Essential Role of PDL1 Expression on Nonhematopoietic Donor Cells in Acquired Tolerance to Vascularized Cardiac Allografts

Riella, Leonardo V.; Watanabe, Toshihiko; Sage, Peter T.; Yang, Jun; Yeung, Melissa Y.; Azzi, Jamil; Vanguri, Vijay K.; Chandraker, Anil; Sharpe, Arlene H.; Sayegh, Mohamed H.; Najafian, Nader

doi:10.1111/j.1600-6143.2011.03451.x

Cited by 62 publications

(63 citation statements)

References 23 publications

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“…In previous studies, PD-L1 chimeric mice that expressed PD-L1 only on hematopoietic cells of the heart showed an accelerated, early graft rejection after heart transplantation, whereas the expression of PD-L1 on non-hematopoietic cells of the heart led to a delayed rejection. These data indicate that PD-L1 expression on nonhematopoietic cells plays a significant role in regulating transplantation immune responses [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Expression of coinhibitory PD-L1 on CD4+CD25+FOXP3+ regulatory T cells is elevated in patients with acute coronary syndrome

Li¹,

Chen²,

Yan³

et al. 2015

Coronary Artery Disease

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Section: Discussionmentioning

confidence: 99%

Expression of coinhibitory PD-L1 on CD4+CD25+FOXP3+ regulatory T cells is elevated in patients with acute coronary syndrome

Li¹,

Chen²,

Yan³

et al. 2015

Coronary Artery Disease

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“…Donor tissue expression of PD-L1 provides protection against host T cell responses in cardiac and kidney allografts (34)(35)(36). More recently, Saha et al (15) reported that PD-L1 expression in host tissues played an important role in the suppression of acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Fujiwara

Maeda

Kobayashi

et al. 2014

The Journal of Immunology

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Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2d) donor to BALB/c (H-2d) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti–PD-1, anti–PD-L1, or anti–PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17+IFN-γ+ T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17+IFN-γ+ T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1−/− recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

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“…In another report, Wang et al determined that the inhibition of mTOR reduces the ability of EC to interact with effector T cells and is associated with reduced T cell recruitment [56]. Thus, intracellular signals, molecular events and/or soluble factors regulate the immunogenicity of EC and have potential to shape the intragraft microenvironment to promote local immunoregulation and sustain alloimmune tolerance [65]. …”

Section: Immunogenic Function Of Microvascular Endothelial Cells As Amentioning

confidence: 99%

The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance

Wedel

Nakayama

Kochupurakkal

et al. 2017

Current Opinion in Organ Transplantation

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Purpose of review Chronic rejection is associated with persistent mononuclear cell recruitment, endothelial activation and proliferation, local tissue hypoxia and related biology that enhance effector immune responses. Despite similarities, the tumor microenvironment elicits signals/factors that inhibit effector T cell responses and promote local immunoregulation. The identification of immunoregulatory check points and/or secreted factors that are deficient within allografts is of great importance in the understanding and prevention of chronic rejection. Recent findings The relative expression of immunomodulatory molecules (cell surface and secreted) on microvascular endothelial cells are deficient within rejecting allografts, and this deficiency is of functional importance in shaping the phenotype of rejection. Furthermore, the expression of co-inhibitory molecules/factors that enhance local immunoregulation are modulated, and the identification of intracellular regulatory signals or secreted factors are the subject of ongoing research. For example, semaphorins may interact with endothelial cells and regulatory T cells to promote local tolerance. Additionally, metabolites and electrolytes within the allograft microenvironment may regulate local effector and regulatory cell responses. Summary Multiple factors within allografts shape the microenvironment either towards local immunoregulation or proinflammation. Promoting the expression of intragraft cell surface or secreted molecules that support immunoregulation will be critical for long-term graft survival and/or alloimmune tolerance.

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Essential Role of PDL1 Expression on Nonhematopoietic Donor Cells in Acquired Tolerance to Vascularized Cardiac Allografts

Cited by 62 publications

References 23 publications

Expression of coinhibitory PD-L1 on CD4+CD25+FOXP3+ regulatory T cells is elevated in patients with acute coronary syndrome

Expression of coinhibitory PD-L1 on CD4+CD25+FOXP3+ regulatory T cells is elevated in patients with acute coronary syndrome

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance

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