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.
DCregs derived from the perfusate of livers resected from a deceased donor can be administered to solid organ recipients to reduce the need for immunosuppressive treatment and prevent rejection of donated organs. Immunotolerance is developed through recipient DCs acquiring Major Histocompatibility Complex (MHC) antigens from donor-derived DCregs in a process referred to as “host cell cross-dressing”.
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
Advantages
Recent work indicated an infusion of DCregs derived from donor blood to living donor liver transplant (LDLT) patients could promote organ tolerance. However, transplantations are more likely to originate from deceased donors. This novel approach isolates DCregs from liver perfusate (always removed during organ harvesting and usually discarded), as a richer source of monocytes, precursors to DCregs, than blood. The production of DCregs from deceased donors is novel and could improve the availability of unique anti-rejection treatments to organ recipients who receive tissue from deceased donors.
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. No safety concerns were reported. Work is now required to test DCreg derived from deceased donors to reduce the need for IS therapy in recipients. Work to explore the use of DCregs in other solid organ treatment and autoimmune diseases is also required.
IP Status
https://patents.google.com/patent/WO2024249289A1
