Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of interleukin‐2 in islet β cells

Abstract

Transgenic mice expressing murine interleukin (IL)-2 constitutively in islet beta cells were generated (RIP-IL-2 mice). They died at an early age, when higher levels of IL-2 were produced, because of a predominant macrophage inflammatory response that destroyed the exocrine pancreas. Animals with lower levels of IL-2 survived and had islets that became increasingly infiltrated with lymphocytes over time. However, in spite of the presence of impressive peri- and intra-islet infiltrates, autoimmunity to islet antigens was not seen. Autoimmunity was also not induced to extrathymic H-2Kb molecules known to induce tolerance by a peripheral mechanism when the RIP-IL-2 mice were mated to other mice expressing H-2Kb in islet beta cells (RIP-Kb mice). Apparently, IL-2 can act only on activated T cells and is unable to reverse tolerance in T cells that have been made unresponsive through inappropriate presentation of antigen.

Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response.

“…tg mice that express constitutive levels of IL-2 alone in their pancreas (RIP IL-2 transgenics) have been characterized (20). When IL-2 is expressed at a high level, mice die at an early age due to destruction of the pancreas associated with a predominantly macrophage-containing inflammatory infiltrate.…”

“…The infiltrates are comprised mainly of CD4+ cells. However, spontaneous incidence of diabetes is infrequent and autoimmunity is not detected (20). We mated tg mice that expressed low levels of IL-2 to RIP NP 25-3 mice that expressed LCMV NP in the pancreas but do not spontaneously develop IDDM.…”

“…IL-2/2A locates within the mouse IL-2 sequence whereas IL-2/2B binds to the growth hormone sequence at the 3' end of the construct. The product is 410 bp in size (20).…”

SNPs upstream of the minimal promoter control IL-2 expression and are candidates for the autoimmune disease-susceptibility locus Aod2/Idd3/Eae3

“…7 In contrast, mice overexpressing IL-2 exhibit exacerbated inflammatory responses but not autoimmunity. [8][9][10] The autoimmune phenomena observed in IL2/IL2R knockout mice and in D3Tx mice have been attributed, in part, to defects in the development and homeostasis of CD4 þ CD25 þ Foxp3 þ T regulatory cells. 6,[11][12][13][14][15] IL2 and IL2Ra have been associated with susceptibility to several human autoimmune diseases including multiple sclerosis, celiac disease, systemic sclerosis and type I diabetes.…”

Cytokines and autoimmunity

“…Furthermore, some patients undergoing IL-2 treatment for neoplasia developed hypothyroidism with lymphomonocytic infiltration of the aflected thyroid tissue [92]. Additional evidence that IL-2 is needed in order to provoke autoimmune reaction is derived from studies using transgenic mice expressing IL-2 in association with the insulin promoter in fi cells [93] which developed insulitis but not IDDM. However, when the animals were crossed with double transgenic mice expressing class I molecule H-2K'' on fi cells and T cells specific for H-2K'' (which also did not develop IDDM), IDDM was rapidly induced, indicating that fi cell-derived IL-2 provided to autoreactive T cell clones was necessary to develop the autoimmune reaction [94].…”