Islet regeneration needed for overcoming autoimmune destruction - considerations on the pathogenesis of type 1 diabetes.
How many new beta-cells need to be generated in order to withstand the attack of an 'average-strength' destructive autoimmune response? An answer to this question is central for the design of intervention approaches aimed at dampening or redirecting parts of the autoimmune response and allowing for the generation of new beta-cells. In this article, we consider quantitative and spatial restrictions of destructive T-cell activity, in balance with the regenerative capacity and neogenesis of beta-cells. We assume that the initial interaction between specific autoaggressive cytotoxic T-lymphocytes (CTL) and beta-cells is a terminal event leading to the elimination of the beta-cell and removal from the pool of potential sources for beta-cell replenishment. Furthermore, we propose that there may be no way to save an individual islet from complete destruction, once a few activated CTL effectors have gained entry, based on the fact that activated CTL are 'committed killers' and hard to turn off. Thus, mechanisms that restrict CTL access to islets or provide 'immune privilege' to defined locations within islets and/or ductal tissue are critical to allow beta-cell regeneration in the face of ongoing autoimmune destruction. The key to halting progression of type 1 diabetes pathogenesis should build on the observation that islets die in a highly non-synchronized fashion, at least during the more chronic disease course. These considerations suggest a compartmentalized view of the diseased pancreas so that substantial histopathological differences among individual islets may be exploited to facilitate preservation and/or regeneration of selected islets. The recent development of novel technologies will allow more precise quantification of in vivo destruction and regeneration in order to test these hypotheses.
von Herrath
Matthias
M
Immune Regulation Laboratory, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA. matthias@liai.org
Homann
Dirk
D
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology*; D012038:Regeneration; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology