Novel Therapy to Prevent Transplanted Organ Rejection (DCreg)
University of Pittsburgh and IRCCS ISMETT in Italy have developed a novel therapy to prevent allograft rejection. The therapy, dendritic cells with a regulatory function (DCreg), is derived from a deceased donor’s liver perfusate and can reduce the need to administer immunosuppressive treatments in organ recipients, normally required to prevent organ rejection. These DCregs can adapt the immune system of organ recipients and could be an alternative to the lifelong need for transplant patients to take immunosuppressants (IS), leading to reduced adverse effects associated with IS and lower lifelong healthcare costs.
Description
Dendritic cells (DC) are antigen-presenting cells that can activate T cells and induce immunological tolerance. DCregs can suppress effector T cell response and could play an important role in regulating a transplant recipient’s response to a donated organ. Given the known risks of lifelong IS therapy in organ recipients include increased risks of infection, some cancers, and heart and kidney issues, there is a need to develop novel effective treatments to prevent organ rejection, and with less adverse effects. DCregs could be a novel approach to wean patients off IS therapy, improve donated organ tolerance and prevent organ rejection.Applications
• Anti-rejection therapy following solid organ transplantation• Autoimmune disease
• Vascularized Composite Allograft (VCA) Transplantation
• Cell Therapy Product to induce immune tolerance
Advantages
• Enables Immunosuppression Withdrawal• Reduces Side Effects
• Utilizes a Novel Cell Source
• High-Purity Product
• Inhibits T-cell Proliferation
Invention Readiness
A novel method of producing DCregs using the perforate of livers from deceased donors has been developed. An early phase safety trial infused LDLT patients (n=13) with DCregs derived from donors’ blood prior to transplant. The recipients’ DCs acquired antigens from the donor DCregs within one hour after infusion. DCreg recipients’ T cell subsets also changed suggesting modulated anti-donor immune reactivity following DCreg infusion. One year after transplant, eligible patients were weaned off IS therapy (n=8) and 37.5% of those remained off all IS therapies for over one year. The process has been developed to be compliant with Good Manufacturing Practices. No safety concerns were reported. Further studies would involve clinical trials to evaluate the safety and efficacy of the DCreg administration in human transplant recipients of a larger pool. Uses in other solid organ treatment and autoimmune diseases can be explored.IP Status
https://patents.google.com/patent/WO2024249289A1Related Publication(s)
Hadjiyannis, Y., & Thomson, A. W. (2023). Regulatory dendritic cell therapy in organ transplantation. Current Opinion in Organ Transplantation, 29(2), 121–130. https://doi.org/10.1097/mot.0000000000001127
Tran, L. M., Macedo, C., Zahorchak, A. F., Gu, X., Elinoff, B., Singhi, A. D., Isett, B., Zeevi, A., Sykes, M., Breen, K., Srivastava, A., Ables, E. M., Landsittel, D., Styn, M. A., Humar, A., Lakkis, F. G., Metes, D. M., & Thomson, A. W. (2023). Donor-derived regulatory dendritic cell infusion modulates effector CD8+T cell and NK cell responses after liver transplantation. Science Translational Medicine, 15(717). https://doi.org/10.1126/scitranslmed.adf4287
Zahorchak, A. F., DeRiggi, M. L., Muzzio, J. L., Sutherland, V., Humar, A., Lakkis, F. G., Hsu, Y.-M. S., & Thomson, A. W. (2023). Manufacturing and validation of Good Manufacturing Practice–compliant regulatory dendritic cells for infusion into organ transplant recipients. Cytotherapy, 25(4), 432–441. https://doi.org/10.1016/j.jcyt.2022.11.005