(J-372) Remote Scaffold Implants Identify Biomarkers of Transplant Rejection by Graft Recipient Sex

Introduction:: Surveillance of the health of a graft in solid organ transplant requires invasive biopsying of the organ in question. Non-invasive methods, such as the Allomap and Allosure blood-based assays, have poor predictive value and limitations in detecting rejection in early stages where therapeutic intervention is possible. “Females account for one third of the SOT recipient's cohort but they have higher survival than males after liver and kidney transplant. [...] While further research is warranted, our findings should encourage clinicians and researchers to consider sex as a factor in their attempts to optimize the management of transplant patients.” (Tejada et al., 2022).We have developed a biomaterial implant that acts as a synthetic immunological niche, providing a remote, non-invasive site to biopsy for analysis of allograft health. We hypothesized that the subcutaneous scaffold implants can capture predictive biomarkers of graft rejection which are differently expressed between male and female graft recipients.

Materials and Methods:: Within this implanted porous scaffold, immune cells accumulate, providing phenotypic information regarding the immune system’s response to non-self. Scaffold implants were serially explanted from skin and heart transplant recipient mice and analyzed using RNA sequencing (Fig 1A, 1B). Elastic net regression and gene set variation analysis compared the stages of rejection between cohorts of male and female transplant recipients to identify novel biomarkers of acute allograft rejection with sex as a biological variable.

Results, Conclusions, and Discussions:: In scaffold implants during pre-symptomatic and symptomatic graft rejection, our elastic net algorithm identified 20 gene expression indicators of rejection (Fig 1D). Principal component clustering in R allowed for the visualization of clear separation between the genetic indicators of the basis of the multiple stages of rejection as well as graft recipient sex (Fig 1C).

In solid organ transplant, genetic variation between indicators of rejection on the basis of sex also provides for helpful analysis in how hospitals may test for rejection of an organ graft. Knowledge of sex-based genetic indicators of early organ rejection may provide information regarding the function of immune genes on the X and Y chromosomes. Furthermore, the identification of sex-specific genes as a predictive factor for organ rejection will allow for the specialization of therapeutic intervention on the basis of sex for more tremendous success in maintaining transplant health. With a narrowed list of genetic indicators, affordable testing for such complications could be increasingly available, providing a window for potential therapeutic intervention. Remotely implanted scaffolds provide a means to gather genetic information regarding the body’s immune state and evaluate how the body is responding to organ transplant, allowing for this necessary early detection.

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References (Optional): : Tejada S, Martinez-Reviejo R, Nogueira TA, Gómez A, Pont T, Liao X, Zhang Z, Manuel O, Rello J. The effect of sex inequality on solid organ transplantation: A systematic review and meta-analysis. Eur J Intern Med. 2023 Mar;109:58-67. doi: 10.1016/j.ejim.2022.12.009. Epub 2022 Dec 28. PMID: 36585321.