Luisa Camoglio

Interleukin-1 Signaling Is Essential for Host Defense during Murine Pulmonary Tuberculosis

Interleukin (IL)-1 signaling is required for the containment of infections with intracellular microorganisms, such as Listeria monocytogenes and Leishmania major. To determine the role of IL-1 in the host response to tuberculosis, we infected IL-1 type I receptor-deficient (IL-1R(-/-)) mice, in which IL-1 does not exert effects, with Mycobacterium tuberculosis. IL-1R(-/-) mice were more susceptible to pulmonary tuberculosis, as reflected by an increased mortality and an enhanced mycobacterial outgrowth in lungs and distant organs, which was associated with defective granuloma formation, containing fewer macrophages and fewer lymphocytes, whereas granulocytes were abundant. Lymphocytes were predominantly confined to perivascular areas, suggesting a defective migration of cells into inflamed tissue in the absence of IL-1 signaling. Impaired host defense in IL-1R(-/-) mice was further characterized by a decrease in the ability of splenocytes to produce interferon-gamma. Analysis of these data suggests that IL-1 plays an important role in the immune response to M. tuberculosis.

Hapten‐induced colitis associated with maintained Th1 and inflammatory responses in IFN‐γ receptor‐deficient mice

IFN‐γ is a potent pro‐inflammatory cytokine thought to be involved in the pathogenesis of Crohns disease. To further define the role of IFN‐γ in intestinal inflammation, we studied the effects of intra‐colonic 2,4,6‐trinitrobenzene sulfonic acid (TNBS) instillation in mice with a functionally inactivated IFN‐γ receptor 1 (IFN‐γR1– / –). Our results indicate that IFN‐γ is not necessary for the induction of hapten‐induced colitis: after TNBS administration both wild‐type and IFN‐γR1– / – mice lost body weight, and the histological features of TNBS‐induced colitis were comparable. Colons of IFN‐γR1– / – mice contained a greater number of cells, represented by macrophages and CD4+ T cells; caudal lymph node cells produced more IFN‐γ and TNF‐α upon stimulation in vitro. Moreover, IL‐18 and IL‐12 p40 RNA levels were comparably up‐regulated after TNBS treatment in IFN‐γR1– / – wild‐type mice. These findings demonstrate that IFN‐γ is dispensable for the development of TNBS‐induced colitis. Importantly, the production of Th1 cytokines (e. g. IFN‐γ and TNF‐α) by caudal lymph node T lymphocytes was enhanced rather than decreased in IFNγR1– / – mice with no evidence for default Th2 development.

Monoclonal antibody therapy of inflammatory bowel disease.

Several anti‐inflammatory drugs have therapeutic efficacy in inflammatory bowel disease, but their targets remain incompletely characterized. The development of monoclonal antibodies that either recognize epitopes on immune‐competent cells, or neutralize pro‐ inflammatory cytokines, has helped to define the importance of inflammatory mediators and their cellular sources in experimental inflammatory bowel disease. Moreover, two monoclonal antibodies, directed against CD4 and tumour necrosis factor, have been used to treat patients with steroid‐refractory Crohns disease. Preliminary data suggest that immune‐modulatory monoclonal antibodies may have beneficial effects in selected patients with severe Crohns disease.