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We have previously shown that transplanted bone marrow stem cells (BMSC) contribute to various cell lineages in the diseased colon including myofibroblasts, fibroblasts, smooth muscle (SM) cells, and epithelial cells. [...]

Introduction: Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1α (MIP-1α) exacerbates colitis in a mouse model. Methods: Colitis was induced in Balb/c mice using trinitrobenzene sulfonic acid (TNBS). Starting four days later, animals received daily intraperitoneal injections of recombinant MIP-1α. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1α on mucosal T cells and fibroblasts in vitro were also investigated. Results: Systemic administration of MIP-1α markedly enhanced colitis with mice developing large transmural ulcers filled with granulation tissue. Treatment resulted in increased numbers of CD4 cells infiltrating the colonic lamina propria, increased interferon γ (IFN-γ) levels, and increased transcripts for tumour necrosis factor α (TNF-α) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-γ and TNF-α transcripts when stimulated with MIP-1α in vitro. Colonic lamina propria fibroblasts also responded to M1P-1α with increased proliferation and decreased collagen 1 synthesis but fibroblast proliferation was not seen in vivo. Conclusions: These experiments show that increasing serum concentrations of a chemokine, MIP-1α, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1α to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

In recent years, I have developed an endurance running art-practice as part of a larger inquiry into the performative nature of human physical activity. In the Absence of Running is series of artworks made using images from medical arthroscopic interventions following the diagnosis of medial meniscus tears to the cartilage and osteoarthritis in both my knees. Faced with not being able to run or to make artworks using running in the long-term, I turned to the tools of medical intervention. If a camera was going inside my knee for the purpose of surgery, I would use it for the purpose of art. The resulting videos and photographs led to a contemplation on the image and viewing practices not previously anticipated, not least on the now endemic uses of advanced imaging technologies as integral parts of surgical operations. Their reassembly as a stop-frame animation and artist's book in physical and electronic form enabled a process of slowing down and re-engagement with the image and physicality of the book itself and processes and with practices of viewing. This was important in reasserting the sense of human agency in our relationship to images in a world where this appears to be increasingly absent.

Background & Aims: Bone marrow (BM) cells form differentiated adult lineages within nonhematopoietic tissues, with a heightened propensity with increasing regenerative pressure dictated by disease. We have previously shown that BM cells engraft into the gut and contribute substantially to the subepithelial intestinal myofibroblast population in the lamina propria. To investigate the reparative capacity of BM in inflammatory bowel disease (IBD), a well-established model of experimental colitis was used., Methods: Lethally irradiated female mice were rescued by a BM transplant from male donors. Colitis was induced 6 weeks posttransplantation by injection of trinitrobenzene sulfonic acid (TNBS), and tissues were analyzed 1-14 days later. Donor-derived cells were detected by in situ hybridization using a Y chromosome-specific probe, and their phenotype was determined by immunohistochemistry., Results: TNBS-induced colitis was manifest as patchy lesions that increased in severity between days 1 and 8, and the mucosa gradually regenerated between days 8 and 14. The contribution of BM to intestinal myofibroblasts was significantly increased in regions of colitis compared with noninflamed regions. Furthermore, BM-derived endothelial cells, pericytes, and vascular smooth muscle cells were frequently interspersed throughout blood vessels, suggesting that these cells facilitate angiogenesis in tissue repair, substantiated by a significant increase in the incidence of BM-derived vascular smooth muscle cells in colitic compared with noninflamed regions. Blood vessels formed entirely from BM-derived cells were also seen, suggesting a role for BM in neovasculogenesis., Conclusions: Our data show that BM contributes to multiple intestinal cell lineages in colitis, with an important function in tissue regeneration and vasculogenesis after injury.

We have identified a large population of CD3(-)7(+) cells in human fetal gut. Three- and four-color flow cytometry revealed a distinct surface Ag profile on this population; the majority were negative for CD4 and CD8, whereas most of the remainder expressed the CD8alphaalpha homodimer. In contrast about half of CD3(+) cells expressed CD4 and half expressed CD8alpha. A large proportion of CD3(-)7(+) cells expressed CD56, CD94, and CD161, and whereas CD3(+) T cells also expressed CD161, they only rarely expressed CD56 or CD94. Further studies were conducted to determine whether the CD3(-)7(+) cells have the potential to differentiate into CD3(+) cells. About half of CD3(-)7(+) cells contain intracellular CD3epsilon. Rearranged TCR gamma-chains were detected in highly purified CD3(-)7(+) cells as an early molecular sign of T cell commitment, and the pattern of rearrangement with V regions spliced to the most 5' Jgamma segment is reminiscent of early thymocyte differentiation. In reaggregate thymic organ cultures, CD3(-)7(+) cells also gave rise to CD3(+) T cells. Thus, we demonstrate that the CD3(-)7(+) cells present in the human fetal gut display a distinct phenotype and are able to develop into CD3(+) T cells.

Infection of mice with the intestinal bacterial pathogen Citrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. Matrix metalloproteinases (MMPs) have been shown to mediate matrix remodeling and cell migration during tissue injury and repair in the intestine. We have previously shown enhanced pathology in infected TNFRp55-/-, IL-12p40-/-, and IFN-gamma-/- mice, and here we show that this is associated with an increase in stromelysin-1 (MMP3) transcripts in colonic tissues. We have therefore investigated the role of MMP3 in colonic mucosal hyperplasia and the local Th1 responses using MMP3-/- mice. In MMP3-/- mice, similar mucosal thickening was observed after infection as in wild-type (WT) mice. Colonic tissues from MMP3-/- mice showed a compensatory increase in the expression of other MMP transcripts, such as MMP7 and MMP12. However, MMP3-/- mice showed delayed clearance of bacteria and delayed appearance of CD4+ T lymphocytes into intestinal lamina propria. CSFE-labeled mesenteric lymph node CD4+ T lymphocytes from infected WT mice migrated in fewer numbers into the mesenteric lymph nodes and colon of MMP3-/- mice than into those of WT mice. These studies show that mucosal remodeling can occur in the absence of MMP3, but that MMP3 plays a role in the migration of CD4+ T lymphocytes to the intestinal mucosa.

The immune response of bovine monocytes-derived dendritic cells (DC) exposed to either live or killed Salmonella enterica serovar Typhimurium was compared. Both live and killed bacteria induced changes in morphology with distinctive formation of processes and up-regulation of the ability of DC to stimulate allogeneic T-cell proliferation. Also, both live and killed bacteria up-regulated the expression of MHC-I, MHC-II and CD80. However, live bacteria induced greater up-regulation of the expression of CD40 and CD86 than killed bacteria. Live bacteria also induced greater up-regulation of transcription for IL-6, IL-12 and GM-CSF than killed bacteria as measured by quantitative RT-PCR. These data suggest that blood-monocyte-derived DC may follow distinct maturation pathways following exposure to live or killed bacteria. These differences are likely to have consequences for the priming of the adaptive immune responses.

Exposing bovine dendritic cells (DC) and macrophages (MPhi) to Salmonella typhimurium at a ratio of 1 cell to 10 bacteria had a cytotoxic effect that was not evident with a ratio of 1000 cells to 1 bacterium. This lower dose was considered to mimic more closely the in vivo situation and a comparison was made with this model of the consequences of infection for MPhi and DC. DC infected with S. typhimurium up-regulated cell surface expression of major histocompatibility class I (MHC-I), MHC-II, CD40, CD80 and CD86. In contrast, infected MPhi did not exhibit detectable changes in expression of cell surface molecules, except for a marginal increase in CD40. mRNA transcription for tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase was up-regulated in both infected DC and infected MPhi, although mRNA transcription for granulocyte-macrophage colony-stimulating factor and IL-12p40 was up-regulated only in infected DC and for IL-10 was only in infected MPhi. Infected DC had an increased ability to stimulate both allogeneic and antigen-specific T-cell responses compared to non-infected controls. In contrast, infected MPhi showed an increased ability to induce allogeneic responses but this was less than seen for DC and no enhancement of ability to induce antigen-specific T cell responses was seen. Thus, in a low-dose infection model that does not result in the cytotoxicity of a substantial percentage of antigen presenting cells, bovine MPhi and DC respond differently to infection with S. typhimurium and this could have important implications for the development of the immune response.

Salmonella typhimurium 4/74 is highly virulent for cattle after oral challenge, causing severe diarrhoea, which is sometimes associated with systemic spread of the micro-organism. Although susceptible to oral challenge, groups of cattle were found to be relatively resistant to subcutaneous challenge with this strain. The virulence of S. typhimurium 4/74 harbouring mutations in htrA and purE was also assessed in cattle. Although S. typhimurium 4/74 htrA and purE are attenuated following oral challenge in mice, cattle were highly susceptible to oral challenge with these mutants. As with the parent S. typhimurium 4/74 strain, cattle exhibited greater susceptibility to oral compared to subcutaneous challenge with S. typhimurium htrA and purE mutants. Following subcutaneous challenge with sublethal levels of S. typhimurium 4/74, calves produced significant levels of antibodies to S. typhimurium soluble extract. No correlation was detected between interferon gamma levels in sera and susceptibility to infection by any route. The concentrations of the acute-phase-associated protein haptoglobin were increased in the sera of five of six cattle inoculated subcutaneously, although increases in concentration were smaller in cattle inoculated orally.