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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 5

OX40 imaging enables specific and sensitive measurement of immunosuppression in allograft recipients.

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OX40 imaging enables specific and sensitive measurement of immunosuppres...
(A) Representative OX40 or isotype (Iso) control PET/CT images of vehicle-treated (PBS) or immunosuppressed (Fk) mice bearing a single allograft (left ear) at d9 after transplantation; n = 5 per group. Data are from 2 independent experiments. CLN, cervical lymph node. (B) Heatmap of max %ID/g in regions of interest (rows) in allograft recipients (columns) from PBS or Fk cohorts at d9. (C and D) Comparison of %ID/g (C) or %ID/g normalized (D) by blood background value in the allograft, allo-draining CLN, and non-allo-draining CLN between PBS and fk groups at d9. (E) Principal component analysis identifies Fk-treated mice from PBS mice. Each dot represents an individual mouse (left). Each line represents key drivers of the delineation (right). L ear, left ear (allograft); L cer, left CLN. (F) Correlation of %ID/g in each ROI versus: left-top, %ID/g of the same respective organs measured ex vivo by a gamma counter; left-bottom, example plot for Liver ROI; middle-top, number of each cell population in allo-CLN; middle-bottom, example plot depicting %ID/g correlation with target OX40 and nontarget FoxP3 frequency measured via FACS; right-top, allograft bioluminescent signals; and right-bottom, example of the correlation of PET Graft + all-CLN ROI values with BLI signal, and PET muscle ROI values with BLI signal. Color and circle size provide a graphical representation of Pearson’s correlation value. (G) Time course plots of average %ID/g for PBS or Fk mice in allograft (left) and in draining CLN (right). (H) ROC curve depicting specificity and sensitivity for determination of PBS or Fk mouse at various time points by the sum of %ID/g values from allograft and allo-CLN; n = 10. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. Calculated with unpaired Student’s t test.

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