In mice with targeted disruption of the gene that encodes interleukin-6 (IL-6), greatly reduced numbers of immunoglobulin A (IgA)-producing cells were observed at mucosae and grossly deficient local antibody responses were recorded after mucosal challenge with either ovalbumin or vaccinia virus. The IgA response in the lungs was completely restored after intranasal infection with recombinant vaccinia viruses engineered to express IL-6. These findings demonstrate a critical role for IL-6 in vivo in the development of local IgA antibody responses and illustrate the effectiveness of vector-directed cytokine gene therapy.

The lamina propria of the intestine contains large numbers of IgA-producing plasma cells which arise from precursors in the gut-associated lymphoid tissue (GALT) 1 in response to antigens in the lumen of the gut (1). The precursors are large lymphocytes which travel from the GALT to the blood in the thoracic duet lymph and then migrate into the lamina propria where they secrete IgA antibody (2-4). The mechanism of this selective migration into the lamina propria is not known and, in particular, there is controversy about the role of antigen in determining the distribution of IgA-secreting cells along the intestine.It has been reported that radiolabeled large lymphocytes from adult syngeneic donors will migrate into the intestinal lamina propria of neonatal rats (5) and into fetal intestine grafted under the kidney capsule of adult mice (6). These experiments with "antigen-free" gut are held to show that factors other than antigen determined the gut-homing of large lymphocytes. On the other hand, Ogra and Karzon (7) showed that local immunization of a segment of human colon with polio vaccine was followed by the appearance of specific IgA antibody which was entirely confined to the immunized segment. Husband and Lascelles (8) reported similar findings in sheep with two Thiry intestinal loops. When different antigens were administered into each loop, IgA antibody against each of the antigens appeared only in the correspondingly immunized loop and never in both loops. In these studies antigen appeared to be decisive in determining the localization of the blood-borne IgA precursors. Similar contradictions were reported by Pierce and Gowans (4). In immunized rats, the density of cells in the lamina propria producing IgA antibody against cholera toxoid was always highest in that region of the intestine which had been challenged with antigen. On the other hand, the small intestine of nonimmunized rats rapidly accumulated anti-toxin-containing cells (ACC) after an intravenous injection of lymphocytes obtained from the thoracic duet of immunized donors.In an attempt to reconcile these contradictory reports the colonization of the lamina propria with specific antibody-producing cells has been studied under more defined conditions using Thiry-Vella intestinal loops in rats and cholera toxoid as antigen. The results indicate that the accumulation of ACC in the gut is probably the result of both antigen-dependent and independent processes.

Summary Salmonella bacteria are a major cause of food‐borne infectious diarrhoea and there is great interest in understanding the pathogenesis of Salmonella infection and in vaccine development. Potential vaccines include the aromatic mutants of S. typhimurium. Such non‐lethal Aro mutants have also been useful for studying Salmonella infections in mouse models. Studies of systemic infection, using these Aro mutants, in both normal and cytokine gene knockout mice, indicate that interferon‐γ (IFN‐γ) plays a key role in the resolution of Salmonella infection. The present studies have investigated the outcome of oral infection in mice with attenuated Salmonella because this infection route mimics natural infection in humans. In IFN‐γ gene knockout (IFN‐γ–/–) mice, intestinal immunity was impaired and oral challenge resulted in disseminated septicaemia 2 weeks later. No dissemination of infection was seen in wild‐type mice. In wild‐type mice, both CD4 and CD8 cell numbers increased in the gut following Salmonella challenge, together with increased expression of major histocompatibility complex (MHC) II and vascular cell adhesion molecule‐1 (VCAM‐1). No such changes were seen in IFNγ–/– mice. Following oral challenge, antilipopolysaccharide (LPS) and antiphosphoryl choline antibodies increased by more than 100‐fold in both serum and faecal pellet extracts of IFNγ–/– mice compared with wild‐type mice. Our data show that IFN‐γ production is essential for resolution of enteric Salmonella infection and that antibody has little effect on this process.

Isoflavones derived from many edible plants have been reported to possess significant antioxidant, estrogenic and tyrosine kinase inhibitory activity. Genistein has been found previously to provide protection from oxidative damage induced by UV radiation both in vitro and following dietary administration. We have therefore examined the potential of a number of isoflavones from red clover (Trifolium pratense) and some metabolically related compounds to offer protection from UV irradiation in hairless mice by topical application after UV exposure. We show that whereas the primary isoflavones, daidzein, biochanin A and formononetin, were inactive, 20 microM lotions of genistein and the metabolites equol, isoequol and the related derivative dehydroequol had powerful potential to reduce the inflammatory edema reaction and the suppression of contact hypersensitivity induced by moderate doses of solar-simulated UV radiation. For equol the protection was concentration dependent and 5 microM equol markedly reduced the UV-induced inflammation but abrogated the UV-induced immunosuppression. Equol protected similarly from immunosuppression induced by the putative epidermal mediator, cis-urocanic acid (UCA), indicating a potential mechanism of action involving inactivation of this UV-photoproduct. Since immunosuppression induced by both UV radiation and by cis-UCA appears to be an oxidant-dependent response our observations support the actions of these topically applied isoflavones and their metabolites as antioxidants. They also indicate that lotions containing equol, unlike topical UV sunscreens, more readily protect the immune system from photosuppression than from the inflammation of the sunburn reaction, even when applied after exposure, and thus such compounds may have a future role as sun-protective cosmetic ingredients.

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