Rolf Ehrhardt

Reciprocal IFN-γ and TGF-β responses regulate the occurrence of mucosal inflammation

Abstract Recent studies of oral tolerance and experimental colitis indicate that the occurrence of gastrointestinal inflammation is determined by a balance between proinflammatory interferon γ responses and anti-inflammatory transforming growth factor β responses. Here, Warren Strober and colleagues discuss the new findings.

Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression

Two key events occur during the differentiation of IFN-γ-secreting Th1 cells: up-regulation of IL-12Rβ2 and IL-12-driven up-regulation of IL-18Rα. We previously demonstrated that IL-12-driven up-regulation of IL-18Rα expression is severely impaired in IFN-γ−/− mice. However, it was unclear from these studies how IFN-γ influenced IL-18Rα since IFN-γ alone had no direct effect on IL-18Rα expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Rα/IL-12Rβ2 was independent of IFN-γ. However, in the presence of IL-4, IFN-γ functions to limit the negative effects of IL-4 on both IL-18Rα and IL-12Rβ2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Rα/IL-12Rβ2 in an IFN-γ-independent fashion. In the absence of both IL-12 and IL-4, IFN-γ up-regulates IL-12β2 expression and primes IFN-γ-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Rα or the IL-12Rβ2 and the capacity of these cells to produce IFN-γ, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-γ in regulation of IL-18Rα/IL-12Rβ2 during both IL-12-dependent and IL-12-independent Th1 differentiation.

Persistence of Pathogenic CD4+ Th1-Like Cells In Vivo in the Absence of IL-12 but in the Presence of Autoantigen

Despite recent successful treatment of murine autoimmune disease with anti-IL-12 mAb, it has not yet been addressed whether anti-IL-12 mAb can also be effective in late stages of disease and whether it can provide lasting protection against recurrence, especially during continued presence of autoantigen. We used a newly developed psoriasis model in scid/scid mice, which allows easy tracking of pathogenic T cells, to show that when anti-IL-12 mAb is given for 2 wk (1 mg/wk) in the late stage of severe disease, inflammation is greatly reduced, as measured by ear thickness and histology (scores, 1.1 ± 0.1 vs 2.0 ± 0.4). Moreover, prolonged treatment (4 wk) of chronic psoriatic mice with high doses of mAb (1 mg/wk; prolonged active anti-inflammatory treatment (PAAIT)) results in the almost complete resolution of lesions (scores, 0.3 ± 0.1 vs 2.7 ± 0.2). Surprisingly, however, despite these significant treatment results, the psoriasis-like lesions return soon after the anti-IL-12 mAb treatment is discontinued. This rapid relapse of disease may be attributed to large populations of activated CD4+ T cells present in the lymph nodes of PAAIT animals still expressing an effector/memory phenotype (CD45RBlow, L-selectinlow). Upon stimulation in vitro such PAAIT lymph node cells secrete high amounts of IFN-γ (129 ng/ml); when transferred into naive scid/scid animals they are able to rapidly induce disease without costimulation. Our data indicates an alternative IL-12-independent pathway for pathogenic Th-1-like cells in vivo during the chronic phase of disease that allows these cells to persist and maintain their pathogenicity in the draining lymph tissue of the autoimmune site.

When Immunization Leads to Autoimmunity: Chronic Inflammation as a Result of Thymic and Mucosal Dysregulation in IL-2 Knock-out Mice

In 1965 Wheelock identified IFN--/ as a new soluble substance produced by activated T cells that inhibited viral replication in fibroblasts [ I ] . This seminal observation led to the explosive research on lymphocyte mediated activators during various aspects of the cellular immune response [2-71, and was followed in 1976 by the discovery of IL-2 by Morgan et al. [S]. IL-2 was discovered as a secreted product of T cells activated by a polyclonal mitogen, phytohemagglutinin (PHA), that stimulated the proliferation of