Beutner U, McLellan B, Kraus E, Huber BT

Beutner U, McLellan B, Kraus E, Huber BT. novel approach for tolerance induction in transplantation. INTRODUCTION Transplantation tolerance, defined NH2-PEG3-C1-Boc as long-term allograft survival without ongoing immunosuppression, is usually a major but elusive goal in the field of transplantation medicine. Tolerance to self is usually managed through central mechanisms involving negative selection of self-reactive T cells in the thymus and peripheral mechanisms including regulatory T cells (Tregs) as well as other mechanisms [1; 2]. Indeed, it is obvious that tolerance to self requires both a central and peripheral component [3]. Building on these observations it is reasonable to suggest that strategies to induce transplantation tolerance should also involved central and peripheral mechanisms to induce and maintain tolerance. Bone marrow derived hematopoietic cells have been shown to be capable of inducing transplantation tolerance [4; 5]. Indeed, tolerance to allogeneic transplants in adults can be established by inducing a state of mixed hematopoietic chimerism through allogeneic bone marrow transplantation [5; 6]. Mixed chimerism prospects to specific tolerance, and permits transplantation of organs matched to the donor bone marrow without immunosuppression [7]. However, the use of allogeneic bone marrow transplantation to induce tolerance is usually associated with severe complications, such as graft-vs-host disease (GvHD), the inability to recover total immunocompetence, engraftment failure, and infectious complications [8; 9; 10; 11; 12; 13]. Furthermore, it has been hard to reliably establish a stable state of mixed host-donor hematopoietic chimerism in primates [14; 15; 16; 17], in most cases resulting in full donor chimerism or a lack of chimerism. Full donor chimerism has been suggested to potentially result in immunoincompetence because developing T cells are selected on host thymic epithelium, but must respond to pathogens in a donor-MHC restricted fashion [18]. Moreover, it has been reported that induction of mixed chimerism through bone marrow transplantation is unable to prevent chronic allograft rejection [19], currently the major factor limiting long-term survival of transplants [20; 21; 22]. Despite the clinical limitations of mixed bone marrow chimerism, it is obvious that donor bone marrow derived cells have potent tolerogenic properties. Therefore, one could hypothesize that if bone marrow derived lineages capable of inducing tolerance could be identified it may be possible to use these cells to induce tolerance without the need for an allogeneic bone marrow transplant. To date, hematopoietic lineages required for tolerance induction in the context of chimerism have been poorly defined. It had been suggested for a number of years that bone marrow derived antigen presenting cells (APCs) are critical for inducing tolerance to MHC antigens [23; 24; 25; 26; 27]. Others reported that high levels of donor type T cell chimerism correlated best with long-term maintenance of donor NH2-PEG3-C1-Boc specific tolerance [28]. It has also been shown that thymocytes are able to induce tolerance to MHC class I antigens Rabbit Polyclonal to MED14 [29], and MHC class I antigens expressed only in CD2+ cells induce CD8 T cell tolerance [30]. T cells have been shown to induce tolerance to minor antigens in neonatal mice [31], and donor bone marrow derived CD8 and CD4 T cells, or CD3e expressing cells are important for inducing tolerance in mixed chimeras [32]. We as well as others have shown that expression of donor alloantigen on T cells can result in tolerance in the context of hematopoietic chimerism [32; 33; 34]. Using a gene therapy model we have shown that expression of a MHC class I allo-antigen ((Kb)) on donor bone marrow derived T cells is required to induce tolerance to MHC class I disparate donor skin grafts [35]. Notably, expression of donor antigen on bone marrow derived APCs alone was not sufficient NH2-PEG3-C1-Boc to induce antigen specific tolerance [35]. NH2-PEG3-C1-Boc Further studies exhibited that adoptively transferred alloantigen expressing mature CD4+ and CD8+ T cells, but not B cells, can induce central tolerance to single MHC class I mismatched skin grafts in recipients treated with either myeloablative or non-myeloablative conditioning [36; 37]. The demonstration that T cells are able to induce tolerance provides a rational basis for studying the tolerance inducing capability of T cells in order to develop approaches.