Biomedical subjects

P T Chapman

Publications and source records attributed to P T Chapman.

At least 19 recordsLinked to original sources

PubMed2005

The epidemiology of Wegener's granulomatosis and microscopic polyangiitis in a Southern Hemisphere region.

OBJECTIVE: To determine the prevalence of Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) in the province of Canterbury, New Zealand. METHOD: Three hospital clinical databases and the immunology laboratory database were searched and case notes reviewed for patients fulfilling either the 1990 American College of Rheumatology (ACR) criteria for WG or a modification of those criteria that allowed for antineutrophil cytoplasmic antibody (ANCA) positivity in the absence of granulomatous vasculitis. MPA was defined by the Chapel Hill consensus definition; however, in the absence of histological evidence of pauci-immune glomerulonephritis, ANCA positivity in association with evidence of active glomerular disease was included as a criterion. The point prevalence at 31 December 2003 and the 5-yr period prevalence for the interval 1 January 1999 to 31 December 2003 were calculated. RESULTS: Seventy-three patients with WG and 28 patients with MPA fulfilled the inclusion criteria. A 5-yr period prevalence of 152 WG cases/million [95% confidence interval (CI) 117-186] and 58 MPA cases/million (95% CI 37-80) was calculated using 2001 census data as denominator. Nineteen patients with WG died and 10 patients with MPA died during the study period, resulting in a point prevalence for survivors at 31 December 2003 of 112 cases/million (95% CI 82-142) and 37 cases/million (95% CI 20-55), respectively. Using unmodified ACR criteria the 5-yr period and point prevalence for WG were 131/million (95% CI 99-163) and 93.5/million (95% CI 66-121), respectively. Apart from respiratory tract involvement, which formed part of the case definition of WG, organ involvement was similar in both diseases. CONCLUSION: The prevalence of WG and MPA in Canterbury is the highest reported to date. Restricting the case definition of WG to the ACR classification criteria we found a prevalence equivalent to that described in northern Norway. The clinical severity and serological characteristics were similar to descriptions in other WG and MPA patient cohorts. Studies of disease prevalence in other Southern Hemisphere centres will determine if the observed north-south negative disease gradient in the Northern Hemisphere is reciprocated.

Adult↗

PubMed2005

Adult-onset inflammatory myopathy: North Canterbury experience 1989-2001.

AIM: To perform a clinical audit of all patients diagnosed with inflammatory myopathy in the North Canterbury region. METHODS: A retrospective case note audit of patients with a discharge diagnosis of inflammatory myopathy from June 1989 to June 2001 was performed. The audit was based at Christchurch Hospital, New Zealand, which services a population of 430,000. RESULTS: Of 77 case notes reviewed, 44 patients were identified who were considered to fulfil clinical criteria for inflammatory myopathy. There was a female preponderance (80% female, 20% male). Diagnostic categories in descending order of frequency included: dermatomyositis (41%), polymyositis (39%), inclusion body myositis (IBM) (14%) and overlap syndromes (6%). Malignancy-associated myositis occurred in 20% overall (dermatomyositis 11%, polymyositis 9%). Delays in diagnosis and late age at presentation (average 72 years) were seen in the IBM group. Proximal limb weakness was common, but not universal at presentation (80%). A muscle biopsy was performed in all patients and electromyography in 82%. All were treated with high dose prednisone (0.5-1 mg/kg) of whom 29% were maintained on prednisone alone. Immunosuppressives/immunomodulators used included: azathioprine (58%), methotrexate (31%), intravenous immunoglobulin (13%), chlorambucil (13%), and cyclophosphamide (9%). Thirteen patients (42%) required more than one agent, with three trialling five agents. There were 59 relapses in 20 patients (45%), with mean time to first relapse of 7.8 months. At audit completion, 33% had deceased with malignancy and respiratory failure the main causes. CONCLUSION: Inflammatory myopathy is a challenging condition in both diagnosis and management. Our audit has shown delays in the diagnosis of IBM, a relatively high incidence of malignancy and a notable risk of relapse and mortality.

Aged↗

PubMed2002

Scintigraphy using a technetium 99m-labelled anti-E-selectin Fab fragment in rheumatoid arthritis.

OBJECTIVE: We previously described a novel radiolabelled monoclonal antibody (1.2B6), which reacts with porcine E-selectin, for targeting activated endothelium as a means of imaging inflammatory disorders, and presented initial clinical work based on (111)In-labelled antibody. The aim of the present study was to evaluate a Fab fragment of 1.2B6 labelled with (99m)Tc in patients with rheumatoid arthritis (RA) by comparison with (i) (111)In-labelled 1.2B6 F(ab')(2) and (ii) conventional bone scanning. METHODS: (99m)Tc-1.2B6-Fab ( approximately 440 MBq) and (111)In-1.2B6-F(ab')(2) ( approximately 27 MBq) were compared in 10 patients using a double-isotope protocol. Images were obtained 4 and 20-24 h after injection. Two normal volunteers were also imaged. In a separate group of 16 patients, (99m)Tc-1.2B6-Fab and (99m)Tc-oxidronate ((99m)Tc-HDP) ( approximately 740 MBq) were compared on the basis of visual and semi-quantitative analysis of joint uptake (joint/soft tissue ratios) 4 h after injection. The respective biodistributions and blood clearances of the two 1.2B6 fragments were also compared. RESULTS: Image contrast was slightly better with (99m)Tc-Fab at 4 h but equal for the two tracers at 24 h. Diagnostic accuracy, taking joint tenderness or swelling as the clinical endpoint, was 76% for both fragments at 24 h. Plasma clearance of (99m)Tc-Fab was faster than that of (111)In-F(ab')(2) (t(1/2) 142 vs 421 min; P<0.0001). (99m)Tc-Fab appeared somewhat unstable in vivo, as shown by activity in the thyroid gland and bowel. The diagnostic accuracy of (99m)Tc-Fab was 88%, higher than that of (99m)Tc-HDP (57%) as a result of the low specificity of the latter in RA. Receiver operating characteristic (ROC) curve analysis using joint/soft tissue ratios as a variable cut-off showed that (99m)Tc-Fab discriminates better than (99m)Tc-HDP between actively inflamed and silent joints (Z=4.72; P<0.0001). No uptake of (99m)Tc-Fab was observed by inactive or normal joints, whereas (99m)Tc-HDP was taken up by all joints to a variable degree, making the decision as to whether a particular joint is actively involved or chronically damaged very difficult. CONCLUSION: (99m)Tc-anti-E-selectin-Fab scintigraphy can be used successfully to image synovitis with better specificity than (99m)Tc-HDP bone scanning. The advantages over (111)In-1.2B6-F(ab')(2) are easier availability of the radionuclide, improved physical properties and optimal imaging 4 h after injection.

Adult↗

PubMed2000

Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis.

OBJECTIVE: To verify the hypothesis that in rheumatoid arthritis (RA), tumor necrosis factor alpha (TNFalpha) plays a critical role in regulating leukocyte trafficking and chemokine levels. METHODS: Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNFalpha monoclonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+ macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, Groalpha, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Anti-TNFalpha therapy in RA significantly reduced 111In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. CONCLUSION: TNFalpha blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.

Aged↗

PubMed1999

The inhibition of myeloperoxidase by ceruloplasmin can be reversed by anti-myeloperoxidase antibodies.

BACKGROUND: The purpose of this study was to characterize the recently reported inhibition of myeloperoxidase (MPO) by ceruloplasmin and to determine whether this may be disturbed in the presence of anti-MPO antibodies. METHODS: Specificity of the binding between ceruloplasmin and MPO was confirmed by Western blotting and enzyme-linked immunosorbent assay (ELISA), and the enzymatic activity of MPO was measured in the presence of ceruloplasmin, affinity-purified anti-MPO antibodies, or both. The affinity of the binding between MPO and ceruloplasmin and MPO and the anti-MPO antibodies was measured using a biosensor, with the results confirmed by chaotrope ELISA. RESULTS: Affinity-purified anti-MPO antibodies from patients with microscopic polyangiitis and florid renal vasculitis inhibited the binding between ceruloplasmin and MPO to a maximum of 72.9 +/- 12.8%, whereas those from patients with Wegener's granulomatosis and only minimal renal involvement inhibited the binding to a maximum of only 36.8 +/- 10.9% (P < 0. 001), with comparable reversal of the ceruloplasmin-mediated inhibition of MPO activity. Measurement of the affinity of the interactions demonstrated that binding between MPO and the anti-MPO antibodies is stronger than that between MPO and ceruloplasmin (1.61 x 107 to 1.33 x 108 vs. 7.46 x 106 m-1), indicating that binding to the autoantibody would be favored in vivo. CONCLUSIONS: This study confirms a role for ceruloplasmin as a physiological inhibitor of MPO, and demonstrates how the inhibition may be disrupted in the presence of anti-MPO antibodies. Because a majority (16 of 21) of the antibodies did not themselves inhibit MPO activity, their interference with the inhibition mediated by ceruloplasmin may be brought about by steric hindrance consequent upon the binding of the antibody to a dominant epitope at or near the active site.

Adult↗

PubMed1999

Pulmonary granulocyte kinetics in relation to endothelial and granulocyte activation.

The aim of the study was to measure the peripheral blood levels of soluble E-selectin in patients with systemic inflammation and compare them with in vivo granulocyte activation, pulmonary intravascular granulocyte pooling, pulmonary extravascular granulocyte migration and 99mTc-diethylenetriaminepenta-acetic acid (DTPA) aerosol clearance, an index of lung injury. The level of soluble E-selectin was measured by capture ELISA. Granulocytes were labelled with 111In and 99mTc for quantification of pulmonary granulocyte kinetics. The pulmonary vascular granulocyte pool (PGP) was expressed as a fraction of the total blood granulocyte pool. Pulmonary granulocyte migration was quantified on 24-h images using the 111In signal. Granulocyte activation was quantified as the percentage of circulating cells showing shape change ('primed'). Lung injury was assessed from the clearance rate of inhaled 99mTc-DTPA aerosol. Eighteen patients with systemic inflammation were studied: five with inflammatory bowel disease, eight with systemic vasculitis, four with graft versus host disease and one with a recent renal transplant. The peripheral blood levels of soluble E-selectin were significantly elevated in patients with systemic inflammation. The level of soluble E-selectin showed a significant association with granulocyte migration (Spearman rank correlation coefficient, Rs=0.53; P<0.05) but not with PGP or with the percentage of cells showing shape change (P>0.05 for both). Granulocyte migration was bimodal: patients were therefore subdivided into 'migrators' and 'non-migrators'. Soluble E-selectin level, 99mTc-DTPA clearance and PGP, but not the percentage of cells showing shape change, were significantly higher in migrators than in non-migrators. We conclude that pulmonary intravascular granulocyte pooling is increased in the presence of increased numbers of circulating primed granulocytes but increased pooling does not by itself promote granulocyte migration into the lung interstitium. Insofar as an elevated level of E-selectin in peripheral blood reflects vascular endothelial activation, the data are consistent with the notion that pulmonary endothelial activation is required, in addition to granulocyte activation and an expanded PGP, for granulocyte migration into lung parenchyma and, therefore, for lung injury to occur.

Adult↗

PubMed1997

Expression of vascular cell adhesion molecule-1 by vascular endothelial cells in immune and nonimmune inflammatory reactions in the skin.

Expression of VCAM-1 was compared with that of E-selectin in cytokine-induced lesions and in delayed-type hypersensitivity reactions to tuberculin purified protein derivative (PPD) in pig skin. Lumenally expressed Ags were quantified by measuring localization in skin of i.v. injected (111)In-mAb 10.2C7 (anti-vascular cell adhesion molecule-1 (anti-VCAM-1), (125)I-mAb 1.2B6 (anti-E-selectin), and (99m)Tc-MOPC21 (control IgG1). Anti-VCAM-1 mAb uptake was greater following intradermal (i.d.) injection of TNF-alpha than following injection of IL-1, while the two cytokines induced similar uptake of anti-E-selectin. In immunologically naive pigs there was no detectable increase in anti-VCAM-1 after i.d. injection of PPD, although anti-E-selectin uptake was increased at 3 and 6 h. In contrast, i.d. injection of PPD in sensitized pigs led to increased uptake of both anti-VCAM-1 and anti-E-selectin at 6, 8, 24, and 48 h, each of which was significantly greater than the uptake of control IgG1 into the same lesions (each p < 0.01). Anti-TNF-alpha mAb abolished the increased uptake of anti-VCAM-1 3 and 8 h following i.d. injection of PPD in sensitized pigs and significantly inhibited uptake at 24 h (p = 0.0025), but did not significantly reduce uptake of anti-E-selectin. We conclude that in this delayed-type hypersensitivity model 1) E-selectin expression by endothelial cells follows sequential Ag nonspecific and immune-specific phases, 2) increased VCAM-1 expression by endothelial cells is only seen in sensitized animals, and 3) expression of VCAM-1 appears to be relatively more dependent on TNF-alpha than E-selectin. Differential expression of E-selectin and VCAM-1 may influence the leukocytic infiltrate during the course of nonspecific and immune-specific inflammatory reactions.

Animals↗

PubMed1997

Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: in vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1.

OBJECTIVE: There is relatively little direct evidence for the roles of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) in activating endothelium in vivo. The aim of this study was to use in vitro and in vivo models to investigate the contribution of these cytokines to both E-selectin expression and the recruitment of polymorphonuclear cells (PMN) in monosodium urate monohydrate (MSU) crystal-induced inflammation. METHODS: MSU crystals were incubated with freshly isolated mononuclear cells, after which the harvested supernatants were tested for their ability to induce E-selectin expression during coculture with human umbilical vein endothelial cells. Subsequent experiments were performed with the addition of neutralizing anticytokine antibodies/antisera. The role of TNF alpha was then studied in an MSU crystal-induced monarthritis model, in the presence or absence of anti-TNF alpha (5 mg/kg intravenously). 99mtechnetium (99mTc)-labeled PMN cells and (111)indium (111In)-labeled anti-E-selectin monoclonal antibody (MAb) 1.2B6 were intravenously administered 4 hours after intraarticular injection to quantify PMN recruitment and E-selectin expression in inflamed joints. RESULTS: MSU crystals were a potent stimulus for IL-1 and TNF alpha production by monocytes in vitro, and these cytokines fully accounted for MSU crystal-stimulated, monocyte-mediated endothelial activation. In the MSU crystal-induced monarthritis model, TNF alpha blockade was very effective in suppressing both E-selectin expression and PMN emigration into the inflamed joints, as judged by gamma-camera image analysis and postmortem tissue counting following the intravenous injection of 99mTc-PMN and 111In-anti-E-selectin MAb. CONCLUSION: IL-1 and TNF alpha appear to be the only factors released by monocytes following incubation with MSU crystals, which induce E-selectin expression in vitro. Anti-TNF alpha is effective in suppressing endothelial activation and PMN recruitment in vivo E-selectin imaging can be used to assess the endothelial response to therapy and may prove useful for clinical studies.

Animals↗

PubMed1997

A comparison between 111In-anti-E-selectin mAb and 99Tcm-labelled human non-specific immunoglobulin in radionuclide imaging of rheumatoid arthritis.

We have developed and validated a method for imaging inflammation using a monoclonal antibody (1.2B6) against E-selectin, an endothelial-cell specific adhesion molecule. This study was undertaken to compare 111In-1.2B6 with 99Tcm-labelled non-specific IgG (99Tcm-HIG) in the detection of synovitis in 11 patients with rheumatoid arthritis (RA). Imaging was performed 4 h and 20-24 h post-injection (pi) of 555 MBq 99Tcm-HIG and 15 MBq 111In-1.2B6. Scintigraphic results were compared with clinical scores of joint involvement. Joint uptake was semiquantitated. The scintigraphic appearances with both tracers correlated well, although 111In-1.2B6 at 24 h showed the highest detection rate. Taking joint tenderness or swelling as evidence of clinical activity, the sensitivity of 111In-1.2B6 at 4 h and 24 h was 69% and 82%, respectively, compared with 69% and 62% for 99Tcm-HIG. 111In-1.2B6 also displayed abnormal activity over a number of joints that appeared silent on clinical examination. Joint-to-soft tissue ratios were higher for 111In-1.2B6 at 24 h (4.0 +/- 1.9; p < 0.0001 vs all) than at 4 h (2.4 +/- 1.4) or than for 99Tcm-HIG at 4 h and 24 h (1.6 +/- 0.5 and 2.3 +/- 0.7, respectively). Net 111In counts over joints increased significantly between 4 h and 24 h (mean change: 54 +/- 40%). This study demonstrates that 111In-1.2B6 scintigraphy is a sensitive method by which to assess RA activity and that targeting is more intense and specific than using 99Tcm-HIG. However, the optimum time for 111In-1.2B6 scintigraphy is 24 h whereas good results are already obtained with 99Tc-HIG at 4 h pi. Current efforts are directed at developing 99Tcm-labelled 1.2B6 for imaging endothelial activation.

Aged↗

PubMed1996

Use of a radiolabeled monoclonal antibody against E-selectin for imaging of endothelial activation in rheumatoid arthritis.

OBJECTIVE: To determine the potential of 111In-labeled anti-E-selectin monoclonal antibody (MAb) to image localized endothelial activation in rheumatoid arthritis (RA). METHODS: Fourteen patients with RA were studied after intravenous administration of 111In-labeled F(ab')2 fragments of MAb against the cytokine-inducible endothelial cell activation antigen E-selectin (MAb 1.2B6). To compare uptake of 1.2B6 with that of nonspecific immunoglobulin, 111In-labeled polyclonal human immunoglobulin (HIG) was separately administered to 6 of these patients and the relative uptake of each tracer was determined. RESULTS: Prominent and discrete uptake of the radiolabeled MAb 1.2B6 was clearly visible in inflamed joints of all patients. Compared with 111In-HIG, 111In-1.2B6 provided superior images in terms of sensitivity and image intensity. Furthermore, the distribution of uptake in inflamed joints was different for the 2 tracers, with 1.2B6 showing a more focal localization in synovium. CONCLUSION: This study demonstrates that it is possible to objectively assess E-selectin expression on activated endothelium in vivo in patients with RA, using a radiolabeled MAb. This technique has considerable potential for monitoring disease activity and response to therapy in inflammatory diseases.

Aged↗

PubMed1996

Characterization of E-selectin expression, leucocyte traffic and clinical sequelae in urate crystal-induced inflammation: an insight into gout.

The self-limiting response to urate crystals allows the exploration of events involved in both the onset and resolution of gout. Using i.v. injected radiolabelled anti-E-selectin monoclonal antibody 1.2b6 together with differentially radiolabelled neutrophils, mononuclear cells and albumin, we have characterized the expression of E-selectin in relation to leucocyte traffic, microvascular permeability and clinical sequelae following intracutaneous injection of monosodium urate crystals. We found that the inflammatory response in this model involved several distinct phases. First, E-selectin expression increased over 2-6 h in the context of increases in neutrophil and mononuclear cell accumulation, and albumin leakage. Secondly, leucocyte accumulation rapidly declined despite persisting E-selectin expression. Thirdly, E-selectin expression peaked at approximately 8 h and then fell despite an increase in clinically detectable erythema and induration. Lastly, these clinical manifestations of inflammation resolved despite the continued presence of urate crystals in the tissues. The further dissection of mechanisms regulating these phases will lead to a better understanding of events in both the pathogenesis and resolution of gout. Of broader significance, this inflammatory model may yield information about the protective events that underly resolution of inflammation, and provide insights into factors which determine chronicity.

Albumins↗

PubMed1995

Clearance pathways of soluble immune complexes in the pig. Insights into the adaptive nature of antigen clearance in humans.

Efficient delivery of immune complexes (ICs) to the mononuclear phagocytic system, and subsequent IC processing, may prevent their potentially harmful effects in other tissues and may also be important in the development of humoral immune responses. In mice, rabbits, and primates, the liver and spleen are the main sites of IC clearance. It has been demonstrated previously that the pulmonary capillaries in the pig are lined with macrophages and that certain particulates, including bacteria, localize to this organ. In this study, we used gamma scintigraphy to explore the sites and kinetics of clearance of soluble IC comprising 123I-labeled hepatitis B surface Ag (HBsAg):porcine anti-HBsAg in the Large White pig. At t = 10 min after i.v. injection, 43 +/- 5% (mean +/- SE) IC localized in the lungs, and 36 +/- 6% counts in the liver. At t = 85 min, values were: lungs, 15 +/- 4% and liver, 29 +/- 2%. Findings were similar following intraarterial injection. Complement depletion resulted in more rapid initial IC clearance (t1/2 = 5 min), reduced lung uptake (23 +/- 3% at 10 min), and impaired IC catabolism. In normal animals, 5 to 7% injected IC bound to PBMCs, but no E binding was seen. A fall in PBMC numbers (46 to 59% of baseline), was observed following IC injection. These findings contrast with our previous observations using analogous IC in humans, in which we did not observe any change in peripheral blood leukocyte counts consequent upon complex processing, suggesting that in humans, Es may function as a buffering system for complement-bearing IC in the circulation, preventing their interaction with leukocytes bearing complement and FcR, and the potential activation of these cells.

Animals↗

PubMed1995

Leukocyte adhesion molecules.

The last few years have seen an enormous expansion of knowledge regarding the role of cell surface adhesion molecules in biological processes. This article discusses the contribution that adhesion molecules make to the traffic of leukocytes into and within synovium and to the capacity of leukocytes to perform their specialised functions. Because of their importance in cellular interactions, adhesion molecules represent a major potential target for antiinflammatory therapy in rheumatoid and other inflammatory arthritides.

Arthritis, Rheumatoid↗

PubMed1995

Inflammatory arthritis: imaging of endothelial cell activation with an indium-111-labeled F(ab')2 fragment of anti-E-selectin monoclonal antibody.

PURPOSE: To use imaging performed with an indium-111-labeled F(ab')2 fragment of monoclonal antibody that recognizes E-selectin (1.2B6) to evaluate inflammation. MATERIALS AND METHODS: After the in vivo immunoreactivity of In-111-F(ab')2 was verified, imaging experiments were conducted on pigs with induced arthritis of the right knee. In-111-labeled 1.2B6-F(ab')2, technetium-99m-hexamethylpropyleneamine oxime-labeled polymorphonuclear leukocytes (PMNs), and iodine-125-MOPC 21-labeled F(ab')2 (the control) were administered by means of intravenous injection. Scintigrams were obtained until 20 hours after injection, and tissue sampling was performed. RESULTS: Scintigrams showed uptake of 1.2B6 in the right knee but only faint filling of the joint space with PMNs. The right knee-to-left knee ratios on images obtained 20 hours after injection of the tracers were 10.8 +/- 3.6 for 1.2B6 and 1.1 +/- 0.4 for PMNs (P < .05). CONCLUSION: Endothelial cell immunotargeting with a radiolabeled anti-E-selectin F(ab')2 monoclonal antibody is feasible for use in imaging of inflammation.

Animals↗

PubMed1994

Noninvasive imaging of E-selectin expression by activated endothelium in urate crystal-induced arthritis.

OBJECTIVE: To assess the expression of the cytokine-inducible endothelial leukocyte adhesion molecule E-selectin during the evolution of urate crystal-induced arthritis, using a recently described radiolabeled monoclonal antibody (MAb) imaging technique. METHODS: Monosodium urate (MSU) crystals and saline alone were injected respectively into the right (inflamed) and left (control) knees of 3 young pigs. Four hours later, 111In-labeled 1.2B6 F(ab')2 (anti-E-selectin MAb) and 125I-labeled MOPC 21 F(ab')2 (control MAb) were injected intravenously. Uptake of 1.2B6 in inflamed and control joints was assessed by scintigraphy 7 and 24 hours after intraarticular injection of MSU crystals. Immunohistochemistry studies and radioactivity counting of tissues were performed postmortem to confirm the observations from scintigraphy. RESULTS: MAb 1.2B6 F(ab')2 scintigraphic images of the knees revealed a significantly increased uptake in the right (inflamed) knee at 7 and 24 hours postinjection, particularly over the joint space. These in vivo images were consistent with E-selectin expression in the inflamed tissue detected by immunohistochemistry and with radioactivity counts postmortem. The synovial localization ratio (inflamed:control synovium counts) was 25.4 +/- 9.7 (mean +/- SD) for the anti-E-selectin MAb compared with 2.5 +/- 0.9 for the control MAb (P < 0.05, by paired Student's t-test). CONCLUSION: E-selectin is expressed by synovial endothelium during the evolution of urate crystal-induced arthritis and can be detected noninvasively using a radiolabeled MAb. This E-selectin imaging technique has considerable potential for the noninvasive assessment of endothelial activation in arthritis and other inflammatory rheumatic diseases.

Animals↗

PubMed1994

Adenocarcinoma of the colon and associated necrotizing vasculitis of mesenteric arteries.

Vasculitis associated with malignancy is uncommon, with the most well-known association being that between hairy cell leukaemia and polyarteritis nodosa. The less common association of vasculitis and solid tumours usually involves a cutaneous leukocytoclastic vasculitis. We report a patient with Duke's C adenocarcinoma of the sigmoid colon with associated necrotizing vasculitis of the mesenteric arteries and postulate that local factors may predominate in its pathogenesis.

Adenocarcinoma↗

PubMed1994

Imaging vascular endothelial activation: an approach using radiolabeled monoclonal antibodies against the endothelial cell adhesion molecule E-selectin.

UNLABELLED: E-selectin is an endothelial cell-specific adhesion molecule for leukocytes expressed on the luminal surface of vascular endothelium during inflammatory responses. Because E-selectin expression is dependent upon ongoing stimulation by cytokines, this molecule offers a potentially useful target for imaging tissues in disease states involving cytokine-mediated endothelial cell activation. METHOD: To assess the imaging potential of an anti-E-selectin monoclonal antibody (Mab) 1.2B6, the accumulation of intravenously injected 111In-labeled Mab 1.2B6 was compared to that of 111In-control antibody in a model of arthritis in the pig. Injection of phytohaemagglutinin (PHA) into a knee led to E-selectin expression on vessels in the synovium and draining deep inguinal lymph nodes, as demonstrated by immunohistology. No E-selectin expression was seen in the control knee injected with buffer alone. Animals were given 111In-Mab 1.2B6 or 111In-control antibody intravenously 3 hr after the intra-articular injection of PHA. Radiolabeled antibody uptake was measured by direct counting of tissues 25 hr postmortem. RESULTS: The accumulation of radiolabeled control IgG in synovium and draining deep inguinal lymph nodes of PHA-injected knees was significantly higher than accumulation in tissues injected with buffer alone; however, the comparable ratios in animals receiving radiolabeled Mab 1.2B6 were significantly greater. Scintigraphy performed 24 hr after 111In-Mab 1.2B6 injection showed obvious localization of activity in the inflamed knee in each of three animals. CONCLUSION: Radiolabeled anti-E-selectin Mab can be used to image localized inflammatory tissues. This approach may be useful for investigating activated endothelium in human disease.

Animals↗

PubMed1993

Respiratory failure in Wegener's granulomatosis: response to pulse intravenous methylprednisolone and cyclophosphamide.

We describe a patient with respiratory failure due to Wegener's granulomatosis (WG) who obtained a dramatic and sustained response to pulse intravenous methylprednisolone and cyclophosphamide. Discussion includes a review of the literature with respect to the relative merits of daily oral cyclophosphamide versus pulse intravenous cyclophosphamide in WG and other vasculitides. While the combination of daily oral steroids and daily oral cyclophosphamide dramatically improves the outcome of WG, this therapy is not without serious side effects. Pulse therapy may be equally as effective and may lessen the frequency of serious side effects.

Administration, Oral↗