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Chapter 17 : Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease

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Abstract:

This chapter introduces and explains the rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) model of vitally induced autoimmune diabetes. Special emphasis is given to the issues of molecular mimicry, the potential involvement of several viral infections in inducing or abrogating insulin-dependent diabetes mellitus (IDDM), new therapeutic perspectives, and pathogenically important findings that stem from the use of this model. The chapter discusses these issues, as well as other factors that precipitate or prevent IDDM. The RIP-LCMV transgenic mouse model differs in some important aspects from other established antigen-specific models of autoimmunity as well as from the nonobese diabetic (NOD) mouse model of spontaneous IDDM. The RIP-LCMV transgenic mouse model is ideally suited for the testing of novel approaches to antigen-specific immune therapy. The induction of IDDM by viral infection can be controlled and is directed to a known and well-characterized self-antigen, the LCMV transgene expressed by the B cells. Mice that expressed LCMV-NP as a transgene in their β cells developed IDDM after LCMV infection. Subsequent inoculation of plasmid DNA that encoded the insulin B chain reduced the incidence of this virally induced autoimmune diabetes by 50%. The protection provided by insulin B-chain DNA proceeded through induction of anti-self, regulatory CD4 lymphocytes that reacted with the insulin B chain, secreted IL-4, and locally reduced the activities of LCMV-NP autoreactive cytotoxic lymphocytes (CTLs) in the pancreatic draining lymph nodes.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17

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Figure 1

Principle of RIP-LCMV transgenic mouse model. Pancreatic β cells of RIP-LCMV transgenic (tg) mice express the NP or GP of LCMV under control of RIP. As the viral gene is integrated into the host's genome and passed on to progeny mice, it becomes essentially a host self-antigen. These mice are not tolerant to the LCMV (self) transgene but are unresponsive since naive autoreactive (LCMV-specific) lymphocytes escape thymic selection and are present in the periphery. Such cells are not activated under normal circumstances. However, infection with LCMV or expression of certain cytokines (IFN-γ) or activation molecules (B7.1) breaks this unresponsiveness, and as a consequence, activated LCMV (anti-self)-specific lymphocytes attack the p cells that express the appropriate LCMV proteins. The result is that autoimmune diabetes develops in 95 to 100% of RIP-LCMV transgenic mice after LCMV infection.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17
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Image of Figure 2
Figure 2

Histological findings in the RIP-LCMV transgenic models of slow- and rapid-onset IDDM. RIP-LCMV transgenic mice without thymic expression of the viral self-antigens expressed in their β cells develop CD4 independent, rapid-onset IDDM. A predominance of INF-γ-producing lymphocytes enters the islets. In contrast, the slow-onset IDDM that develops in mice with thymic expression is CD4 dependent and has a lag phase before IDDM occurs. This is a nondiabetic period during which lymphocytes mainly appear around, but not in, islets. Of the lymphocytes found within islets, the majority express or secrete IL-4 during this stage. He, hematoxylineosin staining.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17
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Image of Figure 3
Figure 3

Important events (numbered 1 through 10) in the pathogenesis of IDDM. Autoreactive lymphocytes (events 1 and 3), once activated, enter the islets in large numbers. There, CD8 CTLs kill (event 1b) some β cells using perforin, but not a sufficient amount to cause clinical IDDM. Antigens released by the dying β cells (event 2) are taken up in the islets by professional APCs (event 5), such as dendritic cells or macrophages. Additionally, an external noxious factor like viral infection (event 4) of the pancreas or another inflammation is likely needed to recruit and activate enough APCs into the area. These APCs (event 5) can then present β-cell antigens to infiltrating CD4 and CD8 lymphocytes (events 6 and 7) and provide crucial costimulatory signals, for example, through B7.1 and B7.2 CD28 interactions (event 8). As a result, the infiltrating lymphocyte population is expanded and can attack more β cells (event 9). Inflammatory cytokines are also secreted and may directly contribute to β-cell destruction (event 10). In this way, the autoimmune process is perpetuated locally until all islet cells are destroyed so that IDDM results. The three main players in this model, autoreactive lymphocytes, activated APCs, and regulatory factors, are all targets with immunotherapeutic potential.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17
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Figure 4

Concept of bystander suppression in treating autoimmune diseases. Destructive lymphocytes reactive with self-antigen A can be negatively influenced in the target organ by regulatory (bystander suppressor) lymphocytes reactive with a different self-antigen B.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17
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Figure 5

“The battle for the islet”: therapeutic approaches to prevention of autoimmune diabetes. Infiltration and destruction of islet cells by autoreactive lymphocytes and APCs constitute a complex process that can be reversed by various mechanisms even after its initiation. Not clear, at this point, is whether “attack” of an islet cell results in increased regeneration of β cells as a way for the islet cells to fight back and prevent their own destruction. Apparently, from present evidence, islet cell destruction should be viewed as a dynamic process that largely depends on the amount of local inflammatory mediators and destructive versus protective lymphocytes.

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17
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Tables

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Table 1

Why the RIP-LCMV model?

Citation: von Herrath M. 2000. Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease, p 235-255. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch17

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