Clinical Islet Xenotransplantation
How Close Are We?
- Dirk J. van der Windt1,
- Rita Bottino1,2,
- Goutham Kumar1,
- Martin Wijkstrom1,
- Hidetaka Hara1,
- Mohamed Ezzelarab1,
- Burcin Ekser1,3,
- Carol Phelps4,
- Noriko Murase1,
- Anna Casu5,
- David Ayares4,
- Fadi G. Lakkis1,6,
- Massimo Trucco2 and
- David K.C. Cooper1⇓
- 1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- 2Division of Immunogenetics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- 3Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy
- 4Revivicor, Inc., Blacksburg, Virginia
- 5Diabetes Unit, Department of Medicine, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), Palermo, Italy
- 6Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
- Corresponding author: David K.C. Cooper, .
D.J.v.d.W. and R.B. contributed equally to this study.
Type 1 diabetes (T1D) is a major health problem throughout the world. In the U.S., it is estimated that about 1.5 million people suffer from T1D. Even when well controlled—by frequent monitoring of blood glucose and administration of insulin, the long-term complications of the disease are significant and include cardiovascular disease, nephropathy, retinopathy, and neuropathy (1). Here we review recent progress in preclinical models of pig islet xenotransplantation and discuss the remaining challenges that need to be addressed before the application of this form of therapy can be established in patients with T1D.
During the past decade, islet allotransplantation alone (without previous kidney transplantation) using deceased human donor pancreata has been indicated mainly in patients who have had T1D for >5 years with life-threatening hypoglycemic episodes and wide fluctuations in blood glucose levels. Although the initial long-term results were rather disappointing (2), the results of islet allotransplantation have improved significantly in recent years, with 5-year insulin-independent normoglycemia achieved in >50% of patients at experienced centers (3). There is increasing evidence that successful islet allotransplantation greatly reduces the incidence of hypoglycemic episodes (2) and reduces or slows the incidence of late complications of T1D (4). This may extend the indications for islet transplantation to patients with progressive complications. For example, islet transplantation in a patient with preterminal renal failure may prevent disease progression, possibly avoiding the need for hemodialysis and kidney transplantation, provided that nonnephrotoxic immunosuppressive drug therapy is administered.
Currently, in the U.S., the median waiting time for a kidney allograft from a deceased human donor is >4 years (5). However, islets from two deceased human donor pancreata are frequently required to achieve normoglycemia in a diabetic patient. Because of the limited number of suitable deceased donor pancreata, the overall number of …