Donna Shows

IL-1RL2 and Its Ligands Contribute to the Cytokine Network in Psoriasis

Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

Dual Infection with Helicobacter bilis and Helicobacter hepaticus in P-Glycoprotein-Deficient mdr1a−/− Mice Results in Colitis that Progresses to Dysplasia

Patients with inflammatory bowel disease (IBD) are at increased risk for developing high-grade dysplasia and colorectal cancer. Animal IBD models that develop dysplasia and neoplasia may help elucidate the link between inflammation and colorectal cancer. Mdr1a-/- mice lack the membrane efflux pump p-glycoprotein and spontaneously develop IBD that can be modulated by infection with Helicobacter sp: H. bilis accelerates development of colitis while H. hepaticus delays disease. In this study, we determined if H. hepaticus infection could prevent H. bilis-induced colitis. Unexpectedly, a proportion of dual-infected mdr1a-/- mice showed IBD with foci of low- to high-grade dysplasia. A group of dual-infected mdr1a-/- animals were maintained long term (39 weeks) by intermittent feeding of medicated wafers to model chronic and relapsing disease. These mice showed a higher frequency of high-grade crypt dysplasia, including invasive adenocarcinoma, possibly because H. hepaticus, in delaying the development of colitis, allows time for transformation of epithelial cells. Colonic epithelial preparations from co-infected mice showed increased expression of c-myc (5- to 12-fold) and interleukin-1alpha/beta (600-fold) by real-time polymerase chain reaction relative to uninfected wild-type and mdr1a-/- animals. This animal model may have particular relevance to human IBD and colorectal cancer because certain human MDR1 polymorphisms have been linked to ulcerative colitis and increased risk for colorectal cancer.

Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease

AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo. METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients. RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.

Sa1755 Peripheral Blood E. coli Outer Membrane Protein C (OmpC)-Specific T-Cells Display a Distinct Immunophenotype

Interleukin-6 Drives Production of Pathogenic Cytokines by Innate Lymphoid Cells in Patients and Mice With Chronic Intestinal Inflammation Nick Powell, Jonathan W. Lo, Paolo Biancheri, Anna Vossenkamper, Eirini D. Pantazi, Emilie Stolarczyk, Alan Walker, Paul Scott, James B. Canavan, Esperanza Perucha, Natividad Garrido-Mesa, Ian Jackson, Francesca Ammoscato, Peter M. Irving, Jeremy D. Sanderson, Bu Hayee, Julian Parkhill, MacDonald Thomas, Graham M. Lord

Tu1295 Effect of Vedolizumab on Circulating Lymphocyte Subsets in IBD

Background: Vedolizumab-mediated blockade of integrin alpha 4/beta 7 on the surface of circulating lymphocytes prevents their trafficking to the intestinal mucosa, and has recently been approved as a therapy for IBD. The effect of such disrupted trafficking on immune cell subset frequencies and the kinetics with which such cells lose this blockade are not known. Methods: Blood from nine patients with IBD was obtained prior to and serially after starting vedolizumab. Thawed lymphocytes from these samples were stained with antibody panels to quantify the frequency of lymphocyte subsets over time. An aliquot of these cells were also stained with labeled vedolizumab, with or without cold competition from unlabeled vedolizumab, to determine the kinetics with which immune cell subsets lose integrin blockade after each dose of vedolizumab. Results: By paired analyses, vedolizumab caused a small but significant increase in the naive (CD45RA+, CCR7+) fraction of CD4+ T cells present in the blood, while reducing the fraction of CD4+ T cells expressing the Th17 marker CD161 and decreasing an IgD+, CD27+ fraction of B cells. Fewer naive cells and more CD45RA-/CCR7effector/memory CD4+ T cells (particularly CD161+ T cells contained therein) expressed integrin alpha 4/beta 7 after vedolizumab exposure. All lymphocyte populations demonstrated rapid and dramatic blockade of integrin alpha 4/beta 7 following vedolizumab exposure, but a small amount of blockade was lost fastest in CD161-high CD8+ T cells, resemblingMAIT cells, followed by CD45RA+/CCR7terminal effector memory CD4+ T cells, naive CD8+ T cells, and CD8+ T cells with intermediate CD161 expression. B cells, NK cells and other T cell populations showed negligible loss of integrin blockade between vedolizumab doses. Conclusions: Vedolizumab caused marked integrin alpha 4/ beta 7 blockade in all lymphocyte populations expressing such integrins. This blockade may be lost more quickly by CD161+ and CD45RA+ T cells than other populations. Integrin blockade was associated with increased naive and decreased CD161+ (Th17-like) CD4 T cells in the blood. More of the latter expressed alpha 4/beta 7 after vedolizumab, suggesting that this agent is causing potentially pathogenic , gut-tropic Th17 cells to accumulate in blood, and thus not traffic to the intestinal mucosa to support bowel inflammation.