The underlying mechanism is thought to be the wave of programmed cell death at 3 weeks of age

Jul 11, 2022 PKM

The underlying mechanism is thought to be the wave of programmed cell death at 3 weeks of age. with TNF- resulted in skewed development of a CD8+CD11b-CD11c+ DC subset such that TNF- decreases the CD8+CD11c+ DC subset, increases the CD11c+CD11b+ subset, and causes an increase in the expression of CD40 and CD54 on mature DCs capable of inducing immunity. Anti-TNF–treated mice had an increase in the CD8+CD11c+ DCs. Notably, adoptively transferred na?ve CD4+ T cells from BDC2.5 T cell receptor transgenic mice proliferated in the pancreatic lymph nodes in TNF–treated NOD mice but not in anti-TNF–treated mice. Finally, we show that anti-TNF–treated mice showed immunological tolerance to islet cell proteins. We conclude that TNF- plays an important role in the initiation of T1D in the NOD mouse by regulating the maturation of DCs and, thus, the activation of islet-specific pancreatic lymph node T cells. (10) in BDC2.5 T cell receptor (TCR) transgenic (tg) mice. Analysis of BDC2.5 tg mice showed that 90% of the T cells expressed the tg BDC2.5 TCR. Insulitis was not detectable in these animals until 19C21 days of age, at which time an explosive insulitis developed, with extensive infiltration of the islets with lymphocytes (10). Although the mechanisms underlying the abrupt onset of severe insulitis in BDC2.5 tg mice at 19C21 days of age were unclear, Mathis (12) showed that presentation of Rabbit Polyclonal to Stefin B antigenic proteins to T cells by immature resting dendritic cells (DCs) results in the induction of a form of tolerance, due either to an increase in regulatory T cells or to the induction of anergy. Second, Wu (13) have shown that neonatal TNF- treatment decreases the number of CD4+ CD25+ regulatory T cells, whereas neonatal anti-TNF- treatment causes a 2- to 3-fold increase in the numbers of these cells. In the present study, we hypothesized that the effects of TNF- and anti-TNF- in the neonatal period are mediated through the effects of TNF- iCRT 14 in activating, and anti-TNF- in preventing, the maturation of DCs in the islets and pancreatic lymph nodes (PLNs). Here, we have explored possible mechanisms underlying the increase and decrease of disease activity by neonatal TNF- and anti-TNF- treatment, respectively, in wild-type NOD mice. We monitored DC maturation in PLNs and other lymph nodes (LNs) in NOD mice treated with TNF- and anti-TNF- and examined the impact on the activation of a pathogenic T cell response in an adoptive transfer model using BDC2.5 TCR tg T cells. Finally, we tested whether neonatal treatment with anti-TNF- renders animals partially or almost completely immunologically tolerant. Our data indicate that, by keeping DCs immature, anti-TNF- induces immunologic tolerance to islet cell proteins whereas TNF- induces DC maturation, resulting in an increased immune response. We conclude that TNF- plays a crucial role in the initiation of T1DM by modulating DCCT cell interactions via modulation of DC development. Materials and Methods Mice. NOD.Lt (NOD) mice were obtained from The Jackson Laboratory and bred in the Stanford University Animal Facility under barrier isolation conditions. Diabetes incidence in the colony is currently 80% in females at 22 weeks. All animals used were female newborns, unless specifically noted. Mice were injected i.p. neonatally with TNF- or anti-TNF- as described (9). There was no iCRT 14 significant difference in weight between control iCRT 14 and treated animals during or after the treatment period. BDC2.5/NOD TCR tg mice were the kind gift of Diane Mathis (Joslin Diabetes Center, Harvard University). The BDC2.5 tg mice express a V1V4 TCR that recognizes an unknown cell antigen presented by I-Ag7 (10). All animals were housed under barrier conditions in Stanford University animal facilities. All animal studies have been approved by Stanford University’s Administrative Panel of Laboratory Animal Care. Assessment of Diabetes. Mice were monitored three times per week for glycosuria. Mice were considered diabetic upon two consecutive positive readings. The onset of diabetes was dated from the first of the sequential measurements. Antigens and Reagents. Insulin B:9-23 chain (SHLVEALYLVCGERG) was synthesized and purified by reverse-phase highperformance liquid chromatography and identified by mass spectroscopy (Genemed Synthesis, South San.