**1. Introduction**

Type 1 diabetes (T1D) is an insulin-dependent diabetes because of insufficient insulin pro‐ duction by the pancreatic islet β cells. Although the pathogenic mechanism of T1D is not yet completely clear, the current view of T1D pathogenesis is that under certain genetic back‐ ground, exogenous and/or endogenous factors trigger autoimmunity against islet β cells in the pancreas causing β cell damage and subsequent insufficiency of insulin production [1, 2]. About two decades ago, it was first demonstrated that T cells specific to β cell antigens were activated and participated in the pathogenesis of T1D [3, 4]. A great deal of work fol‐ lowing these reports in both animal models and humans has provided convincing data fur‐ ther supporting T1D is a T cell-mediated autoimmune disease. On the other hand, the evidence showing that majority of T1D patients have high titers of autoantibodies against islet β cells [5, 6] suggests that self-reactive B cells must also be involved in the autoimmune process. The role of B cells in the pathogenesis of T1D was further supported by the recent research and clinical data demonstrating B cell depletion by anti-CD20 antibodies delayed the disease process.

The clinical presentation of T1D is preceded by a period of time of active autoimmune re‐ sponse occurring in the pancreatic islets. When overt diabetes occurs, approximately 95% of islets are destroyed. Therefore, tremendous efforts have been pulled in halting or slowing down autoimmune process for the purpose of preventing T1D. Several clinical trials in T1D prevention have been put forward. However, there is, thus far, no effective approach to the prevention of human T1D despite that many have shown promising results in T1D animal models. Further effort is needed to discover new ways to prevent T1D. Importantly, from a practical point of view, reversing overt diabetes is much needed. In this chapter, we will fo‐

© 2013 Xia 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.

cus on recent research in immune intervention of disease process in T1D including modula‐ tion of T cells, B cells by antibodies as well as cellular therapies such as autologous hematopoietic stem cell transplantation (ASCT), treatment with mesenchymal stem cells (MSC) and cord blood transplantation.

*2.1.1.2. Antibody-dependent cellular cytoxicity (ADCC)*

*vivo* mechanism of anti-CD20 action [13].

*2.1.1.3. CD20 binding induces B cell apoptosis*

*2.1.2. Animal studies on anti-CD20 therapy in T1D*

ADCC effect in anti-CD20 therapy represents killing of target cells (B cells) by the effector cells that are activated by binding the Fc fragment of anti-CD20 antibody bound on B cells. Members of the Fcγ receptor family are expressed on monocytes, macrophages and granulo‐ cytes, and include the activating high-affinity FcγRI (CD64) and low-affinity FcγRIIIA (CD16), as well as the inhibitory low affinity FcγRIIB (CD32). FcγRIIB is believed to be a key regulator on B lymphocytes [13-15]. ADCC was recently demonstrated as an important *in*

Antibody-Based and Cellular Therapies of Type 1 Diabetes

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

565

Although the major role of anti-CD20 therapy is cell and complement-mediated cell lysis, there is evidence that anti-CD20 antibody mediates B cell death through inducing B cells to undergo apoptosis [16]. Anti-CD20 antibody, such as Rituximab induces B cell apoptosis through activation of caspase-3 [17], whereas the FAS ligand/FAS death pathway does not seem necessary. Therefore, the mitochondrial-dependent pathway is likely the death path‐

Most research on the mechanisms of action of anti-CD20 therapy was conducted in B cell lymphoma to study how anti-CD20 therapy kills lymphoma tumor cells but not normal B cells. Anti-CD20 antibody therapy may work differently when used to modulate normal ma‐ ture B cells. Although the existing evidence shows that anti-CD20 therapy induces regulato‐ ry T cells or regulatory B cells in autoimmune settings [18-20], the mechanisms of action of anti-CD20 in modulating normal mature B cells are not fully understood and need to be fur‐ ther addressed. The insight into the mechanisms of action of anti-CD20 therapy in autoim‐ mune settings is of great importance in guiding anti-CD20 therapy in autoimmune diseases.

NOD (nonobese diabetes) mouse is an animal model of human T1D. In this strain of mice, diabetes starts to occur usually around 10 weeks of age. Tremendous measures have been tested for T1D prevention in NOD mice including anti-CD20 therapy. Hu reported for the first time that anti-CD20 therapy not only prevented but also reversed T1D in humanized NOD mice (Hu-NOD, CD20 transgenic mice). Furthermore, anti-CD20 therapy-modulated B cells can transfer diabetes-protective effect when co-transferred with diabetogenic spleen cells in NOD-scid mice, suggesting post anti-CD20 depletion the reconstituted B cells might acquire tolerogenic, or regulatory capacity. Additionally, the authors discovered that anti-CD20 therapy significantly induces CD4+CD25+Foxp3+ regulatory T cells [21]. It has been shown that NOD mice deficient for B cells from the birth fail to develop autoimmune diabe‐ tes [22]. Xiu, et al [23] directly tested how depletion of B cells influenced T1D pathogenesis in wild-type NOD mice with an intact immune system. NOD female mice at early and late pre-clinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term anti-CD20 mAb treatment in 5-week old NOD female mice reduced B cell numbers by 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. The treatment

way induced by anti-CD20. The role of bcl-2-dependent pathways remains unclear.
