PROJECT SUMMARY
Solid organ transplantation (SOT) has transformed the survival and quality of life of patients with end-stage
organ failure. In 2019, 39,719 transplant surgeries were conducted in the US. However, allograft rejection
represents a significant cause of morbidity with an estimated 25-50% of transplant recipients experiencing some
of form of acute or chronic cellular rejection. Effective immunosuppression management is therefore essential to
improve organ transplant recipient outcomes. Clinically used immunosuppression regimens are overall effective
in reducing rejection, but come with potentially life threatening side effects including cardiotoxicity, nephrotoxicity
and diabetes.
Regulatory T cell (Treg) infusion, alongside SOT, is an emerging strategy which focuses on rebalancing the
Treg ratio in the transplanted organ to prevent rejection or loss. However, developing effective therapeutics using
live cells necessitates means to determine their in vivo biodistribution, persistence, and efficacy after
administration. Clinicians do not know the fate of injected cells, thus, interpreting cases of non-responding
patients remains a barrier to wider use. We posit that developing imaging-guided biomarker-based therapeutic
approaches capable of visualizing Treg homing to tissue targets in vivo would be invaluable for assessing of
expected therapeutic activity following infusion.
Magnetic resonance imaging (MRI) is the only technique that is radiation-free, clinically translatable, and
enables direct visualization of labeled cells in vivo. Due to the clinical translation potential, MRI applications and
contrast agent development continue to see remarkable growth, especially in the cell tracking sphere. Labeling
generally occurs by co-incubation with iron oxide or fluorinated moieties in vitro, resulting in internalization of the
contrast agent. Safe and efficient labeling of non-phagocytic cell types, such as T cells, remains challenging and
often requires use of transfection agents, which are not U.S. FDA approved. Indeed, increased cell manipulations
exacerbate the risk of cell contamination, transformation and viability impairment.
Here, we propose a fundamentally different approach. The microbeads used in the process of T cell
purification from human blood leukapheresis will directly label the target cells, producing proton contrast. This
new labeling approach, recently published and patented by our lab with CD25 microbeads, does not involve any
additional manipulation compared to clinical T cell isolation protocols. Our goal is to develop a one-stop-shop
Treg labeling protocol with cell sorting microbeads to track Treg distribution and homing for clinical applications.
If successful, this project will address the clinical bottleneck of in vivo cell surveillance, providing rapid and
quantitative methods to tailor specific treatment regimens to individual patients and improve overall outcomes
by preventing potentially life-threatening toxicities.
