**1. Introduction**

transfusion in young children with type 1 diabetes fails to preserve C-peptide. Diabe‐

[71] Friedenstein AJ, Gorskaja JF, Kulagina NN: Fibroblast precursors in normal and irra‐

[72] Liu ZJ, Zhuge Y, Velazquez OC: Trafficking and differentiation of mesenchymal stem

[73] Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisan‐ ti S, Gianni AM: Human bone marrow stromal cells suppress T-lymphocyte prolifer‐ ation induced by cellular or nonspecific mitogenic stimuli. Blood 2002, 99(10):

[74] Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C: Im‐ munosuppressive effect of mesenchymal stem cells favors tumor growth in allogene‐

[75] Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M et al: Mesenchymal stem cells for treatment of steroidresistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008,

[76] Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM, Locatelli F, Fibbe WE: Cotransplantation of ex vivo expanded mesenchymal stem cells acceler‐ ates lymphocyte recovery and may reduce the risk of graft failure in haploidentical

[77] Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JW, Petrou P, Ben-Hur T, Abramsky O et al: Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis

[78] Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Mine‐ lli A, Alvisi C, Vanoli A, Calliada F et al: Autologous bone marrow-derived mesen‐ chymal stromal cells in the treatment of fistulising Crohn's disease. Gut 2011, 60(6):

[79] Vija L, Farge D, Gautier JF, Vexiau P, Dumitrache C, Bourgarit A, Verrecchia F, Lar‐ ghero J: Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes.

[80] Urban VS, Kiss J, Kovacs J, Gocza E, Vas V, Monostori E, Uher F: Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 2008, 26(1):

[81] Si Y, Zhao Y, Hao H, Liu J, Guo Y, Mu Y, Shen J, Cheng Y, Fu X, Han W: Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identifica‐ tion of a novel role in improving insulin sensitivity. Diabetes 2012, 61(6):1616-1625.

hematopoietic stem-cell transplantation. Blood 2007, 110(7):2764-2767.

and amyotrophic lateral sclerosis. Arch Neurol 2010, 67(10):1187-1194.

diated mouse hematopoietic organs. Exp Hematol 1976, 4(5):267-274.

tes Care 2011, 34(12):2567-2569.

3838-3843.

582 Type 1 Diabetes

788-798.

244-253.

Diabetes Metab 2009, 35(2):85-93.

371(9624):1579-1586.

cells. J Cell Biochem 2009, 106(6):984-991.

ic animals. Blood 2003, 102(10):3837-3844.

Type I diabetes (insulin-dependent diabetes mellitus, IDDM) is a chronic autoimmune disease caused by the selective destruction of insulin-producing β-cells in the pancreatic islets of Langerhans, which results in severe insulin deficiency. Insufficient circulating levels of insulin lead to potentially fatal metabolic dysfunction. Although the exact mechanism of islet cell destruction is unclear, a T-cell-mediated autoimmune process seems to be the most likely explanation. Other factors, genetic and environmental, are likely contributing causes, but have not been fully identified as of yet.

Although whole pancreas transplantation has been considered as a therapeutic option for selected patients with IDDM, most individuals with the disease are not likely candidates for this therapy. Since the discovery of insulin in the 1920's, the main therapeutic approach to treating IDDM patients has been insulin replacement [1]. The standard of care for most patients with Type 1 diabetes is based on exogenous insulin therapy delivered through several daily injections. Despite great improvements in insulin delivery systems seen in the last two decades, it's still difficult to provide the precise amount of insulin that is required by the patient at any given time. This results in hypo- and hyperglycemic episodes, potentially leading to cell damage in many tissues, ultimately resulting in the development of severe long-term compli‐ cations. Therefore, insulin delivery systems which can quickly and continuously respond to constantly changing physiological needs of the organism by adjusting the amount of insulin released into the circulation would be of great benefit.

Due to the fact that IDDM is a disorder in which β-cells in the pancreatic islets of Langerhans are selectively destroyed by an autoimmune attack, cell replacement strategies offer a very attractive treatment option. Recent successes in the field of islet cell transplantation have led to renewed optimism in this area. Clinical trials clearly demonstrated that islet transplantation not only offers a viable option for patients with severe forms of IDDM, but can successfully

© 2013 Linetsky et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

treat the disease [2,3,4]. It is, however, apparent that islet transplantation is not currently a viable option for the treatment of all potential recipients, due to the limited source of islet cells, i.e. limited number of available donors. Another feature of islet transplantation, as currently performed, is the requirement for life-long immunosuppression that limits the patients' eligibility to individuals with the most severe cases of IDDM. These issues have driven the investigation of alternative cell sources, which include xenografts from other species, embry‐ onic and adult stem cells, and gene therapy products. Such therapies will also likely require immunological protection provided by means such as conventional immunosuppression, administration of immunomodulatory cell subsets or a combination and manipulation of the islets by shielding and/or encapsulation, which can protect transplanted cells from recognition by the immune system and, in particular, from recurrence of autoimmunity.

little is potentially lethal, so the cells must be able to rapidly respond to changes in plasma

Cell Replacement Therapy in Type 1 Diabetes

http://dx.doi.org/10.5772/54943

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This chapter will offer a detailed discussion of the latest developments in islet transplantation and its future direction. In addition, attention will be paid to alternative approaches for achieving insulin homeostasis and glycemic control through various novel cell replacement therapies, as well as potential advantages and risks associated with each therapeutic option.

Diabetes Mellitus (DM) poses a significant challenge in the United States and around the world. It's increasing in prevalence and, at the present time, affects almost 20 million peo‐ ple in the United States alone [1]. DM is considered to be the sixth leading cause of death in the USA and is a major morbidity hazard [6,7] because of its associated complications that may negatively impact a patient's quality of life. Presently, the disease lowers aver‐ age life expectancy by about 15 years, increases cardiovascular disease (CVD) risk by about two- to four-fold, and is the main cause of kidney failure, lower limb amputations, and adult-onset blindness. DM is a costly disease: its estimated attributable costs in 2010

IDDM has an early childhood or young adulthood onset, although it can be diagnosed at any age. It is characterized by profound deficiency in insulin secretion caused by the autoimmune destruction of insulin-producing cells in the pancreas, the pancreatic β-cells. IDDM accounts for approximately 5-10% of all disease cases. Factors that have been associated with the development of Type 1 DM are both genetic and environmental [8-10]. In animal models such as the NOD mouse and BB rat, and in human Type 1 diabetes, there is strong evidence of a role of the class II gene, I-A in NOD mouse (equivalent to human DQ beta gene), most probably in combination with lack of I-E expression (equivalent to human DR) [11]. Although it is entirely possible that the genetic response can be triggered by environmental factors such as infections or drastic change in diet, the clear definition of such factors has been elusive to date [11]. Ultimately, though, it is the autoimmune component of Type 1 diabetes that is responsible for the progressive and selective autoimmune destruction of insulin-producing β-cells in the pancreas. Due to the fact that the disease is the result of the loss of a single cell type, i.e. β-cell,

The discovery of insulin in 1922 by the Canadian physician Frederic Banting brought about the realization that it was the pancreas that produced the "sugar-reducing sub‐ stance" [1], i.e. insulin. Since then scientists have been interested in how this hormone is synthesized and secreted, and the main therapeutic approach to IDDM has been focused on insulin replacement. Until recently, the only available treatment for Type 1 diabetes was the administration of exogenous insulin. The Diabetes Control and Complications Tri‐ al (DCCT) [12] demonstrated that, in patients with Type 1 diabetes, intensive insulin re‐ placement therapy can control blood glucose levels to a certain extent [12]. Unfortunately, even intensive care it is not able to mimic normal hormone release that regulates glucose homeostasis [8] and results in the fine-tuned physiological balance [13]. Even in patients with good glycemic control achieved through intensive insulin therapy blood glucose lev‐

it is considered to be amenable to treatment by cell replacement therapy.

glucose in either direction.

**1.1. Allogeneic islet transplantation**

were approximately 135 billion dollars [6].

An adult pancreas contains approximately one million (1 x 106 ) islet cells, which represent a minor part of the organ, i.e. 2-3 % of the pancreatic tissue. Islets designated for transplantation must be isolated from the whole pancreas using the method that combines enzymatic digestion with mechanical disruption. Despite considerable improvements made in the islet isolation process (the process itself, the reagents used during the procedure), that led to improved quantity and quality of islet preparations, it still remains a largely inefficient process. Clinical symptoms of Type 1 diabetes do not develop until 60-80% of the β-cell mass is lost to the autoimmune attack [5]. This means that adequate glycemic control can be maintained with as little as 20-40% of the normal β-cell mass. Intrahepatic islet transplantation is the accepted gold standard at the present time. Ample scientific evidence suggests [4] that a significant number of islets are lost during the immediate post-transplant period, mostly due to the inflammation and thrombosis following initial islet-blood contact and activation of hepatic microenviron‐ ment. Thus, if the goal of islet transplantation is to replace 1 x 106 islets to achieve long-term normoglycemia, several donors may be requires for each recipient. In fact, it has been previ‐ ously demonstrated [2,3] that insulin independence is achieved with ≥13,000 islet equivalents (IEQ)/kg of recipient body weight, using more than one islet preparation per recipient, at the same time or in succession. This means that a single islet transplant may require 3-4 donor pancreata. At the present time, the only source of islet cells are pancreata obtained from a deceased, heart-beating, brain-dead donor. This type of donor, especially of suitable age, is rare, making current protocols for human islet transplantation an unlikely candidate for widespread treatment for patients with IDDM. In the US alone, there are approximately 2 million people diagnosed with Type 1 diabetes. This demand is driving the current research trends into alternative functionally competent, i.e. insulin secreting and sensing, β -cell sources as potential replacement therapies for IDDM.

A number of different cell types have been proposed as a starting material to generate sufficient cell mass for transplantation; these include insulin-secreting cell lines, non-β-cell sources engineered through gene therapy, β-cells from non-human species, and β-cells generated from adult (bone marrow, pancreas, liver and neural tissue) and embryonic stem cells [5]. Regardless of the cell source, i.e. β- or non-β cells, many agree that the optimal treatment for Type 1 diabetes should ideally consist of an autologous cell source, which can synthesize, store and release insulin in a highly regulated fashion to maintain glucose homeostasis. Too much or too little is potentially lethal, so the cells must be able to rapidly respond to changes in plasma glucose in either direction.

This chapter will offer a detailed discussion of the latest developments in islet transplantation and its future direction. In addition, attention will be paid to alternative approaches for achieving insulin homeostasis and glycemic control through various novel cell replacement therapies, as well as potential advantages and risks associated with each therapeutic option.
