Lessons on autoimmune diabetes from animal models

Abstract

T1DM (Type I diabetes mellitus) results from selective destruction of the insulin-producing beta-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of T1DM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that T1DM is caused by autoreactive T-lymphocytes and revealed that the development of T1DM is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of T1DM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of T1DM. In this review, we summarize the contribution of studies in animal models of T1DM to our current understanding of four fundamental aspects of T1DM: (i) the nature of genetic elements affording T1DM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and beta-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

“…32,33 Similarly, initiation of the immune response following LCMV or Listeria monocytogenes infections is mediated by the cross-presentation of pathogenderived antigens to CD8 1 T cells. 22 IL-15 has been implicated in antigen presenting functions of DCs.…”

Plasmid-based gene therapy of diabetes mellitus

“…In these mice, the disease is more severe in females and occurs because insulin-producing b-cells are destroyed following infiltration of islets of Langerhans by macrophages and islet-cell antigenreactive, auto-aggressive T cells. 32,33 The islet inflammatory process is termed insulitis and begins as a relatively benign peri-islet infiltrate (peri-insulitis), which eventually evolves into an invasive and destructive intra-islet lymphocytic infiltrate. The disease can be adoptively transferred with T lymphocytes, provided both CD4 + and CD8 + cells are included.…”

Experimental rodent models of prostatitis: limitations and potential

“…45 Currently, many human noncancer diseases have appropriate animal models that serve as sources for obtaining new research data and testing new therapeutic strategies. [46][47][48][49][50][51][52][53][54][55][56] It should be noted that almost half the articles published on prostatitis and available on PubMed were published between the year 2000 and 2006. Nevertheless, the cause of category III and IV prostatitis has remained elusive.…”