Human Monocytes Recognize Porcine Endothelium via the Interaction of Galectin 3 and α-GAL

Jin, Rongyu; Greenwald, Allen; Peterson, Mark D.; Waddell, Thomas K.

doi:10.4049/jimmunol.177.2.1289

Cited by 59 publications

(42 citation statements)

References 38 publications

(28 reference statements)

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“…Besides Fc␥ and complement receptors, it has been postulated that lectin-mediated carbohydrate binding provides activating signals to macrophages without opsonization (26). A recent study has shown that Galectin-3, an Ϸ30-kDa lectin composed of a terminal carbohydrate recognition domain, which is responsible for the specific recognition of ␤-galactose [Gal␤(1-3/4) GlcNAc] and an N-terminal domain, is expressed in human macrophages (27). This lectin has been shown to be a receptor for xenoantigens, including not only ␣-Gal but also Nglycolylneuraminic acid, which is expressed on porcine cells.…”

Section: Discussionmentioning

confidence: 99%

Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Ide

Wang

Tahara

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

277

256

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We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)␣ is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRP␣, prevents autologous phagocytosis. Considering the limited compatibility (73%) in amino acid sequences between pig and human CD47, we hypothesized that the interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. In the present study, we have demonstrated that porcine CD47 does not induce SIRP␣ tyrosine phosphorylation in human macrophage-like cell line, and soluble human CD47-Fc fusion protein inhibits the phagocytic activity of human macrophages toward porcine cells. In addition, we have verified that manipulation of porcine cells for expression of human CD47 radically reduces the susceptibility of the cells to phagocytosis by human macrophages. These results indicate that the interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRP␣ on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection.xenotransplantation ͉ phagocytosis ͉ reticuloendothelial system

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Section: Discussionmentioning

confidence: 99%

Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Ide

Wang

Tahara

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

277

256

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“…It is probable that the vigorous rejection of human RBCs by macrophages is accounted for predominantly by the xenoantigens on human RBCs that can activate macrophages. 34,35 Previous studies have shown the presence of human macrophages and dendritic cells in the humanized mice. 12,13,36 However, we do not fully understand why human macrophages did not reject mouse RBCs in these mice.…”

Section: Discussionmentioning

confidence: 99%

Macrophages prevent human red blood cell reconstitution in immunodeficient mice

Rooijen

Yang

2011

Blood

130

138

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IntroductionRed blood cells (RBCs) are part of nonimmune blood-lineage cells derived from hematopoietic stem cells. Anemia continues to exert tremendous burdens to human health. [1][2][3][4] Thus, a considerable effort has been made to develop new therapies for the treatment of anemia. Although the focus in the treatment of anemia has been on growth factors (eg, erythropoietin [EPO]), derivation of hematopoietic cells from human embryonic stem cells and induced pluripotent stem cells are considered a worthwhile endeavor in the areas of transfusion therapies. 5 It has been reported that enucleated RBCs can be differentiated from human embryonic stem cells with functional oxygen-carrying ability on large scale. 6 However, these studies have been limited to in vitro assays because of the lack of a suitable animal model. Immunodeficient mice provide a very useful in vivo model for the study of human lymphohematopoietic cell function. Human hematopoietic stem cell engraftment and differentiation can now be reproducibly established in NOD/SCID mice or their derivatives. 7 However, it remains unclear whether immunodeficient mice are suitable for the study of human RBC differentiation and function. Although a previous report showed detectable human RBCs in NOD/SCID/IL2r null (NSG) mice receiving human cord blood CD34 ϩ cell transplantation via the facial vein at the newborn stage, 8 the ability of immunodeficient mice to support human erythropoiesis and/or survival of human RBCs has not been confirmed by other studies. 9 Recently, hydrodynamic injection of pcDNA-encoding EPO and IL-3 was found to improve human RBC reconstitution in NSG mice receiving CD34 ϩ cells, but the levels of human RBCs in these mice were extremely low compared with the levels of human PBMCs. 10 We have previously developed a humanized mouse model, in which cotransplantation of human fetal thymic tissue (under renal capsule) and CD34 ϩ fetal liver cells (FLCs; intravenously) resulted in sustained repopulation with multilineages of human lymphohematopoietic cells, including T, B, and dendritic cells, and the formation of secondary lymphoid organs in NOD/SCID mice. [11][12][13] In this study, we assessed human RBC reconstitution in these humanized mice. We observed that human RBCs were undetectable in blood circulation, despite that large numbers of human normoblasts were detected in the bone marrow. Furthermore, the lack of human RBCs in blood circulation was largely accounted for by the extremely high susceptibility of human RBCs to rejection by recipient mouse macrophages. Methods Animals and human tissues and cellsNOD.CB17-Prkdc scid /J (NOD/SCID), NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NOD/SCID/␥c Ϫ/Ϫ or NSG), and B6.129-Itgp tm1Fpl (CD47 KO B6) mice were purchased from The Jackson Laboratory and were housed in a specific pathogen-free microisolator environment and used in experiments at 6 to 10 weeks of age. GFP-transgenic CD47 KO mice were generated by Submitted November 24, 2010; accepted September 5, 2011. Prepublished online as Blood First E...

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“…Nevertheless, these results are consistent the Gal antigen. These ligands are known to participate in the human monocyte-PAEC interactions (19,21). with previous observations in pig arthritic joints in which the majority of chondrocytes expressed high lev-…”

Section: Pcc Secrete Pil-8 and Pil-6 In Response Tomentioning

confidence: 99%

TNF, Pig CD86, and VCAM-1 Identified as Potential Targets for Intervention in Xenotransplantation of Pig Chondrocytes

2009

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Xenotransplantation of genetically engineered porcine chondrocytes may benefit many patients who suffer cartilage defects. In this work, we sought to elucidate the molecular bases of the cellular response to xenogeneic cartilage. To this end, we isolated pig costal chondrocytes (PCC) and conducted a series of functional studies. First, we determined by flow cytometry the cell surface expression of multiple immunoregulatory proteins in resting conditions or after treatment with human TNF-α, IL-1α, or IL-1β, which did not induce apoptosis. TNF-α and to a lesser extent IL-1α led to a marked upregulation of SLA I, VCAM-1, and ICAM-1 on PCC. SLA II and E-selectin remained undetectable in all the conditions assayed. Notably, CD86 was constitutively expressed at moderate levels, whereas CD80 and CD40 were barely detected. To assess their function, we next studied the interaction of PCC with human monoblastic U937 and Jurkat T cells. U937 cells adhered to resting and in a greater proportion to cytokine-stimulated PCC. Consistent with its expression pattern, pig VCAM-1 was key, mediating the increased adhesion after cytokine stimulation. We also conducted coculture experiments with U937 and PCC and measured the release of pig and human cytokines. Stimulated PCC secreted IL-6 and IL-8, whereas U937 secreted IL-8 in response to PCC. Finally, coculture of PCC with Jurkat in the presence of PHA led to a marked Jurkat activation as determined by the increase in IL-2 secretion. This process was dramatically reduced by blocking pig CD86. In summary, CD86 and VCAM-1 on pig chondrocytes may be important triggers of the xenogeneic cellular immune response. These molecules together with TNF could be considered potential targets for intervention in order to develop xenogeneic therapies for cartilage repair.

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Human Monocytes Recognize Porcine Endothelium via the Interaction of Galectin 3 and α-GAL

Cited by 59 publications

References 38 publications

Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Macrophages prevent human red blood cell reconstitution in immunodeficient mice

TNF, Pig CD86, and VCAM-1 Identified as Potential Targets for Intervention in Xenotransplantation of Pig Chondrocytes

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