Animal models have little to teach us about Type 1 diabetes: 1. In support of this proposal

Abstract

Sir Winston Churchill summed up our position in this debate when he said that “Men stumble over the truth from time to time, but most pick themselves up and hurry off as if nothing happened”. To our thinking, we (the Type 1 diabetes research community) have stumbled both in terms of the way in which data derived from animal models of Type 1 diabetes have been handled, and in the manner in which the field continues to move forward without proper acknowledgement of what has been learned. Animal models such as the non-obese diabetic (NOD) mouse and the biobreeding (BB) rat develop immune-mediated disease with features resembling Type 1 diabetes in humans [1]. Although these animal models of autoimmune diabetes have proved to be valuable tools to study certain aspects of the disease process [2], they have also led to misconceptions and erroneous extrapolations, as well as false expectations with regard to the efficacy of immunotherapy. Hence, on a number of counts, we would argue that animal models have limited value when it comes to teaching us about Type 1 diabetes in humans. The immune system There are profound differences between the immune systems of mice and men. These have recently been summarised comprehensively by Mestas and Hughes, and include discrepancies in both innate and adaptive immunity [3]. Relevant examples of more than 80 known incompatibilities would include: balance of leucocyte subsets, defensins, toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signalling pathway components, Thy-1, gamma delta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. Given the breadth of these functional differences, these discrepancies surely limit the usefulness of mouse models in studying Type 1 diabetes. Therefore, such differences should be taken into account when animals are used as preclinical models of human disease. Nonetheless, they are generally ignored.