transplant patients. These studies may also provide insight into fundamental regulation of self-nonself recognition.
|Jindra, P T; Tripathi, S; Tian, C et al. (2013) Tolerance to MHC class II disparate allografts through genetic modification of bone marrow. Gene Ther 20:478-86|
|Zhao, X; Boenisch, O; Yeung, M et al. (2012) Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. Am J Transplant 12:90-101|
|Tian, Chaorui; Yuan, Xueli; Jindra, Peter T et al. (2010) Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen. Clin Immunol 136:174-87|
|Jindra, Peter T; Bagley, Jessamyn; Godwin, Jonathan G et al. (2010) Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten. J Immunol 185:990-7|
|Tian, Chaorui; Yuan, Xueli; Bagley, Jessamyn et al. (2008) Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells. Clin Immunol 127:130-7|
|Tian, C; Bagley, J; Iacomini, J (2007) Homeostatic expansion permits T cells to re-enter the thymus and deliver antigen in a tolerogenic fashion. Am J Transplant 7:1934-41|