Application of xenogeneic stem cells for induction of transplantation tolerance: present state and future directions

Abstract

Xenotransplantation using pig organs provides a possible solution to the severe shortage of allogeneic organ donors, one of the major limiting factors in clinical transplantation. However, because of the greater antigenic differences that exist between different species than within a species, the immune response to xenografts is much more vigorous than to allografts. Thus, tolerance induction is essential to the success of clinical xenotransplantation. Tolerance induced by mixed hematopoietic chimerism across the MHC barrier is remarkably robust, but its ability to induce tolerance across highly disparate xenogeneic barriers remains poorly studied. None of the current available regimens of host conditioning, which permit hematopoietic stem cell engraftment and chimerism induction in allogeneic or closely related (concordant) xenogeneic combinations, has been demonstrated to be effective in establishing porcine hematopoietic chimerism in a discordant xenogeneic species. Unlike bone marrow transplantation within the same species, the innate immune system and the species specificity of cytokines and adhesion molecules essential to hematopoiesis pose formidable obstacles to the establishment of donor hematopoiesis across discordant xenogeneic barriers. The genetic incompatibility between species may also impede xenograft tolerance induction by mixed chimerism. While we remain far from achieving tolerance in clinical xenotransplantation, recent studies using a transgenic mouse model have proven the principle that mixed hematopoietic chimerism may induce mouse and human T cell tolerance to porcine xenografts. This review article focuses on the barriers to porcine hematopoietic engraftment in highly disparate xenogeneic species and the possible application of mixed hematopoietic chimerism to xenograft tolerance induction.

Porcine UL16-Binding Protein 1 Expressed on the Surface of Endothelial Cells Triggers Human NK Cytotoxicity through NKG2D

“…These include direct cellular activation of pEC, the release of chemokines and cytokines such as porcine TNF-␣ and IL-8 leading to further EC activation, and the recruitment of additional human leukocytes to the graft. Moreover, the proposed protection of pEC from human NK cytotoxicity by interfering with pULBP1/human NKG2D interactions indicates a possible use to facilitate hemopoietic stem cell xenotransplantation, which has been proposed as a method to induce xenogeneic tolerance (48,49). Finally, the potential of pULBP1 to induce additional xenogeneic human NK cell responses such as IFN-␥ secretion by triggering NKG2D remains to be considered.…”

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

“…30,31 However, unlike bone marrow transplantation within the same species, the innate immune system poses a formidable obstacle to the establishment of donor hematopoiesis across discordant xenogeneic barriers. 32 Macrophages are one of the factors mediating strong rejection of xenogeneic hematopoietic cells. 5,6 The rejection of porcine hematopoietic cells by host macrophages developing de novo in porcine hematopoietic chimeras 5 suggests that mixed chimerism may not overcome the macrophage barrier.…”

The fate of transplanted xenogeneic bone marrow‐derived stem cells in rat intervertebral discs

“…24,25 Immune rejection is still a large burden for allogeneic or xenogeneic cell transplantation. 26 However, MSCs are immunoprivileged with immunosuppressive capacities. 27,28 The role of MSCs in escaping immune recognition, inhibition of the immune responses during allogeneic transplantation, and treatment of severe steroid-resistant acute graft-versus-host disease (GVHD) in a clinical trial has been reported.…”