Международный эндокринологический журнал 6 (54) 2013
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Virus induced diabetes in animals (short review)
Авторы: Grytsiuk M.I., Boychuk T.M., Petryshen O.I., Olenovych O.A. - Department of Social Medicine and Public Health Service Organization, Department of Histology, Cytology and Embryology, Department of Clinical Immunology, Allergology and Endocrinology, Bukovinian State Medical University, Chernivtsi
Рубрики: Эндокринология
Разделы: Медицинские форумы
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Diabetes is a chronic disease, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Type 1 diabetes results from the progressive destruction of insulinproducing pancreatic beta cells. Although the etiology of type 1 diabetes is believed to have a major genetic component, studies on the risk of developing type 1 diabetes suggest that environmental factors, such as viruses, may be important etiological determinants (H.S. Jun, J.W. Yoon, 2001).
Main goal of the research. The existence of experimental animal models of this disease helps not only to understand the pathophysiological mechanism of its development, but also to find proper medical drugs for its treatment.
Basic theoretical items of information. More than 10 viruses have been reported to be associated with the development of type 1 diabeteslike syndromes in animals. They are coxsackie B viruses in mice and/or nonhuman primates, encephalomyocarditis (EMC1) virus in mice, mengo virus in mice, footandmouth disease virus in pigs and/or cattle, retrovirus in mice, rubella virus in hamsters and rabbits, bovine viral diarrheamucosal disease virus in cattle, reovirus in mice, Kilham rat virus (KRV1) in rats, and cytomegalovirus in the Degu (YoungHwa Chung, Hee Sook Jun, 2000). Among those viruses, the most clear and unequivocal evidence that a virus induces type 1 diabetes in animals comes from studies on EMC virus in mice. EMC virus is considered to be a primary agent that is selectively injurious to pancreatic beta cells, whereas KRV is considered to be a triggering agent of beta cellspecific autoimmunity without infection of beta cells (Travis R.Wolter, Danny Zipris, 2011).
KRV is a small DNA virus that can induce diabetes by provoking autoimmune responses against the beta cell, rather than by direct beta cell cytolysis, in diabetesresistantBioBreeding (DRBB1) rats. These rats are derived from diabetesprone progenitors, but they do not normally develop the disease (Zipris et al. 2003). When infected with KRV at 3 weeks of age, approximately 30 % of DRBB rats develop autoimmune diabetes within 2 to 4 weeks, and a further 30 % show insulitis without diabetes. The incidence of diabetes can be increased to between 80 and 100 % if DRBB rats are given injections of poly (I : C) along with KRV. It is not clear how KRV causes the destruction of beta cells in DRBB rats without infection of these cells (Annie J. Kruger, Chaoxing Yang, 2010). Molecular mimicry, such as the existence of a common epitope between a KRVspecific peptide and a beta cell autoantigen, has been suggested as a mechanism for the initiation of beta cellspecific autoimmune diabetes. If molecular mimicry is involved in the initiation of beta cellspecific autoimmunity, then KRV antigenspecific T cells generated by KRV peptides might crossreact with beta cells and attack them, resulting in the development of insulitis and, subsequently, diabetes. To induce KRV antigenspecific T cells, recombinant vaccinia viruses (rVVs1) expressing KRV proteins were used, because previous work showed that rVVs were successful in inducing cellmediated immune responses against a target protein. In addition, the wildtype strain of vaccinia virus does not induce insulitis or diabetes in DRBB rats. When DRBB rats were infected with these rVVs expressing the KRV peptides (VP1, VP2, or nonstructural proteins 1 or 2), it was found that each viral peptide was clearly expressed in the infected DRBB rats, viral peptidespecific T cells were generated, and antibodies against the KRV peptides were also induced. However, none of the DRBB rats developed insulitis or diabetes. This result suggests that molecular mimicry between KRV peptides and beta cellspecific autoantigens in DRBB rats is unlikely to be a mechanism by which KRV induces beta cellspecific autoimmune diabetes (Elizabeth P. Blankenhorn, 2009).
In the rat, CD4+ T cells can be divided into Th1like CD45RC+CD4+ T cells, which express IL2 and IFN and play an important role in cellmediated immune responses, and Th2like CD45RC–CD4+ T cells, which express IL4 and IL10 and play an important part in humoral immune responses. It has been suggested that the immune balance between Th1 and Th2type cells plays an important role in the maintenance of peripheral tolerance. The dominance of Th1 cells over Th2 cells is associated with the development of autoimmune type 1 diabetes, whereas the dominance of Th2 cells over Th1 cells is associated with the prevention of type 1 diabetes. It was previously found that KRV infection in DRBB rats increased the expression of Th1type cytokines in the splenocytes and pancreatic infiltrates. Therefore, it is possible that the proportions of Th1 and Th2 cells are altered during KRV infection in DRBB rats (Todd J.A., Walker N.M., 2007).
Conclusions. Different experimental models of diabetes give an opportunity to find the new approaches for this disease treatment as well as to prevent complications connected with it.