Absence of P-Selectin in Recipients of Allogeneic Bone Marrow Transplantation Ameliorates Experimental Graft-versus-Host Disease

Lu, Sydney X.; Holland, Aliya; Na, Il‐Kang; Terwey, Theis H.; Alpdoğan, Önder; Bautista, Jhoanne L.; Smith, Odette M.; Suh, David; King, C. H.; Kochman, Adam A.; Hubbard, Vanessa M.; Rao, Uttam K.; Yim, Nury; Liu, Chen; Laga, Alvaro C.; Murphy, Gëorge F.; Jenq, Robert R.; Zakrzewski, Johannes L.; Penack, Olaf; Dykstra, Lindsay; Bampoe, Kevin; Perez, Lia; Furie, Bruce; Furie, Barbara C.; Brink, Marcel R.M. van den

doi:10.4049/jimmunol.0903148

Cited by 22 publications

(30 citation statements)

References 31 publications

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“…Likewise, ameliorated aGVHD was observed in P-selectin-deficient mice, which underscores the importance of the interaction between P-selectin and its ligands that are highly expressed on migrating effector T cells [13]. In our experiments we also found significantly higher α4β7 integrin and P-selectin ligand expression on migrating allogeneic T cells than in syngeneic controls.…”

Section: Resultssupporting

confidence: 82%

“…The tissues of syngeneic controls displayed only mild T cell infiltrates and no tissue damage at this time (see Additional file 2A,B). As aGVHD target organ infiltration depends on the appropriate cellular homing receptors [3] we considered whether alloreactive T cells could be more precisely characterized by the expression of the homing receptors α4β7 integrin and P-selectin ligand, implicated in intestinal and skin aGVHD manifestation, respectively [12,13]. Therefore, we examined the dynamic changes in their expression daily after HCT to test a possible correlation between their upregulation and the identified phase of massive cell migration (Figure 2C,D).…”

Section: Resultsmentioning

confidence: 99%

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A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

Bäuerlein

Riedel

Baker

et al. 2013

BMC Med

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BackgroundAcute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.MethodsMurine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.ResultsWe identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.ConclusionsBased on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

Bäuerlein

Riedel

Baker

et al. 2013

BMC Med

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“…NK cells, neutrophils, monocytes and T cells utilize selectins to adhere to endothelium and transmigrate from the blood into tissue (83-86). Donor specific MHC I antibodies cause platelet activation in skin allograft recipients (80), and attachment of platelets to endothelium can support monocyte tethering through P-selectin (87).…”

Section: Discussionmentioning

confidence: 99%

Blockade of P-Selectin Is Sufficient to Reduce MHC I Antibody-Elicited Monocyte Recruitment In Vitro and In Vivo

Valenzuela

Shen

et al. 2013

American Journal of Transplantation

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Donor specific HLA antibodies significantly lower allograft survival, but as yet there are no satisfactory therapies for prevention of antibody-mediated rejection. Intracapillary macrophage infiltration is a hallmark of antibody-mediated rejection, and macrophages are important in both acute and chronic rejection. The purpose of this study was to investigate the Fc-independent effect of HLA I antibodies on endothelial cell activation, leading to monocyte recruitment. We used an in vitro model to assess monocyte binding to endothelial cells in response to HLA I antibodies. We confirmed our results in a mouse model of antibody-mediated rejection, in which B6.RAG1-/- recipients of BALB/c cardiac allografts were passively transferred with donor specific MHC I antibodies. Our findings demonstrate that HLA I antibodies rapidly increase intracellular calcium and endothelial presentation of P-selectin, which supports monocyte binding. In the experimental model, donor specific MHC I antibodies significantly increased macrophage accumulation in the allograft. Concurrent administration of rPSGL-1-Ig abolished antibody-induced monocyte infiltration in the allograft, but had little effect on antibody-induced endothelial injury. Our data suggest that antagonism of P-selectin may ameliorate accumulation of macrophages in the allograft during antibody-mediated rejection.

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“…106 P-selectin-deficient recipients exhibit decreased GVHD of the skin, liver and small bowel, associated with diminished infiltration of alloactivated T-cells into the Peyer’s patches and small bowel, and increased donor T-cells in the spleen and secondary lymphoid organs. 107 Blockade of selectin/ligand interactions can be used for homing inhibition of alloreactive T-cells, although concerns have been raised about the deleterious effects on wound healing and protection against infection.…”

Section: Targeting T-cell Homingmentioning

confidence: 99%

Advances in graft-versus-host disease biology and therapy

2012

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Preface Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of both donor and host adaptive and innate immune stimulatory and immune suppressive factors that influence GVHD pathogenesis. New insights in basic immunology, preclinical models and clinical studies have led to novel prevention or treatment approaches. This review highlights recent advances in GVHD pathophysiology and its treatment with a focus on immune system manipulations that are amenable to clinical application.

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Absence of P-Selectin in Recipients of Allogeneic Bone Marrow Transplantation Ameliorates Experimental Graft-versus-Host Disease

Abstract: Material Supplementary 8.DC1http://www.jimmunol.org/content/suppl/2010/07/06/jimmunol.090314

Cited by 22 publications

References 31 publications

A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

Blockade of P-Selectin Is Sufficient to Reduce MHC I Antibody-Elicited Monocyte Recruitment In Vitro and In Vivo

Advances in graft-versus-host disease biology and therapy

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