The prevalence of type 1 diabetes mellitus (T1D) increased by 30% in the United States from 2017- 2020. Diabetes increases the incidence of ESRD, with the 30-year cumulative incidence ranging from 3.3% to 7.8% among diabetic patients. Transplantation of allogeneic islets is radical therapy for T1D. Although much progress has been made over the past 10 years in free islet transplantation (Tx) with the Edmonton protocol, this procedure has required pooling of islets from multiple deceased donor pancreas grafts to achieve insulin independence. Moreover, while recent advances in immunosuppressive protocols have improved results of islet Tx, availability of allogeneic islets remains a major obstacle to progress in allogeneic islet transplantation. Deceased pancreas donation is less common than liver or kidney donation, but even a dramatic scale-up of deceased human donor pancreas donation would not be able to provide sufficient islets for the treatment of all patients who could benefit from allogeneic islet transplantation.
Xenotransplantation is becoming a more realistic strategy for solving the organ shortage crisis, due in large part to significant advances in porcine gene editing to correct species incompatibilities. Using recent gene-editing technologies, xenotransplantation from multi-transgenic, including alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of xenograft survival, ranging from days to greater than 6 months for islets, 1 year for life-supporting kidneys and >2 years in a heterotopic non-life-supporting cardiac xenograft model. However, it is not clear which gene manipulations are essential for successful xenogeneic islet transplantation, leading to uncertainty about which animals should be used. Additionally, although > 6 months survival of porcine islets in non-human primate models were reported in 2006, continuous administration of multiple immunosuppressive drugs was required and recipients typically succumbed to infection associated with chronic immunosuppression. Even if patients become insulin-independent following porcine islet transplantation, they will have to take multiple, life-long, immunosuppressive medications, as attempts to taper immunosuppression have been unsuccessful in xeno islet transplantation in preclinical models. These facts provide a compelling rationale to pursue a clinically applicable strategy for the induction of tolerance.
New York University’s recent description of 54-hour survival of renal xenograft in a brain death patient renewed public excitement about the prospect of xenotransplantation. Given popular enthusiasm for xenotransplantation in the context of recent scientific advances, this review aims to summarize experimental data to understand the current status of both immunologic and regulatory barriers to clinical islet xenotransplantation.
We welcome the submissions of Review, Methods, and Original Research articles on the following, and related, subtopics:
- Advantage of xenogeneic islets over allogeneic islet transplantation
- Regulation of xenotransplantation to clinical trials
- Ethical issues in xenotransplantation
- Recent advance in gene editing for xenotransplantation
- Porcine islet isolation – procedures and tips
- Assessment of porcine islets in vivo and in vitro
- Xeno islet transplantation preclinical studies
- Immune modulation strategy for acceptance of allogeneic and xenogeneic islet transplantation
- Immune tolerance strategy to xenogeneic islet transplantation – small animal model and preclinical model
- Other advanced strategies to cure T1D
The prevalence of type 1 diabetes mellitus (T1D) increased by 30% in the United States from 2017- 2020. Diabetes increases the incidence of ESRD, with the 30-year cumulative incidence ranging from 3.3% to 7.8% among diabetic patients. Transplantation of allogeneic islets is radical therapy for T1D. Although much progress has been made over the past 10 years in free islet transplantation (Tx) with the Edmonton protocol, this procedure has required pooling of islets from multiple deceased donor pancreas grafts to achieve insulin independence. Moreover, while recent advances in immunosuppressive protocols have improved results of islet Tx, availability of allogeneic islets remains a major obstacle to progress in allogeneic islet transplantation. Deceased pancreas donation is less common than liver or kidney donation, but even a dramatic scale-up of deceased human donor pancreas donation would not be able to provide sufficient islets for the treatment of all patients who could benefit from allogeneic islet transplantation.
Xenotransplantation is becoming a more realistic strategy for solving the organ shortage crisis, due in large part to significant advances in porcine gene editing to correct species incompatibilities. Using recent gene-editing technologies, xenotransplantation from multi-transgenic, including alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of xenograft survival, ranging from days to greater than 6 months for islets, 1 year for life-supporting kidneys and >2 years in a heterotopic non-life-supporting cardiac xenograft model. However, it is not clear which gene manipulations are essential for successful xenogeneic islet transplantation, leading to uncertainty about which animals should be used. Additionally, although > 6 months survival of porcine islets in non-human primate models were reported in 2006, continuous administration of multiple immunosuppressive drugs was required and recipients typically succumbed to infection associated with chronic immunosuppression. Even if patients become insulin-independent following porcine islet transplantation, they will have to take multiple, life-long, immunosuppressive medications, as attempts to taper immunosuppression have been unsuccessful in xeno islet transplantation in preclinical models. These facts provide a compelling rationale to pursue a clinically applicable strategy for the induction of tolerance.
New York University’s recent description of 54-hour survival of renal xenograft in a brain death patient renewed public excitement about the prospect of xenotransplantation. Given popular enthusiasm for xenotransplantation in the context of recent scientific advances, this review aims to summarize experimental data to understand the current status of both immunologic and regulatory barriers to clinical islet xenotransplantation.
We welcome the submissions of Review, Methods, and Original Research articles on the following, and related, subtopics:
- Advantage of xenogeneic islets over allogeneic islet transplantation
- Regulation of xenotransplantation to clinical trials
- Ethical issues in xenotransplantation
- Recent advance in gene editing for xenotransplantation
- Porcine islet isolation – procedures and tips
- Assessment of porcine islets in vivo and in vitro
- Xeno islet transplantation preclinical studies
- Immune modulation strategy for acceptance of allogeneic and xenogeneic islet transplantation
- Immune tolerance strategy to xenogeneic islet transplantation – small animal model and preclinical model
- Other advanced strategies to cure T1D
