A Strategy to Simultaneously Cure Type 1 Diabetes and Diabetic Nephropathy by Transplant of Composite Islet-Kidney Grafts

Abstract

In recent years islet cell transplant has proven itself to be a viable clinical option for a select group of diabetic patients. Graft loss after transplant however continues to hinder the long-term success of the procedure. Transplanting the islets as a pre-vascularized composite islet-kidney graft has emerged as a relevant solution. Much groundbreaking research has been done utilizing this model in conjunction with strategies aimed towards islet cell survival and prolongation of function in the host. Transplanting the islet cells as a prevascularized graft under the capsule of the donor kidney as a composite islet-kidney graft has been shown to provide long term durable blood glucose control in large animal studies by limiting graft apoptosis as well as providing a physical barrier against the host immune response. While promising, this technique is limited by long term immunosuppression requirements of the host with its well-known adverse sequelae. Research into tolerance inducing strategies of the host to the allogeneic and xenogeneic islet-kidney graft has shown much promise in the avoidance of long-term immunosuppression. In addition, utilizing xenogeneic tissue grafts could provide a near-limitless supply of organs. The islet-kidney model could provide a durable and long-term cure for diabetes. Here we summarize the most recent data, as well as groundbreaking strategies to avoid long term immunosuppression and promote graft acceptance.

Advancements in innate immune regulation strategies in islet transplantation

“…In the non-human primate model, this strategy will not affect the renal function of the donor’s kidney, and it results in better islet function compared to Intraportal transplantation and renal capsule transplantation without prevascularization. Maintaining proper islet function benefits the long-term survival of the donor kidney ( 109 ). Compared with the cotransplantation of islets and MSCs, another popular area of research in recent years is the transplantation of islets into MSC-rich tissues.…”

Applying stem cell therapy in intractable diseases: a narrative review of decades of progress and challenges

“…Due to DM’s high morbidity and mortality, substantial research is done on the treatment and management of DM. The only satisfactory option available for DM patients who are unresponsive to conventional exogenous insulin treatment is to either undergo islet or pancreas cadaveric transplantation ( 126 ). However, this treatment option is challenging due to the shortage of cadaveric donors and the need for life-long immunosuppressants.…”

Establishment of transplantation platform for delivering mouse induced pluripotent stem cell-derived insulin-producing cells (mips-ipcs) for diabetes treatment

“…Current benefits of the cell replacement for diabetes treatment focus on investigating the microenvironment of transplantation sites, including their extracellular matrix content, vascularization and invaded immune cells (Assoc 2006;Mitrousis et al 2018;Pomposelli et al 2021). Nowadays, an increasing amount of research is focusing on engineered biomaterials, promote angiogenesis and protect the graft from the immune system (Mitrousis et al 2018).…”

“…The blood vessel regeneration is formed from the host body and/or additional injection of the vascular endothelial growth factors (VEGFs) (Pepper et al 2015b;Smink and de Vos 2018;Vlahos et al 2021b). Importantly, the success of beta cell transplantation mainly depends on 1) the capacity of tissue volume, amount of IPCs, and velocity of injection, 2) blood vessel networks, 3) the potential of crosstalk between the engraftment place and physiologically systemic circulation in relative manner, 4) facilitate the grafting invasion, 5) minimally reduce the inflammation and attack of immunogenicity, and 6) improve the transplantation survival in the long time (Janowski et al 2013;Yu et al 2020;Pomposelli et al 2021). Accordingly, transplantation into the subcutaneous backside is recommended.…”

“…Notably, the microenvironment of transplantable space is focused on extracellular matrix contents, vascularization, and invaded immune cells (Assoc 2006;Mitrousis et al 2018;Pomposelli et al 2021). In post-transplantation, the host autoimmune cells incidentally attack the beta-cell activity and their longevity (Stabler et al 2019;Roep et al 2021).…”