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Bioinformatics, Computational and Systems Biology

Bioinformatics, Computational and Systems Biology - Poster Session E

Poster A2 - State Transition Model of Resistance to Costimulatory Blockade Tolerance Induction in Organ Transplantation Using a Minimally-Invasive Implant

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Solid organ transplants are crucial for many individuals with end-stage organ failure; however, these recipients must undergo lifelong immunosuppressive therapy (IS) to avoid graft rejection, which can lead to substantial side effects. This is especially challenging for young heart transplant recipients who face intense IS for life. Current methods to monitor graft rejection are invasive, costly, and based on delayed tissue damage biomarkers, lacking reliable tests to trend toward tolerance or rejection. Co-stimulatory blockade (CoB) offers promise by disrupting T cell signals to extend allograft survival but fails in clinical trials due to memory T cells (Tmem). These cells quickly respond to foreign antigens, causing CoB resistance and rejection. The Shea lab has created microporous scaffolds implanted under the skin, which become vascularized, promote immune cell infiltration, and allow for longitudinal study. These scaffolds capture immune aspects of diseased tissue to predict rejection or tolerance.

Materials and

Methods:  In this work, we use poly-caprolactone (PCL) scaffolds to monitor the progression of rejection or tolerance in mice receiving CoB and HTx. By sensitizing these mice with varying degrees of donor antigen prior to HTx, we aim to elucidate the role of Tmem and their impact on CoB resistance, as captured by the scaffold. We model the post-transplant transition from immune quiescence to either tolerance or rejection by creating a two-dimensional state space of the transcriptome that represents either tolerance or rejection to predict the trajectory of the immune system in the allograft recipients as a 6th order polynomial of triple well quasipotential.

Results, Conclusions, and Discussions: By modeling the transcriptome as a particle moving along the 2D state-space, we identify the critical points which commit the trajectory of the immune response towards one stable state over the other, i.e. tolerance or rejection, and their associated eigengenes. We show how the transcriptome changes gene expression at various time points over the course of rejection or tolerance and highlight key players that drive tolerance or rejection. We hope that this model can assist physicians in modifying CoB regiments to drive the patient’s allograft towards tolerance while minimizing comorbidities. This approach provides a robust framework for precision tolerance induction and graft monitoring, holding the promise of improving graft acceptance and reducing immunosuppression health complications.

Acknowledgements (Optional):