A University of Pittsburgh researcher has implicated a transcription factor in the function and maintenance of tissue-resident memory T (TRM) cells which are known to contribute to solid organ transplant rejection and other immune mediated conditions. ErbB3 binding protein 1 (EBP1) is uniquely upregulated in graft-infiltrating TRM cells. A small molecule, WS6, can inhibit EBP1, depleting TRM cells thus preventing organ transplant rejection and failure. WS6 could be a new treatment for transplant patients suffering from immunosuppression resistant T cell mediated rejection and reducing the overall risk of developing transplant rejection.
Description
Following an organ transplant most patients require life-long treatment with immunosuppressing medication to prevent rejection of the donor organ. The treatment regimen can have numerous adverse effects including an increased risk of infections, and cardiovascular and gastrointestinal conditions. Even with immunosuppressing treatment, organ rejection can still occur and there remains a pressing clinical need to develop safer and more effective treatments to prevent organ rejection and improve patient outcomes. Chronic rejection can occur over time due to infiltration of T cells migrating to transplanted organs followed by upregulation of EBP1 in the TRM subset of these infiltrating T cells which proliferate in the graft and can drive T cell mediated rejection (TCMR). The understanding of the role of EBP1 can be harnessed to control TRM cell function and maintenance. Using an inhibitor, WS6, active TRM cells are selectively depleted without affecting other T cells and could be a novel approach to prevent organ transplant rejection.
Applications
• Solid organ anti-rejection therapy
• Non-responders to immunosuppression therapy
Advantages
Current therapies to prevent organ rejection have well documented adverse effects. Chronic solid organ transplant rejection is a clinical challenge, and no therapy currently exists to treat immunosuppression resistant T cell mediated rejection.
This novel approach is designed to target TRM cells, by selectively interfering with the role of a transcription factor that is essential to their function and maintenance. WS6 can selectively inhibit EBP1 function and deplete rejection driving TRM cells without affecting other T cells, reducing impact on the rest of the immune system.
Invention Readiness
In a mouse model of kidney allograft rejection, almost all alloantigen-specific CD8+ T cells which infiltrate the graft acquire a cell surface and transcriptional TRM phenotype. These TRM cells do not recirculate, are maintained locally, and drive rejection. Treatment of kidney allograft recipient mice daily with WS6 at a low dose changed the phenotype of these TRM cells with decreased expression of CD69, a known TRM and T cell activation marker. At higher doses, WS6 can deplete alloantigen-specific TRM cells while not impacting other T cells. High dose WS6 treatment significantly improves the survival of fully mismatched heart allografts despite treatment with only two doses of co-stimulation blockade. Fully mismatched kidney transplant survival mouse experiments are underway. WS6 offers the promise of an antirejection medication particularly for patients who do not respond to current treatments.
IP Status
Patent Pending
