**3.2. Umbilical cord blood (UCB) cell therapy for TID**

Bone marrow is a rich source of stem cells, but its application is hampered by the limited availa‐ bility of bone marrow donors and the invasive procedure for cell collection. Human umbilical cord blood (HUCB) is another source of stem cells. Compared to bone marrow, HUCB has some major advantages such as easy availability, absence of risk to the donor, low risk of graftvs-host disease and tumorigenicity, high capacity for expansion [62]. UCB has been used suc‐ cessfully in transplantation for diseases like acute anemia, and sickle cell anemia [63]. There have been both animal and clinical studies evaluating the use of UCB cells as a potential thera‐ py for T1D. The rationale is based on experimental studies. *In vitro* cultures of HUCB can yield islet-like structures capable of insulin and C-peptide production [64]. *In vivo*, human cord blood-derived cells is also shown to be able to differentiate into islet cells when transfused into 2 day old NOD-scid mice [65]. A recent report demonstrated that cord blood-derived multipo‐ tent stem cells reversed T1D through islet β cell regeneration following immune modulation [66]. Second, UCB contains a population of immature unprimed functional regulatory T cells. Theoretically, these cells could limit inflammatory reaction and anergize effector T cells, which are believed to mediate cellular autoimmune processes. In addition, UCB stem cells may act as nurse cells to stimulate the proliferation of new islets from the remaining viable tissue [67]. Ende et al. [68, 69] reported in two separate studies that infusions of HUCB improved hyper‐ glycemia and diabetic nephropathy in obesity-induced diabetic mice. In addition, nonobese di‐ abetic (NOD) mice can be protected from developing insulitis and diabetes by HUCB dosedependently. However, the results of available clinical study is disappointing. In a recently completed phase I clinical study [70], 24 children aged 3.4-6.9 years, with new onset T1D re‐ ceived a single autologous UBC infusion within 6 months of diagnosis. After 2 years of followup, there was no evidence of reservation of β cell function, as evaluated by the area under the curve C-peptide that was 2% of baseline 2 years after UBC infusion, despite that the numbers of regulatory T cells (Tregs) and naïve Tregs were increased 6 and 9 months after. In that study, there are several possibilities as to why UCB infusion may fail to preserve β cell function. First, the stem cell number is insufficient. Second, there exist memory T cells refractory to regulation by Tregs. Finally, it cannot be excluded that the UCB cells from the T1D patients may have in‐ trinsic defects with compromised biological function. In future, autologous or allogeneic trans‐ plantation with expanded UBC Tregs either alone or in combination of immunomodulatory drugs may be worth trying. Importantly, randomized controlled studies are needed before de‐ finitive conclusions can be finally reached.

cell (DC) [73]. Moreover, MSCs can modulate immune response through stimulating the

trophic mediators such as growth factors and cytokines (M-CSF, IL-6, IL-11, IL-15, SCF, VEGF) that are involved in the regulation of immune response and hematopoieses. This could be a major mechanism underlying the immunomodulatory action of MSCs. Recently, MSCs have been used in clinical trials for the treatment of acute graft-versus-host disease (GVHD) following allogeneic HSC transplantation [75,76], and for autoimmune diseases such as multiple sclerosis and Crohn disease [77,78]. Another striking characteristic of MSCs is the ability to differentiate into insulin-producing cells (IPCs). *In vitro*, MSCs can be differ‐ entiated into IPCs when cultured under proper conditions. The types of MSCs that have been successfully induced to generate IPCs includes BM-MSCs, umbilical cord blood MSCs

By now, the use of MSCs for treatment of diabetes have been explored in two animal studies. In a model of murine STZ-induced diabetes, co-administration of BM cells with syngeneic or semi-allogeneic MSCs normalized blood glucose and serum insulin levels. The beneficial effect of this treatment does not seem due to the reconstitution of the damaged islet cells from the transplant since no donor-derived β cells were found in the recovered animals. Instead, the benefits may be due to the immunosuppressive effect of MSCs on the β cell-specific T cell re‐ sponse since MSCs injection caused the disappearance of beta-cell-specific T lymphocytes from diabetic pancreas, which may allow the regeneration of recipient-derived pancreatic insulinsecreting cells [80]. In another study [81], the mechanism underlying the beneficial effects of MSCs on blood glucose was investigated in a diabetic rat model induced by high-fat diet/strep‐ tozotocin (STZ) administration. Autologous MSCs were administered either 1 or 3 weeks after STZ injection. Infusion of MSCs during the early phase not only promoted β cell function but also ameliorated insulin resistance, whereas infusion in the late phase merely ameliorated in‐ sulin resistance. The improved insulin sensitivity induced by MSCs infusion is associated with an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor sub‐

Taken together, these *in vitro* and *in vivo* experiments suggest that multiple mechanisms may be involved for the beneficial effect of MSCs on blood glucose control in T1D. Thus far, the use of MSCs to treat T1D is limited to animal studies. The efficacy of MSCs to treat pa‐

In conclusion, both anti-lymphocyte antibody-based and cellular therapies are promising in stopping ongoing autoimmunity against islet antigens and likely leading to a hopeful resto‐ ration of self-tolerance. The regimens combining anti-lymphocyte antibodies, islet antigens and cellular therapies could maximize the preventive and/or therapeutic efficacy for T1D.

This work was supported by Natural Science Foundation of China (Grant number 81172854

(UCB-hMSCs), pancreatic MSCs and adipose-derived MSCs,etc. [79].

strate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues.

tients with T1D needs to be further evaluated in well-designed clinical trials.

Treg (regulatory T cells) [74]. MSCs are known to secrete a variety of

Antibody-Based and Cellular Therapies of Type 1 Diabetes

http://dx.doi.org/10.5772/53495

575

production of CD8+

**Acknowledgement**

to CQX), and NIH 1R21DK080216-01A2 to CQX

### **3.3. Mesenchymal stem cell therapy for TID**

Mesenchymal stem cells (MSCs) were originally identified by Friedenstein et al. in 1976 [71] in the bone marrow as a fibroblast-like cell population capable of generating osteogenic pre‐ cursors. MSCs from the bone marrow (BM) are a heterogeneous, stromal population of mul‐ tipotent non-hematopoietic progenitor cells capable of differentiating into multiple mesenchymal lineages including bone, fat and cartilage. In addition to bone marrow, MSCs have been found to be present in other tissues such as adipose tissue, umbilical cord blood, synovial membrane, skeletal muscle, dermis, deciduous teeth, pericytes, trabecular bone, ar‐ ticular cartilage, umbilical cord, placenta, liver and spleen. It is now known that MSCs are able to differentiate into mesodermal and non-mesodermal cell lineages, including osteo‐ cytes, adipocytes, chondrocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epi‐ thelial cells, and neurons [72].

In addition to their pluripotency to differentiate, MSCs have high immunomodulatory ca‐ pacity. The immunomodulatory property of MSCs are associated with their inhibitory ef‐ fects on the proliferation and differentiation of both T cells and B cells, as well as dendritic cell (DC) [73]. Moreover, MSCs can modulate immune response through stimulating the production of CD8+ Treg (regulatory T cells) [74]. MSCs are known to secrete a variety of trophic mediators such as growth factors and cytokines (M-CSF, IL-6, IL-11, IL-15, SCF, VEGF) that are involved in the regulation of immune response and hematopoieses. This could be a major mechanism underlying the immunomodulatory action of MSCs. Recently, MSCs have been used in clinical trials for the treatment of acute graft-versus-host disease (GVHD) following allogeneic HSC transplantation [75,76], and for autoimmune diseases such as multiple sclerosis and Crohn disease [77,78]. Another striking characteristic of MSCs is the ability to differentiate into insulin-producing cells (IPCs). *In vitro*, MSCs can be differ‐ entiated into IPCs when cultured under proper conditions. The types of MSCs that have been successfully induced to generate IPCs includes BM-MSCs, umbilical cord blood MSCs (UCB-hMSCs), pancreatic MSCs and adipose-derived MSCs,etc. [79].

By now, the use of MSCs for treatment of diabetes have been explored in two animal studies. In a model of murine STZ-induced diabetes, co-administration of BM cells with syngeneic or semi-allogeneic MSCs normalized blood glucose and serum insulin levels. The beneficial effect of this treatment does not seem due to the reconstitution of the damaged islet cells from the transplant since no donor-derived β cells were found in the recovered animals. Instead, the benefits may be due to the immunosuppressive effect of MSCs on the β cell-specific T cell re‐ sponse since MSCs injection caused the disappearance of beta-cell-specific T lymphocytes from diabetic pancreas, which may allow the regeneration of recipient-derived pancreatic insulinsecreting cells [80]. In another study [81], the mechanism underlying the beneficial effects of MSCs on blood glucose was investigated in a diabetic rat model induced by high-fat diet/strep‐ tozotocin (STZ) administration. Autologous MSCs were administered either 1 or 3 weeks after STZ injection. Infusion of MSCs during the early phase not only promoted β cell function but also ameliorated insulin resistance, whereas infusion in the late phase merely ameliorated in‐ sulin resistance. The improved insulin sensitivity induced by MSCs infusion is associated with an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor sub‐ strate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues.

Taken together, these *in vitro* and *in vivo* experiments suggest that multiple mechanisms may be involved for the beneficial effect of MSCs on blood glucose control in T1D. Thus far, the use of MSCs to treat T1D is limited to animal studies. The efficacy of MSCs to treat pa‐ tients with T1D needs to be further evaluated in well-designed clinical trials.

In conclusion, both anti-lymphocyte antibody-based and cellular therapies are promising in stopping ongoing autoimmunity against islet antigens and likely leading to a hopeful resto‐ ration of self-tolerance. The regimens combining anti-lymphocyte antibodies, islet antigens and cellular therapies could maximize the preventive and/or therapeutic efficacy for T1D.
