**2. History of allogeneic islet transplantation**

The idea of isolating islets of Langerhans using collagenase was originally published in 1965 [5]. With this method, Guinea pig pancreas was minced and digested with collagenase resulting in obtaining isolated islets. Washington University group introduced the intra-ductal injection method to improve the islet isolation method [6]. In fact, the Washington University group demonstrated that the first successful reversal of diabetes by islet isolation using diabetic rat model [7]. An important innovation was reported by the Stanford University group. They inject collagenase into pancreatic duct resulting in adequate islets for transplantation from a single donor using a canine model [8]. This method enables to initiate the first clinical trial of allogeneic islet transplantation at the University of Minnesota.

The first clinical trial of allogeneic islet transplantation was performed in 1970s' at the University of Minnesota (**Table 1**), however, did not achieve improving metabolic control [9, 10, 21]. The first successful allogeneic islet transplantation into type 1 diabetic patients was reported by Zurich University group (**Table 1**) [10]. In this first successful case, the patient received simultaneous kidney and islet transplantation, and islets were transplanted into a spleen. The patient achieved insulin independence 8 months after transplantation and maintained it for 10 months. Notably, the age of the donor was 2 years old, and islets from young donor can be suitable for islet transplantation. However, the patient suffered



#### **Table 1.**

*History of islet transplantation.*

rejection and died after one month of rejection. Intrasplenic pancreatic islets were detected in the necrotic specimens.

A turning point for clinical islet transplantation was the introduction of the automated method of pancreas dissociation by Camillo Ricordi (**Table 1**) [11]. This method consists of a mechanically enhanced enzymatic digestion based on a dissociation-filter chamber (Ricordi chamber) allowing islets freed from gland to be removed promptly from the system to avoid over-digestion while preserving cluster integrity. This method is called Ricordi method. Washington University group performed a clinical trial of islet transplantation for three type 1 diabetic patient using the Ricordi method, however, all patients lost graft function [22].

The first series of sustained insulin independence following islet transplantation with Ricordi method was achieved for the patients after excision of liver and pancreas, and transplant of allogeneic liver and islet from the same cadaveric donors (**Table 1**) [12]. In these cases, 6 out of 10 patients achieved insulin independence for 5 to more than 16 months [23]. The group also conducted the combined liver-islet allograft transplantation for 4 patients with cirrhosis and diabetes, and the combined kidney and islet transplantation for 7 patients with end-stage renal disease due to type 1 diabetes [23]. None of the patients achieved insulin independence although islet graft function was confirmed.

In 1990, Washington University group reported the first case of insulin independence after purified allogeneic islet transplantation for the treatment of type 1 diabetes [24]. Since then insulin independence after islet transplantation was reported by other centers.

In 1994, Justus-Liebig University reported 30% insulin independence after allogenic islet transplantation [25], in 1997, the San Raffaele Institute reported 45% insulin independence after allogeneic islet transplantation [26].

The Islet Transplant Registry reported the outcomes of 267 allogeneic islet transplantation cases from several centers from 1990 until 2001 [27]. Insulin independence rate was 12.4% for periods greater than one week and 8.2% for greater than one year.
