Transplantation of autoimmune regulator‐encoding bone marrow cells delays the onset of experimental autoimmune encephalomyelitis

Abstract

AustraliaThe autoimmune regulator (AIRE) promotes ''promiscuous'' expression of tissue-restricted antigens (TRA) in thymic medullary epithelial cells to facilitate thymic deletion of autoreactive T-cells. Here, we show that AIRE-deficient mice showed an earlier development of myelin oligonucleotide glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). To determine the outcome of ectopic Aire expression, we used a retroviral transduction system to over-express Aire in vitro, in cell lines and in bone marrow (BM). In the cell lines that included those of thymic medullary and dendritic cell origin, ectopically expressed Aire variably promoted expression of TRA including Mog and Ins2 (proII) autoantigens associated, respectively, with the autoimmune diseases multiple sclerosis and type 1 diabetes. BM chimeras generated from BM transduced with a retrovirus encoding Aire displayed elevated levels of Mog and Ins2 expression in thymus and spleen. Following induction of EAE with MOG , transplanted mice displayed significant delay in the onset of EAE compared with control mice. To our knowledge, this is the first example showing that in vivo ectopic expression of AIRE can modulate TRA expression and alter autoimmune disease development.Key words: Autoimmune regulator Á Bone marrow Á Experimental autoimmune encephalomyelitis Á Immune tolerance Supporting Information available online à These authors contributed equally to this study.Ãà The laboratories of these authors contributed equally to this work. IntroductionIn humans, deficiency of the autoimmune regulator (AIRE) results in the autosomal recessive disorder, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy otherwise known as autoimmune polyglandular syndrome type 1 [1,2]. Studies of Aire À/À mice confirm AIRE as a transcriptional regulator that controls the intra-thymic expression of peripheral tissue-restricted antigens (TRA) implicated in the induction of immunological tolerance [3][4][5]. While the exact number of genes regulated by AIRE is not known, estimates in mouse and man suggest this may be hundreds to thousands of genes [4,[6][7][8].Within the thymus, the AIRE protein is expressed predominantly within medullary thymic epithelial cells (mTEC), although expression has also been reported in dendritic cells (DC) [9][10][11]. More recent reports also suggest Aire expression in peripheral cells and tissues [12][13][14][15], but its presence and function in these cells still remains an area of debate [9,16]. The generation of AIRE-deficient mice (Aire À/À ) has been instrumental in deciphering the role of AIRE in immune tolerance and susceptibility to autoimmune disease. To date, four Aire À/À mouse models have been reported [4,[17][18][19] and while there is intra-and inter-strain variation, Aire À/À mice develop a range of organ-specific autoimmune diseases that are generally directed towards specific TRA [4,17,20,21]. Furthermore, manipulation of Aire expression can influence central tolerance by altering TRA levels in mTRA...

A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

“…Mice also received 300 ng pertussis toxin (Sigma) intravenously on days 0 and 2 (ref. 50). For disease score studies, mice were either left untreated or intraperitoneally injected twice daily with vehicle or 20 mg kg À 1 WEHI-345, for six consecutive days from day 9 after immunization.…”

GM-CSF–Responsive Monocyte-Derived Dendritic Cells Are Pivotal in Th17 Pathogenesis

“…Mice and bone marrow chimeras Neurological impairment was scored: 0, no clinical signs; 1, limp tail; 2, hind limb weakness; 3, hind limb paralysis; 4, hind and fore limb paralysis; and 5, moribundity or death (38).…”

“…Mice were treated three times (CCR2.DTR) or five times (BM chimeras) every second day from day 1 after immunization. Mixed BM chimeras were given additional injections of DT because they had a slower onset of disease than did unirradiated mice (38).…”

Tackling autoimmunity with gene therapy

“…Experimentally, the transduction and transfer of bone marrow has been shown to promote tolerance to a range of antigens including neoantigens, 10 alloantigens, 11 allergens 12 and self-antigens such as myelin oligodendrocyte glycoprotein (MOG) as demonstrated in our model of EAE. 13,14 Together, these findings with such a broad array of molecules support the general rule that antigen specific tolerance can be generated in the immune system by targeting the bone marrow compartment.…”