WO1995014230A1 - Marker for crohn's disease and multiple sclerosis - Google Patents
Marker for crohn's disease and multiple sclerosis Download PDFInfo
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- WO1995014230A1 WO1995014230A1 PCT/CA1994/000635 CA9400635W WO9514230A1 WO 1995014230 A1 WO1995014230 A1 WO 1995014230A1 CA 9400635 W CA9400635 W CA 9400635W WO 9514230 A1 WO9514230 A1 WO 9514230A1
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- WIPO (PCT)
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- cells
- crohn
- disease
- cd45ro
- antigen
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/285—Demyelinating diseases; Multipel sclerosis
Definitions
- the invention relates to the detection of Crohn's disease and multiple sclerosis by means of a B cell marker.
- Crohn's disease is a systemic immunoregulatory disorder, with primarily intestinal manifestations. Although the etiology of this disease is poorly understood, an increase in intestinal permeability has been suggested as a key initiating event (Hollander et al. (1986), Ann. Int. Med. , v. 105, pp. 883-885) .
- the present inventors have identified a B-cell differentiation antigen or marker which provides a useful marker for Crohn's disease. Presence of this marker permits differentiation of Crohn's disease from ulcerative colitis and celiac sprue by means of a simple, rapid blood test. This B-cell marker has also been found to be useful as a means of monitoring disease progression and predicting likely severity in Crohn's disease patients. Examination of relatives of patients suffering from Crohn's disease has also revealed that this B-cell marker is the basis of a convenient blood test for pre- clinical Crohn's disease. Presence of this marker in relatives shows a correlation with above-normal intestinal permeability.
- MS Multiple sclerosis
- a method for detecting Crohn's disease in a human subject comprising obtaining a peripheral blood sample from the subject; isolating or identifying B cells from the blood sample; and determining the antigen CD45RO on the surface of the B cells, the presence of the antigen being indicative of Crohn's disease.
- a method for distinguishing Crohn's disease from ulcerative colitis and celiac sprue in a human subject presenting with intestinal symptoms comprising obtaining a peripheral blood sample from the subject; isolating or identifying B cells from the blood sample; and determining the antigen CD45RO on the surface of the B cells, the presence of the antigen being indicative of Crohn's disease.
- a method for detecting pre-clinical Crohn's disease in a human subject comprising obtaining a peripheral blood sample from the subject; isolating or identifying B cells from the blood sample; and determining the antigen CD45RO on the surface of the
- a method for detecting multiple sclerosis or pre-clinical multiple sclerosis in a human subject comprising obtaining a peripheral blood sample from the subject; isolating or identifying B cells from the blood sample; and determining the antigen CD45RO on the surface of the B cells, the presence of the antigen being indicative of multiple sclerosis or pre-clinical multiple sclerosis.
- kits for detecting Crohn's disease or pre-clinical Crohn's disease in a human subject comprising
- CD45RO a second antibody specific for the CD45 isoform
- Figure 1A shows CD45RA expression on CD19 + PBMC
- Figure 2A shows CD45RO expression on CD19 + PBMC
- Figure 2D from Crohn's disease. Axes as in Figure 1.
- Figure 3 shows a plot of the percentage of
- FIG. 4 shows CD45RA " RO + expression on CD19 +
- PBMC B-cells from patients with Crohn's disease X axis
- CDAI Crohn's Disease Activity Index
- Figure 5 shows intestinal permeability, expressed as lactulose/mannitol excretion ratio (Y axis) of indicated groups of subjects (X axis) .
- Figure 6 shows the percentage of CD19 + peripheral B-cells positive for CD45RO (Y axis) in
- Figure 7 shows the percentage of CD19 + peripheral B-cells positive for CD45RO (Y axis) in
- IBD inflammatory bowel diseases
- Humoral immune abnormalities in IBD involve various autoantibodies including rheumatoid factor and anti-colon antibodies disputedly secondary to the underlying mucosal inflammation and not a primary pathophysiologic factor (Pallone et al., (1986), J. Clin. Lab. Immunol., (1986) , v. 19, p. 175; Vecchi et al., (1988) , in "Inflammatory Bowel Disease: Current Status and Future Approach", Ed. MacDermott, R.P., Excerpta Medica, 1988, pp. 455 - 460) . None of these studies disclosed any conveniently assayed peripheral blood markers indicative of IBD.
- the present inventors have analysed the phenotypes of B and T cells from patients with various IBD's, with an emphasis on changes in the B-cells populating the lamina intestinal in comparison to those in peripheral blood nuclear cells (PBMC) and on the selective expression of CD45 isoforms as a marker for differentiation within the B-cell lineage. Also analysed were CD5 and CDllb which have been associated with autoimmune B-cells or the activation status of the B-cell (Marcos et al., (1988), Immunol. Today, v. 9, pp. 204- 207).
- CD45 the leukocyte common antigen
- the CD45 isoforms, CD45RA and CD45RO are distinguished by differences in molecular weight, glycosylations and are encoded by alternatively spliced mRNA.
- CD45RA high molecular weight CD45RA
- pl80 low molecular weight CD45RO
- B-cells are also found among the mucosal lymphocytes in normal and disease states.
- a transition in CD45 isoforms similar to that found in T-cells has been found in B cells (Marcos et al., (1988) , Immunol. Today, (1988), v. 9, pp. 204-207; Jensen et al., (1989), Int. Immunol., v. 1, p. 229) .
- Pre-B cells express exclusively CD45RA at low density, with an increase in CD45RA density as differentiation proceeds towards mature B-cell function.
- a transition from CD45RA to CD45RO expression appears to occur on in vivo antigen stimulated B-cells which has been confirmed by in vitro studies.
- Early plasma cells express only the low molecular weight CD45 isoforms, while end stage plasma cells eventually lose all CD45 expression (Jensen et al. , supra) .
- the present inventors have examined CD45 isoforms in both lamina limbal lymphocytes (LPL) and peripheral blood mononuclear cells (PBMC) , both T-cells and B-cells, in normal subjects and in patients suffering from Crohn's disease, ulcerative colitis and celiac sprue. Crohn's PBMC were studied by multiple regression analysis in relation to a number of clinical parameters corresponding to patients studied. Cells were probed with differently labelled antibodies to CD45RA and CD45RO.
- LPL lamina limbal lymphocytes
- PBMC peripheral blood mononuclear cells
- CD45 isoform expression on CD3 + T-cells from mucosal LPL were similar to normal in Crohn's disease or UC, with a preponderance of CD45RA"RO + cells (normals 66% ⁇ 8%) as shown in Table 1, third column) .
- CD45 isoforms were identified on CD19 + B-cells from mucosal LPL.
- UC, Crohn's and normal LPL CD19 + B-cells included more cells bearing a transitional pattern of CD45 isoform expression
- PBMC from patients with Crohn's disease included 44% of B-cells with an abnormal phenotype, either lacking expression of CD45RA, or coexpressing CD45RA and CD45RO (Table 4, Line 1) .
- CD45RA Fifteen percent of CD19 + PBMC B-cells of patients with Crohn's disease expressed CD45RA " RO + , 13% coexpressed both CD45RA and RO, and 16% were CD45RA " RO " .
- CD45RA RO
- these B- cells have a CD45 isoform distribution consistent with their being a population of late stage antigen-activated B lymphocytes.
- Non-malignant CD45RO + CD19 + PBMC have so far been identified only after n vitro stimulation or in PBMC from patients with multiple myeloma, Waldenstrom's macroglobulinemia and chronic lymphocytic leukemia
- CD45 isoforms on B-cells from Crohn's disease PBMC was very heterogeneous, unlike that from normal donors, UC or celiac sprue.
- Figure 1 shows the consistently high and relatively uniform CD45RA density on normal, UC and celiac sprue B-cells in contrast to the broad density distribution on PBMC B- cells from Crohn's disease.
- Crohn's B-cells included a clearly CD45RA " negative population and a broad distribution of CD45RA + cells.
- a similar degree of heterogeneity was evident for the CD45RO expression on B- cells ( Figure 2) .
- PBMC from Crohn's patients included a bimodal but heterogeneous population of CD45RO + B-cells with predominantly high antigen density (Figure 2) .
- those cells with a low intensity of CD45R0 were those cells coexpressing CD45RA ( Figure 1 and Table 4) .
- Example 4 As seen in Example 4 , no increase of CD5 or CDllb expression was found on CD19 + B-cell PBMC from Crohn's disease patients, suggesting that the isolation procedures have not led to activation of the B-cells.
- CD45RA + R0 " as well as RA " R0 " subset phenotypes were represented among CD19 + PBMC from patients with Crohn's disease in contrast to UC or normal PBMC.
- This pattern of CD45RO "1" and transitional isoform expression suggests a population of activated or late stage B-cells as might be predicted if they play a role in the general heightened immune response associated with Crohn's disease.
- the heterogeneity of CD45 expression on CD19 + PBMC from patients with Crohn's disease was statistically studied with a number of clinical parameters (including the Crohn's disease activity index (Best, W.R. et a., (1976) , Gastroenterology, v. 70, pp.
- CD45RA RO + CD19 + PBMC
- CDAI results from a stimulated immune system in more severely ill patients either as a primary event initiating intestinal inflammation or as part of an inflammatory cascade once inflammation has been initiated.
- CD5 and CDllb were absent from LPL or PBMC B-cells, suggesting that these represent late stage B-cells, possibly memory cells, rather than cells in the process of activation which would express both of these antigens based on patterns of activation in vitro.
- a method for detecting Crohn's disease in a human subject and for distinguishing Crohn's disease from ulcerative colitis and celiac sprue in human subjects presenting with clinical symptoms which would be associated with any of these diseases.
- the method comprises obtaining a blood sample from the subject, isolating or identifying a samnle of B cells from the blood sample and examining the B cells for expression of ;ne CD45 isoform designated CD45RO.
- CD45RO a CD45 isoform designated CD45RO.
- the presence of increased CD45R0 on peripheral blood B cells is indicative of Crohn's disease. Where potentially confusing intestinal symptoms are present, the presence 11 of increased CD45RO on B cells points to Crohn's disease and excludes ulcerative colitis and celiac sprue.
- peripheral blood mononuclear cells are prepared from the subject's blood sample and contacted with a first antibody bearing a first label, the antibody being specific for a B cell antigen and with a second antibody bearing a second label detectable separately from the first label, the second antibody being specific for the antigen CD45RO.
- Detection of the first label permits identification of the B cells and these are examined for the presence of the second label, indicative of CD45RO expression.
- One suitable means of carrying out this examination is by flow cytometry of the labelled cells, where the labels are immunofluorescent labels.
- the first antibody may be specific for any antigen which identifies or characterises B cells.
- Anti-CD19 or anti-CD20 antibodies are preferred.
- the first label may be FITC and the second label may be PE.
- the antibodies used to bind to B cell antigen and to CD45RO may themselves be unlabelled and may be rendered detectable after binding by coupling to a signal generating moiety.
- the bound antibody may be coupled with detectable label or may be coupled to one member of a signal generating pair, such as anti- 12 immunoglobulin biotin, which is in turn contacted with the other member of the pair, such as Streptavidin- Tandem.
- kits for detecting Crohn's disease in a human subject and for distinguishing Crohn's disease from ulcerative colitis and celiac sprue.
- the kit comprises a first antibody specific for a B cell antigen, a second antibody specific for the CD45 isoform, CD45RO, and reagent means for detecting the binding of these antibodies to B cells.
- MS patients have an epidemiologic link to Crohn's disease. Crohn's disease patients are 40 times more likely to acquire MS than controls and patients having both MS and Crohn's disease are more prevalent than expected given the overall incidence of these two diseases in a population.
- a method for detecting MS in a human subject by isolating or identifying peripheral B cells from the subject and examining the B cells for increased expression of the CD45 isoform, CD45R0.
- Specimens of colon from patients with Crohn's disease and ulcerative colitis were obtained with the assistance of a pathologist to sample disease-involved ucosa.
- Normal mucosa was obtained from colon at least 15 cm distal to carcinoma in patients undergoing resection as well as from normal areas in patients having resection for diverticulosis. Normal colon was also 14 obtained from deceased persons donating organs for transplantation. A total of 10 "normal”, 8 Crohn's and 4 ulcerative colitis colons were analysed.
- PBMC Peripheral blood mononuclear cells
- INT MNC Normal large bowel intestinal mononuclear cells
- HBSS Hanks balanced salt solution
- antibiotics 1 mg/ml Ticarcillin, (Beecham, Pointe-Claire, QC) , 0.5 mg/ml Amikacin (Bristol Labs, Ottawa, ON), 0.4% Septra (Burroughs-Wellcome, Kirkland, QC) , 2 mg/ml Fungizone Grand Island Biological Co (Gibco, Grand Island, NY), 10 mm Hepes and NaOH to adjust to pH 7.4.
- HBSS Hanks balanced salt solution
- the minced pieces were stirred in multiple changes of medium containing 0.75 M EDTA (Sigma, St. Louis, MO) and 5% heat inactivated pooled human serum to remove epithelial cells.
- the tissue was then incubated overnight in HBSS-collagenase medium containing 16 mg/ml chromatographically purified collagenase (Worthington Biochemical, Freehold, NJ) and 20% heat-inactivated pooled human serum.
- HBSS-collagenase medium containing 16 mg/ml chromatographically purified collagenase (Worthington Biochemical, Freehold, NJ) and 20% heat-inactivated pooled human serum.
- cells were layered over a ficoll-hypaque gradient (S.G. 1.077) and centrifuged at 400 g for 20 minutes. The interface was collected, diluted with HBSS, resuspended in 10 ml Percoll solution (S.G.
- HLE-FITC CD45 common determinant marker
- CDllb Leu 15-PE
- IgGl-FITC IgG, PE, IgG2a, FITC and IgG2aPE were purchased from Becton-Dickinson (Mountainview, California) .
- B4-FITC, B4-RD1 (CD19), Bl-FITC or B1-RD1 (CD20) and T1-RD1 (CD5) were purchased from Coulter (Hialeah, Florida) .
- Biotinylated goat anti-mouse immunoglobulin and Tandem avidin were purchased from Southern Biotechnology (Birmingham, Alabama) .
- UCHLI (CD45RO) was a generous gift 16 of Dr. P. Beverley.
- UCHLI is also available from Becton Dickinson, Inc.
- Monoclonal antibodies to CD45RA were CD45RAFITC, purchased from Gen Track (Wayne, Pennsylvania) and FMC44-PE (21,22) (Pilarski et al., (1989), Eur. J. Immunol., v. 19, pp. 589-597; Jensen et al., (1991) , Blood, v. 78, p. 711).
- IF Three-Color Immunofluorescence
- MNC were resuspended in 50 ⁇ l of uncoupled monoclonal antibody diluted approximately in phosphate- buffered saline containing 0.5% bovine serum albumin and 0.02% sodium azide.
- the cells were incubated for 30 minutes at 4°C, spun down and washed twice in buffer solution and incubated for 10 min at room temperature, spun down and resuspended in 20 ⁇ l Streptavidin-Tandem.
- the other two monoclonal antibodies coupled to FITC and PE were added directly and 25 ⁇ l of buffer added. This was incubated for 30 min at 4°C. Cells were washed three times and fixed with 1% formalin for flow cytometric analysis.
- ESR erythrocyte sedimentation rate
- CDAI Crohn's disease activity index
- CD45RA and/or CD45RO high or low molecular mass isoforms
- the students T-test was used to compare CD45 isoform expression on T or B-cells between types of disease.
- Lamina limbal lymphocytes isolated from fresh intestinal mucosa were analysed from normal, Crohn's disease and UC tissue. Normal mucosa was derived from patients with diverticular disease, areas distal to neoplasms and deceased organ donors. 18
- CD45RA was detected by FMC44PE.
- CD45RO was detected by UCHL1 and indirectly stained with biotinylated goat anti-mouse immunoglobin followed by Tandem-avidin, and CD3 was detected by Leu4- FITC.
- CD45 isoform staining (CD45RA and RO) on CD3 + T-cells was detected by three color immunofluorescence as described in Example 1.
- CD45RA and RO are organ donor, diverticulosis and neoplasm resections.
- CD45 isoform staining CD45RA and RO
- CD19 + or CD20 + B-cell lamina basement lymphocytes was detected by three color immunofluorescence.
- CD45RA was detected by FMC44PE.
- CD45RO was detected by UCHLI and stained indirectly with biotinylated goat anti-mouse 19 immunoglobulin and Tandem-avidin, and CD19 by B4-FITC, or CD20 by Bl-FITC. Similar results were obtained using either CD19 or CD20.
- Files were gated for CD19 + cells and CD45 isoform expression as described in Example 1.
- CD45 isoform staining CD45RA and RO
- CD19 + PBMC from individual patients with Crohn's disease showed considerable individual variation, in clear contrast to the normal pattern, as shown in Figure 3.
- clinical data were obtained on each patient.
- a number of parameters known to be associated with Crohn's clinical disease severity were tabulated, and multiple regression analysis was performed on these values using the statistical program SPSS/PC+.
- CD45 isoforms defined by CD45 isoforms as dependent variables and the clinical parameters (Crohn's disease activity index (CDAI), disease duration, erythrocyte sedimentation (ESR) , medications, age of patient and disease severity) as independent variables.
- CD45RO + B-cells were divided into 2 groups, group 1 included B-cells with expressing 0-49% CD45RO + .
- CD45RA " RO + CD19 + B-cells Furthermore, there is a significant correlation of high levels of CD45RA " RO + CD19 + with high CDAI values, as shown in Figure 4. No other combination of parameters or any B-cell phenotype had such a significant relationship.
- CDAI Crohn's disease activity index
- ESR erythrocyte sedimentation rate
- Intestinal permeability was examined in fifteen patients with Crohn's disease, as determined by standard clinical criteria, in thirteen of their first degree relatives and in ten control volunteers of similar age. All relatives and controls were entirely free of gastrointestinal symptoms, had no history of renal disease or diabetes and had not taken nonsteroidal anti- inflammatory medications or alcohol for at least two weeks prior to the study. The same drug and alcohol 22 exclusion criteria were also applied to the patient population.
- the CD45 common determinant marker (HLE-FITC) and the control antibodies IgGl-FITC, IgGl-PE, IgG2a-FITC and IgG2a-PE were purchased from Becton-Dickinson (Mountainview, California) .
- ⁇ -FlTC , -RDl (CD19) , ⁇ -FITC or /3-RDl (CD20) were purchased from Coulter (Hialeah, Florida) .
- Biotinylated goat anti-mouse immunoglobin and Tandem Avidin were purchased from Southern Biotechnology (Birmingham, Alabama) , UCHL1 (CD45RO) was a generous gift of Dr. P. Beverley.
- CD45RA-FITC Monoclonal antibodies to CD45RA were CD45RA-FITC and were purchased from Gen Track (Wayne, Pennsylvania) . The specificity of CD45 antibodies used was confirmed by their appropriate molecular weights and all were tested for their reactivity with a panel of CD45 transfectants. 23
- Urine samples (10 ml) were deionized by adding 1 g of a 1:15 (wt:wt) mixture of Amberlite IR-120 and IRA-400 resin (BDH Chemicals, Toronto, Ontario, Canada) . Sucrose was added as an internal standard, and the supernatant filtered through a 40 ⁇ m millepore filter (Millepore, Bedford, MA) . Samples were separated on a Hamilton RCX-10 anion exchange column (Reno, NV) in a HP 1090 HPLC (Hewlett Packard, Toronto, Ontario, Canada) at room temperature using 30 mmol/L NaoH as the isocratic mobile phase.
- Peak identification was accomplished with the use of authentic standards and detected using pulsed amperometric electrochemical detection on a gold electrode. Samples were diluted as necessary after addition of the internal standard. Quantitation was performed using known standards at multiple concentrations with linear interpolation between concentrations. All samples were diluted so that concentrations of interest fell within the range of standards. Data were expressed as the fractional excretion of lactulose or mannitol and the lactulose/mannitol ratio calculated directly from these numbers.
- Figure 6 illustrates the lactulose/mannitol ratio found in all study groups.
- the upper limit of normal (defined as the mean of this group plus 2STD) is shown by the dotted line in Figure 5. Ratios above 0.022 are considered abnormal.
- Controls used in this study current controls
- a significant proportion of patients with Crohn's disease had increased intestinal permeability, some with very high values.
- Ten of the 15 patients (67%) had high permeability while 5 fell within our normal range. Seven of 13 relatives (54%) also demonstrated high permeability in the absence of either symptoms or signs of disease.
- B-cells bearing the CD45RO isoform is illustrated for both controls and patients with Crohn's disease. In all 10 controls, less than 6% of peripheral B-cells were found to be positive for this isoform. This value was, therefore, used as the upper limit of normal and is represented by the dotted line in Figure 6.
- Figure 6 patients are grouped as having either normal permeability or high permeability based on the data shown in Figure 5. Of the 10 patients with high permeability, 8 demonstrated an abnormally high fraction of B-cells positive for CD45RO. This situation was found in only 2 of the 5 patients with normal permeability. 25
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7514131A JPH08508572A (en) | 1993-11-15 | 1994-11-15 | Markers for Crohn's disease and multiple sclerosis |
EP95900585A EP0679258A1 (en) | 1993-11-15 | 1994-11-15 | Marker for crohn's disease and multiple sclerosis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939323542A GB9323542D0 (en) | 1993-11-15 | 1993-11-15 | Lymphocyte marker specific for corhn's disease |
GB9323542.2 | 1993-11-15 |
Publications (1)
Publication Number | Publication Date |
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WO1995014230A1 true WO1995014230A1 (en) | 1995-05-26 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/CA1994/000635 WO1995014230A1 (en) | 1993-11-15 | 1994-11-15 | Marker for crohn's disease and multiple sclerosis |
Country Status (5)
Country | Link |
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EP (1) | EP0679258A1 (en) |
JP (1) | JPH08508572A (en) |
CA (1) | CA2153975C (en) |
GB (1) | GB9323542D0 (en) |
WO (1) | WO1995014230A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011918A1 (en) * | 1996-09-18 | 1998-03-26 | Research Corporation Technologies, Inc. | Use of antibodies to cd45r leukocyte antigens for immunomodulation |
US6099838A (en) * | 1993-06-02 | 2000-08-08 | Reasearch Corporation Technologies, Inc. | Pharmaceutical compositions comprising anti-CD45RB antibodies for the inhibition of T-cell mediated immune responses |
US9993550B2 (en) | 1999-05-07 | 2018-06-12 | Genentech, Inc. | Treatment of pemphigus |
-
1993
- 1993-11-15 GB GB939323542A patent/GB9323542D0/en active Pending
-
1994
- 1994-11-15 EP EP95900585A patent/EP0679258A1/en not_active Withdrawn
- 1994-11-15 WO PCT/CA1994/000635 patent/WO1995014230A1/en not_active Application Discontinuation
- 1994-11-15 JP JP7514131A patent/JPH08508572A/en not_active Ceased
- 1994-11-15 CA CA 2153975 patent/CA2153975C/en not_active Expired - Fee Related
Non-Patent Citations (7)
Title |
---|
F.PALLONE, S.FAIS, O. SQUARCIA, L.BIANCONE, P.POZILLI AND M.BOIRIVANT: "Activation of peripheral blood and intestinal lamina propria lymphocytes in Crohn's disease. In vivo state of activation an in vitro response to stimulation as defined by the expresssion of early activation antigens", GUT, vol. 28, no. 6, June 1987 (1987-06-01), LONDON,GB, pages 745 - 753 * |
GITTE S. JENSEN ET AL.: "Transition in CD45 isoform expression during differentiation of normal an abnormal B cells", INTERNATIONAL IMMUNOLOGY, vol. 1, no. 3, July 1989 (1989-07-01), OXFORD, GB, pages 229 - 236 * |
GITTE S. JENSEN ET AL.: "Transitions in CD45 Isoform Expression Indicate Continuous Differentiation of a Monoclonal CD5+ CD11+ B Lineage in Waldenstrom's Macroglobulinemia", AMERICAN JOURNAL OF HEMATOLOGY, vol. 37, no. 1, May 1991 (1991-05-01), NEW YORK, NY, US, pages 20 - 30 * |
P. BRANDTZAEG ET AL.: "T Lymphocytes in Human Gut Epithelium Preferentially Express the alpha/beta Antigen Receptor and are often CD45/UCHLI1-Positive", SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol. 30, no. 1, July 1989 (1989-07-01), OXFORD, GB, pages 123 - 128 * |
SENJU M ET AL: "TWO-COLOR IMMUNOFLUORESCENCE AND FLOW CYTOMETRIC ANALYSIS OF MINA PROPRIA LYMPHOCYTE SUBSETS IN ULCERATIVE COLITIS AND CROHN 'S DISEASE.", DIG DIS SCI 36 (10). 1991. 1453-1458. CODEN: DDSCDJ ISSN: 0163-2116 * |
YACYSHYN B R ET AL: "Expression of CD45RO on circulating CD19+ B-cells in ohn 's disease.", GUT 34 (12). 1993. 1698-1704. ISSN: 0017-5749 * |
YACYSHYN B R ET AL: "Increased intestinal permeability appears to correlate with the peripheral blood CD19+ B - cell CD45RO + phenotype.", 95TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION, NEW ORLEANS, LOUISIANA, USA, MAY 15-18, 1994. GASTROENTEROLOGY 106 (4 SUPPL.). 1994. A280. ISSN: 0016-5085 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6099838A (en) * | 1993-06-02 | 2000-08-08 | Reasearch Corporation Technologies, Inc. | Pharmaceutical compositions comprising anti-CD45RB antibodies for the inhibition of T-cell mediated immune responses |
US6106834A (en) * | 1993-06-02 | 2000-08-22 | Research Corporation Technologies, Inc. | Use of anti-CD45 leukocyte antigen antibodies for immunomodulation |
US6379668B1 (en) | 1993-06-02 | 2002-04-30 | Research Corporation Technologies, Inc. | Use of anti-CD45 leukocyte antigen antibodies for immunomodulation |
US7160987B2 (en) | 1993-06-02 | 2007-01-09 | Alimunne, L.L.C. | Use of anti-CD45 leukocyte antigen antibodies for immunomodulation |
WO1998011918A1 (en) * | 1996-09-18 | 1998-03-26 | Research Corporation Technologies, Inc. | Use of antibodies to cd45r leukocyte antigens for immunomodulation |
US9993550B2 (en) | 1999-05-07 | 2018-06-12 | Genentech, Inc. | Treatment of pemphigus |
Also Published As
Publication number | Publication date |
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CA2153975A1 (en) | 1995-05-26 |
EP0679258A1 (en) | 1995-11-02 |
CA2153975C (en) | 1999-03-23 |
GB9323542D0 (en) | 1994-01-05 |
JPH08508572A (en) | 1996-09-10 |
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