Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.

Abstract

SummaryBeginning at the time of insulitis (7 wk of age), CD4 + and CD8 + mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from >7-wk-old NOD mice was virtually undetectable after treatment with either anti-TCR c~/B, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age-and sexmatched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR o~/B or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-2 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous rlL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rlL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rlL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

“…IL-4 may be important in the maintenance of a protective Th2 response [5], but it has also been implicated in the stimulation of a broader T cell repertoire composed of non-pathogenic cells [6] and in differential expression of B7.1 and B7.2 molecules by DCs, affecting the quality of CTL responses [7]. Systemic administration of IL-4 appeared to alleviate a form of unresponsiveness among NOD thymocytes and peripheral T cells, which correlated with disease protection [8].…”

“…Systemic IL-4 administration, via regular intraperitoneal injections [5,8,22], gene gunor carrier-mediated DNA delivery [23,24] or IL-4-encoding adenoviral vectors [25], prevented T1D when NOD mice were treated at a young age (up to 7 weeks). At the level of cellular gene therapy, IL-4-expressing transduced T cells [26,27] or dendritic cells (DCs) [28] have been used with some success.…”

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

“…Autoimmunity in NOD mice is T cell-dependent [1,2], and a role for the thymus has been evoked. Specific deficiency in thymic NKT cells is relevant to the immunopathology seen in this mouse [6,7]; NOD thymocytes produce low amounts of IL-4 [8], respond poorly to cytokines [9] and are relatively insensitive to apoptotic signals [10,11]. Experiments with F1 chimeras showed that the hemopoietic-derived thymic microenvironment is essential for development of diabetes [12,13] and intrathymic injection of Langerhans' islets abrogates autoimmunity [14].…”

Augmentation of natural immunity to a pro-inflammatory cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis

“…22,23,[30][31][32][68][69][70][71][72] The current study demonstrates, for the first time, the appearance of 'natural' antiself antibodies to a key pro-inflammatory cytokine, TNF-␣, during the development of a T cell-mediated autoimmune disease of the CNS. These antibodies developed in rats immunized with p68-86/CFA and not with the CFA alone (Figure 3), even though both groups exhibited an extensive local inflammatory process at the site of CFA immunization.…”

“…[12][13][14][15][16][17][18][19][20][21] Th1 cells selected in response to various autoantigens transfer T cell-mediated autoimmune diseases, whereas IL-4-secreting Th2 cells, selected in response to these same antigens, either inhibit or exert no profound effect on the inflammatory process. 16,[22][23][24][25][26][27][28][29][30][31][32][33][34] High levels of IFN-␥ and low levels of IL-4 positively select for Th1 cells, whereas low levels of IFN-␥ together with high levels of IL-4 mediate Th2 selection. [12][13][14][15][16][17] In a recent study, we isolated mRNA encoding interferon gamma-inducing factor (IGIF, IL-18) from the EAE brain, generated neutralizing antibodies against its gene product and explored the critical role of IGIF in T cell selection and regulation of disease.…”