Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model

Interleukin 1 (IL-1) is an important mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). The balance between IL-1 and IL-1Ra as a natural inhibitor plays a vital role in a variety of diseases. Here, we investigated whether changes seen during IBD are induced spontaneously in mice lacking a functional IL-1rn gene. Histological staining was performed on the jejunum and ileum of BALB/c IL-1rn+/+ and IL-1rn-/- mice to characterize crypt-villus height, villus width, and number of goblet cells per villus. Pro-inflammatory cytokines, immune cell infiltration and matrix-degrading enzymes, together with the production of intestinal enzymes and the integrity of tight and adherent junction proteins were determined using immunohistochemistry. In the small intestine of BALB/c IL-1rn-/- mice the villus heights were significantly reduced; and in the ileum this was accompanied by a decrease in villi width. There was also an increase in goblet cell number and mucin production compared to wild-type mice. IL-1α and IL-1β immunopositivity were increased, whilst IL-1R1 expression was decreased in IL-1rn-/- mice. IL-15 and TNFα were also increased in older IL-1rn-/- mice. Increased polymorphonuclear and macrophage infiltration were seen in IL-1rn-/- mice, whilst expression of matrix-degrading enzymes and digestive enzymes were unchanged, except for dipeptidyl peptidase IV which was increased in younger IL-1rn-/- mice compared to wild type mice. The expression of tight and adhesion junctions were also dramatically decreased in IL-1rn-/- mice. In conclusion, IL-1rn-/- mice developed spontaneous abnormalities which displayed features associated with IBD, demonstrating a clear role for IL-1 in IBD

IN VITRO AND IN VIVO STUDIES OF THE IMMUNE RESPONSE TO SHEEP ERYTHROCYTES USING PARTIALLY PURIFIED CELL PREPARATIONS

The BSA density-gradient technique for separating mouse spleen cells into partially purified populations has been used to compare the responsiveness of such populations to SRBC using in vivo and in vitro techniques. Two major populations were distinguished, one of which responded very well in vivo with an exponential dose response and poorly in vitro (fraction 3), and another which responded in vivo and in vitro with a linear dose response (fraction 2). A light density, radiation-resistant component was identified which markedly stimulated the response of fraction 3 in vitro, and a density gradient profile was obtained for this cell which did not correspond with a macrophage profile. A high density, radiation-sensitive cell was identified which stimulated the response of PFC precursors in lighter regions of the gradient. The activity of this cell could be replaced using thymus cells. A density profile for the PFC precursor cell was obtained by assaying small numbers of spleen cell fractions in the presence of an excess of the two auxiliary cell types

Breast conservation, mastectomy and axillary surgery in New South Wales women in 1992 and 1995

To measure the increase in uptake of BCT in NSW and its determinants, we examined Cancer Registry records of 2020 women with breast cancer in 1992 and 2883 in 1995 linked to records of their surgical treatment in the NSW Inpatient Statistics' Collection. In parallel, we examined trends and determinants in axillary surgery for breast cancer. Breast conservation increased from 39% of breast cancer in 1992 to 45% in 1995, mainly in women with the smallest cancers. In 1995, mastectomy was still most common in women with larger cancers (OR for breast cancers 3+ cm relative to <1 cm = 5.6, 95% CI 2.9–10.7) and cancers that had spread beyond the breast (OR = 2.0, 95% CI 1.4–2.7 relative to localized to the breast). Urban women had fewer mastectomies than rural women. Axillary surgery, common in 1992 (78%) and 1995 (82%), fell steeply with increasing age and more often accompanied mastectomy (93% in 1995) than BCT (67% in 1995). In 1995 the odds for axillary surgery were some two-fold or more higher for all cancers 1 cm or more in diameter compared with those <1.0 cm and highest for 2.0–2.9 cm cancers (OR = 3.3 95% CI 1.7–6.7 relative to <1.0 cm). Regional spread of the cancer at diagnosis was not a strong predictor. In the absence of collection of treatment data by cancer registries, linkage of cancer registry records with hospital inpatient data is an effective alternative for monitoring breast cancer treatment trends. © 2001 Cancer Research Campaign http://www.bjcancer.co

Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene

Branch points and flexures in the high pressure arterial system have long been recognized as sites of unusually high turbulence and consequent stress in humans are foci for atherosclerotic lesions. We show that mice that are homozygous for a null mutation in the gene encoding an endogenous antiinflammatory cytokine, interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation involving branch points and flexures of the aorta and its primary and secondary branches. We observe massive transmural infiltration of neutrophils, macrophages, and CD4(+) T cells. Animals appear to die from vessel wall collapse, stenosis, and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do not die from arteritis within a year of birth but do develop small lesions, which suggests that a reduced level of IL-1ra is insufficient to fully control inflammation in arteries. Our results demonstrate a surprisingly specific role for IL-1ra in the control of spontaneous inflammation in constitutively stressed artery walls, suggesting that expression of IL-1 is likely to have a significant role in signaling artery wall damage

Mononuclear-cell infiltration in ovarian cancer. I. Inflammatory-cell infiltrates from tumour and ascites material.

Malignant effusions and tumour tissue obtained at surgery provided material for a study of the prognostic value of the various inflammatory cells in the prognosis of human ovarian cancer. Ascitic fluids predominantly contained inflammatory cells; tumour cells, both singly and in clusters, were a minor component. Tumour cells were usually in excess in dispersed solid material. Some patients had significant proportions of lymphocytes and macrophages in their solid tumour, and these patients invariably responded to therapy. Sedimentation-velocity separation at unit gravity provided tow populations of inflammatory cells. One consisted of mononuclear cells similar in size to those in the patients blood: the other consisted of one or more large macrophage populations, distinct in morphology and enzymatic markers from both blood monocytes and each other. T lymphocytes were enriched in ascites fractions (78%) and in the tumour-derived mononuclear fraction (71%) compared to patient blood (60%). The T-cell subset characterized by ANAE reactivity was markedly depleted in the tumour-infiltrating fraction (17%) compared to patient blood (62%) or patient blood (51%). Esterase-positive monocyte-like cells were more frequent in the tumour-infiltrating fraction (17%) than ascites (7%) or blood (12%). B lymphocytes were infrequent in solid tumours and difficult to assess in ascites. Histiocyte-like macrophages were present in the higher-velocity tumour-cell containing fractions of both solid and ascitic material. The variation in infiltrating cells between patients and between tumour and ascites of the same individual was marked

CLASSIFICATION OF THYMUS-DERIVED AND MARROW-DERIVED LYMPHOCYTES BY DEMONSTRATION OF THEIR ANTIGEN-BINDING CHARACTERISTICS

Antigen-binding cells of T and B origin can readily be determined by quantitating the number of sheep erythrocytes per rosette after glutaraldehyde fixation. The T1 and T2 populations have low antigen-binding properties and are very unstable without fixation. The B1 and B2 populations are stable and correlate with precursor and secretory cells. Fixation of rosettes permits a sensitive test for studying differentiation of T and B cells