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Blocking MHC class II on human endothelium mitigates acute rejection
Parwiz Abrahimi, … , W. Mark Saltzman, Jordan S. Pober
Parwiz Abrahimi, … , W. Mark Saltzman, Jordan S. Pober
Published January 21, 2016
Citation Information: JCI Insight. 2016;1(1):e85293. https://doi.org/10.1172/jci.insight.85293.
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Research Article Immunology Transplantation

Blocking MHC class II on human endothelium mitigates acute rejection

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Abstract

Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell–mediated destruction in vivo. We conclude that human CD8+ TEM–mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules.

Authors

Parwiz Abrahimi, Lingfeng Qin, William G. Chang, Alfred L.M. Bothwell, George Tellides, W. Mark Saltzman, Jordan S. Pober

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Figure 1

HLA-DR blockade reduces acute T cell–mediated injury to implanted allogeneic vessel segments in vivo.

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HLA-DR blockade reduces acute T cell–mediated injury to implanted alloge...
(A and B) In an MHC-mismatched model of arterial rejection by allogeneic T cells (n = 6 per group), blockade of class II MHC by anti–HLA-DRα F(ab)′2 fragment reduces intimal area expansion and increases lumen area as measured by H&E and EVG staining (scale bar: 50 μm) (A) and reduces disruption of EC lining the vessel lumen, a hallmark of intimal arteritis/endothelialitis, as measured by percent of circumferential coverage (scale bar: 20 μm) (B), both at 21 days. Arrows indicate areas of intact endothelial lining. *P < 0.05, 2-tailed Student’s t test. EVG, Elastia-van Gieson; MHC, major histocompatibility complex; EC, endothelial cells.

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