Intervention Presentation on Diabetes

REVIEW ARTICLE

The state of the art of islet transplantation and cell therapy in type 1 diabetes

Silvia Pellegrini1 • Elisa Cantarelli1 • Valeria Sordi1 • Rita Nano1 • Lorenzo Piemonti1

Received: 15 January 2016 / Accepted: 6 February 2016 / Published online: 29 February 2016

� Springer-Verlag Italia 2016

Abstract In patients with type 1 diabetes (T1D), pan-

creatic b cells are destroyed by a selective autoimmune attack and their replacement with functional insulin-pro-

ducing cells is the only possible cure for this disease. The

field of islet transplantation has evolved significantly from

the breakthrough of the Edmonton Protocol in 2000, since

significant advances in islet isolation and engraftment,

together with improved immunosuppressive strategies,

have been reported. The main limitations, however, remain

the insufficient supply of human tissue and the need for

lifelong immunosuppression therapy. Great effort is then

invested in finding innovative sources of insulin-producing

b cells. One old alternative with new recent perspectives is the use of non-human donor cells, in particular porcine b cells. Also the field of preexisting b cell expansion has advanced, with the development of new human b cell lines. Yet, large-scale production of human insulin-producing

cells from stem cells is the most recent and promising

alternative. In particular, the optimization of in vitro

strategies to differentiate human embryonic stem cells into

mature insulin-secreting b cells has made considerable progress and recently led to the first clinical trial of stem

cell treatment for T1D. Finally, the discovery that it is

possible to derive human induced pluripotent stem cells

from somatic cells has raised the possibility that a sufficient

amount of patient-specific b cells can be derived from patients through cell reprogramming and differentiation,

suggesting that in the future there might be a cell therapy

without immunosuppression.

Keywords b Cell replacement � Islet transplantation � Xenotransplantation � Pluripotent stem cells

Introduction

The International Diabetes Federation (IDF) estimates that

415 million people worldwide have diabetes, a number that

is predicted to increase to 642 million by 2040 (http://

www.diabetesatlas.org). Type 1 diabetes (T1D), a disease

characterized by selective and progressive loss of insulin-

producing b cells caused by an autoimmune-mediated destruction, accounts for approximately 10 % of these

cases. Administration of exogenous insulin, regular blood

glucose monitoring and dietary restrictions are the funda-

mental means of treating hyperglycemia in all patients with

T1D. Although lifesaving, insulin therapy does not restore

the physiological regulation of blood glucose [1] and is not

able to prevent either the dangerous states of hypoglycemia

or long-term complications [2] and the life expectancy of

these patients is still shorter compared to that of the general

population [3]. Although new technologies like slow-re-

lease insulin or insulin pumps have been developed in the

last years and have substantially improved glycemic con-

trol as well as the quality of life of patients with T1D [4], a

fail-safe physiological regulation of systemic blood glu-

cose levels remains challenging. The only possible defini-

tive cure for this disease consists in replacing the destroyed

b cell mass capable of sensing blood sugar levels and secreting appropriate amounts of insulin in a glucose-de-

pendent manner. Increasing evidence indicates that b Cell replacement restores protection from severe hypoglycemia,

Managed by Massimo Federici.

& Lorenzo Piemonti piemonti.lorenzo@hsr.it

1 Diabetes Research Institute, IRCCS San Raffaele Scientific

Institute, Milan, Italy

123

Acta Diabetol (2016) 53:683–691

DOI 10.1007/s00592-016-0847-z

 

 

reduces levels of glycated hemoglobin (HbA1c) and slows

progression of microvascular complications in patients

with T1D [5]. So far, the only available clinical approaches

able to restore b cell mass in patients with T1D are pan- creas or pancreatic islet transplantation, which consists in

endocrine cells infusion into the recipient’s portal vein and

requires only a minimally invasive surgical procedure

compared to the complex vascularized pancreas trans-

plantation [6–8]. The field of islet transplantation has

evolved significantly over the last three decades thanks to

the incredible efforts of the research community worldwide

with continuous improvements in islet manufacturing

process and transplantation techniques, coupled with better

patient management and the development of more effective

induction and maintenance immunosuppressive protocols

[9]. In addition, islet transplantation represents an excellent

platform toward the development of cellular therapies

aimed at the restoration of b cell function using alternative sources of b cells like xenogeneic islets or insulin-pro- ducing cells derived from the differentiation of stem cells.

This review deals with the state of the art of islet

transplantation and the most promising sources of new b cells for functional replacement in diabetes (Fig. 1).

Established procedures, ongoing clinical trials (Table 1)

and future developments of cell therapies will be discussed.

b Cell replacement with allogeneic pancreatic islets

Pancreatic islet transplantation has recently become an

accepted therapeutic option in subjects with unstable T1D.

The procedure itself may be performed as islet transplant

alone (ITA) in non-uremic patients with T1D, as simulta-

neous islet-kidney (SIK) in subjects with end-stage renal

disease or, if renal transplantation has already undergone,

as islet after kidney (IAK) transplantation. Ongoing clinical

trials are recruiting 18- to 65-year-old T1D subjects with

frequent metabolic instability (i.e., hypoglycemia, hyper-

glycemia, ketoacidosis) requiring medical treatment

despite intensive insulin therapy [10].

The first attempt of islet isolation and transplantation

was reported in 1972 by Ballinger and Lacy in chemically

induced diabetic rats [11], with Kemp et al. [12] estab-

lishing the liver as the most suitable site for islet implan-

tation. Five years later, the first islet infusion in human was

performed, with azathioprine and corticosteroid as

immunosuppressive drugs [13]. Since then, many efforts

and significant progress have been achieved in the field in

terms of human islet isolation [14], immunosuppression

strategies [15] and setting the optimal number of trans-

planted islets per kilogram of body weight [16].

Altogether these advances culminated in 2000 with the

publication of the Edmonton Protocol achieving a 100 %

insulin independence in seven patients with T1D receiving

islets from multiple donors and treated with a steroid-free

immunosuppression protocol [17]. The Edmonton Protocol

represented a fundamental proof-of-concept of the possi-

bility to achieve insulin independence through islet trans-

plantation. Few years later, the same group reported

sustained islet function as measured by the presence of

C-peptide in 73 % of their transplanted subjects with 15 %

insulin independence at 9 years after transplantation [18].

Recently, they reported a further update on long-term fol-

low-up of a cohort of the 36-patient international Immune

Tolerance Network trial having persistent graft survival at

the end of the clinical study. All patients remained free of

severe episodes of hypoglycemia and maintained HbA1c

\7.0 % showing an overall long-lasting graft function with a gradual decline in C-peptide levels during time. Impor-

tantly, the long follow-up showed long-term safety of the

procedure with the absence of severe infection, malig-

nancy, hypoglycemia and the stability of renal function

[19]. Intervention Presentation on Diabetes