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Imaging alloreactive T cells provides early warning of organ transplant rejection
Toshihito Hirai, … , Robert S. Negrin, Sanjiv S. Gambhir
Toshihito Hirai, … , Robert S. Negrin, Sanjiv S. Gambhir
Published July 8, 2021
Citation Information: JCI Insight. ;6(13):e145360. https://doi.org/10.1172/jci.insight.145360.
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Resource and Technical Advance Immunology Transplantation

Imaging alloreactive T cells provides early warning of organ transplant rejection

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Abstract

Diagnosis of organ transplant rejection relies upon biopsy approaches to confirm alloreactive T cell infiltration in the graft. Immune molecular monitoring is under investigation to screen for rejection, though these techniques have suffered from low specificity and lack of spatial information. ImmunoPET utilizing antibodies conjugated to radioisotopes has the potential to improve early and accurate detection of graft rejection. ImmunoPET is capable of noninvasively visualizing the dynamic distribution of cells expressing specific immune markers in the entire body over time. In this work, we identify and characterize OX40 as a surrogate biomarker for alloreactive T cells in organ transplant rejection and monitor its expression by utilizing immunoPET. In a dual murine heart transplant model that has both syngeneic and allogeneic hearts engrafted in bilateral ear pinna on the recipients, OX40 immunoPET clearly depicted alloreactive T cells in the allograft and draining lymph node that were not observed in their respective isograft counterparts. OX40 immunoPET signals also reflected the subject’s immunosuppression level with tacrolimus in this study. OX40 immunoPET is a promising approach that may bridge molecular monitoring and morphological assessment for improved transplant rejection diagnosis.

Authors

Toshihito Hirai, Aaron T. Mayer, Tomomi W. Nobashi, Po-Yu Lin, Zunyu Xiao, Tomokatsu Udagawa, Kinya Seo, Federico Simonetta, Jeanette Baker, Alan G. Cheng, Robert S. Negrin, Sanjiv S. Gambhir

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Figure 3

Imaging OX40 T cells detects allograft rejection prior to organ failure.

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Imaging OX40 T cells detects allograft rejection prior to organ failure....
(A) An image atlas and guide for interpreting OX40 PET/CT scans of BALB/c mice bearing ear pinna cardiac grafts from C57BL/6 (allo, right ear) or BALB/c (iso, left ear). Three-dimensional images were reconstructed, and regions of interest (ROIs) were drawn as indicated utilizing coronal, axial, and sagittal cross sections as anatomical guides. (B) Top: imaging schedule for transplant recipients. Middle: zoomed-in view of 3D volume rendered images (VRT) of a representative mouse bearing cardiac allografts (right ear) and isografts (left ear) at d6, d9, and d12 after transplantation. Scale bar represents OX40 PET signal intensity. Bottom: whole body images of the same respective mouse at various time points. Images are representative of n = 7 mice from 2 independent experiments. (C) Heatmap visualization of normalized max % injected dose per gram (%ID/g) OX40 PET tracer uptake values in each ROI at d6, d9 and d12 (rows) from transplant recipients (columns). (D) Correlation of %ID/g at each ROI versus ex vivo measurements of the same respective organs utilizing a gamma counter. Color and circle size provide a graphical representation of Pearson’s correlation value. H, native heart; A, allograft; L, liver; M, muscle; Is, isograft; S, spleen; aLN, allo dLN; iLN, iso dLN. (E and F) Comparison of %ID/g uptake calculated from image ROIs for allo- and isografts (E) or allo- and iso-dLNs (F) at d6, 9 and 12. Significant increase in uptake is shown in allograft and allo-dLN on d9 and d12. (G) Receiver operator characteristic (ROC) curve depicting specificity and sensitivity of OX40 PET signal-based determination of engraftment or rejection of transplant at various time points. Predictor ([graft %ID/g]2 + [dLN %ID/g]2); n = 14. *P < 0.05, ****P < 0.0001. Calculated with unpaired 2-tailed Student’s t test.

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