WO1991007508A1 - Methode de mesure d'antigenes de surface de cellules en t chez les humains - Google Patents

Methode de mesure d'antigenes de surface de cellules en t chez les humains Download PDF

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WO1991007508A1
WO1991007508A1 PCT/US1990/006613 US9006613W WO9107508A1 WO 1991007508 A1 WO1991007508 A1 WO 1991007508A1 US 9006613 W US9006613 W US 9006613W WO 9107508 A1 WO9107508 A1 WO 9107508A1
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cells
cell
toxins
body fluid
fluid sample
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PCT/US1990/006613
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Brian L. Kotzin
Philippa Marrack
John Kappler
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National Jewish Center For Immunology And Respiratory Medicine
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Priority claimed from US07/437,370 external-priority patent/US5336598A/en
Application filed by National Jewish Center For Immunology And Respiratory Medicine filed Critical National Jewish Center For Immunology And Respiratory Medicine
Priority to KR1019920701151A priority Critical patent/KR920703844A/ko
Priority to AU77873/91A priority patent/AU651346B2/en
Publication of WO1991007508A1 publication Critical patent/WO1991007508A1/fr
Priority to NO92921879A priority patent/NO921879L/no
Priority to FI922197A priority patent/FI922197A/fi

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • 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
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5094—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for blood cell populations

Definitions

  • This invention relates to a method for diagnosing a pathological condition, via assaying or measuring
  • T-cell subtypes in a sample taken from a patient suspected of having the pathological condition.
  • it relates to measuring cell surface antigens of T-cells which are characteristic of
  • Antibodies are protein molecules which are produced by B cells in response to infection. It is well known that these antibodies act to "disable” or to inactivate infectious agents in the course of combating the
  • antigen recognition requires interaction of an "antigen presentation cell”, a “processed antigen”, and a T-cell. See Grey and Male, supra.
  • the "processed antigen”, in an infection, is a molecule characteristic of the pathogen which has been treated, i.e., "processed”, by other cells which are a part of the immune system.
  • the processed antigen in an infection, is a molecule characteristic of the pathogen which has been treated, i.e., "processed”, by other cells which are a part of the immune system.
  • MHC major histocompatibility complex
  • HLA human leukocyte antigen
  • TCR T-cell antigen receptor
  • the TCR is recognized as a heterodimer, made up of alpha ( ⁇ ) and beta ( ⁇ ) chains.
  • Five variable elements, coded for by germline DNA and known as "V ⁇ , J ⁇ , v ⁇ , D ⁇ , and J ⁇ " as well as non-germline encoded amino acids contribute to the TCR. See, in this regard, Marrack, et al., Immunol. Today 9 : 308-315 (1988); Toyonaga, et al., Ann. Rev. Immunol 5: 585-620 (1987); Davis, Ann. Rev. Immunol 4: 529-591
  • This feature is one aspect of the invention, i.e., the ability to assay for particular subtypes or subclasses of T-cells, based upon the cell surface antigens presented by these subclasses.
  • Staphylococcus aureus has long been implicated in morbidity and mortality in humans. See Bergdoll, in Feed Bourne Infections and Intoxications (Riemann and Bryan, ed., Acad. Press, N.Y.) pp. 443-494 (1979).
  • the various toxins presented by S. aureus are responsible for most food poisoning cases, as well as severe shock, and other life threatening pathological conditions.
  • the mechanism of action of the toxins associated with S. aureus is unknown.
  • the primary structure of the toxins while showing some relationship, also show some great
  • Figure 1 shows the results of staphylococcal toxin stimulation of human T cells.
  • Figure 2 depicts studies showing V ⁇ specific stimulation of T cells by toxins is donor independent.
  • Figure 3 depicts a standard curve used to normalize polymerase chain reaction values (PCRs) to percentages of T cells carrying particular V ⁇ s in mixed populations.
  • PCRs polymerase chain reaction values
  • Figure 4 shows autoradiograms of coamplified cDNA of human TCR transcripts following stimulation with anti-CD3 antibody or a S. aureus toxin.
  • FIG. 6 shows autoradiograms of T cell receptor
  • transcripts amplified by polymerase chain reaction from cells Patient 1 (P) and control individual (C).
  • FIG. 7 shows longitudinal changes in T cell repertoire in 2 patients studied serially after toxic shock
  • T cells of a human individual were first isolated from that individual's peripheral blood. These T cells were then examined before and after stimulation with one of (i) anti-CD3 antibody, (ii) SEC2; (iii) SED, or (iv) SEE. Items (ii), (iii) and (iv) are known S. aureus molecules which act as toxins.
  • the anti-CD3 antibodies had been rendered
  • adherent antibody or a S. aureus antigen was used to stimulate peripheral blood T cells.
  • the blast cell fractions were then incubated with one of (i) purified antibody to CD3 or with a monoclonal antibody to (ii) V ⁇ 5 (mAb 1C1); (iii) V ⁇ 6 (mAb OT145); (iv) V ⁇ 8 (mAb MX6), or (v) V ⁇ 12 (mAb S511).
  • the cells were stained with fluoroscein-conjugated goat anti mouse IgG, following Kappler, et al., Cell 49: 173 (1987).
  • the staining pattern was then studied on an EPICS C device, using a forward angle and 90° light scatter pattern to gate large blast cells, which were easily distinguished from small lymphocytes, and constituted 50% or more of all surviving cells in culture.
  • Panels A-D shows the degree of staining using the mAbs before stimulation.
  • Panels E-H show it after stimulation with anti-CD3.
  • panels I-L show the pattern following stimulation with SED, SEE, and SEC2.
  • Staphylococcal entertoxin (SE) D greatly increased the percentage of T cells bearing V ⁇ 5 in the blast population and nearly excluded cells bearing V ⁇ 6.
  • T cells blasts stimulated with SEC2 were depleted of V ⁇ 6- and V ⁇ 8 bearing T cells and were greatly enriched in V ⁇ 12 bearing T cells.
  • V ⁇ 8 T cells stimulated V ⁇ 8 T cells, while excluding cells bearing V ⁇ 12. Reciprocal results for each of the toxins were found if the resulting T cells contaminating the blast populations were analyzed for V ⁇ usage. After SEE stimulation, for example, the resting T cells were selectively depleted of V ⁇ 8 + cells. This result
  • One or more of the toxins was a stimulus for T cells positive for each of the V ⁇ families (albeit weakly for V ⁇ 6) , indicating that a toxin superantigen had been identified for each of the V ⁇ families. Conversely, toxins could be identified which specifically failed to stimulate T cells bearing each of the V ⁇ s.
  • V ⁇ 5-bearing cells were similar, for example, in
  • V ⁇ , J ⁇ , or J ⁇ could quite often prevent interaction of this toxin with V ⁇ 5, a phenomenon that has been noticed before for superantigen reaction with mouse T cell receptor V ⁇ s.
  • TSST may react with only one member of the V ⁇ 5 family.
  • the increase in blasts bearing this member may be offset by a disappearance of T cells bearing other members of the family, but also reactive with 1C1. Discrimination by superantigens among different members of V ⁇ families has been seen in mice, where the self superantigen Mls-1 stimulates T cells positive for V ⁇ 8.1 but not those bearing V ⁇ 8.2 or
  • V ⁇ 8. 3 (Kappler, et al. Nature 332: 35 (1988), and SEC1 stimulates T cells bearing V ⁇ 8.2 but not those bearing V ⁇ 8.1 or V ⁇ 8.3.
  • T cells that stained with anti-CD4 or anti CD9 were checked before and after stimulation.
  • the starting percentages were virtually unchanged by toxin stimulation.
  • T cells from one donor, for example, were initially 78% CD4 + and 23% CD8 + .
  • the percentages in the blast of CD4 + cells ranged from 74% to 79%, and of CD8 cells from 20% to 25%, suggesting that all these stimuli affected CD4 and CD8 cells
  • Fig. 2 is the consistency of the results from one
  • each toxin is able to stimulate only a
  • T cells in humans are still powerful T cell stimulants, active at low concentrations. Some or all of the toxic effects of these proteins in humans may be mediated by their ability to stimulate large numbers of human T cells. For example, the ability of these toxins to induce secretion of large quantities of lymphokines is probably secondary to their ability to stimulate, in a v ⁇ - specific way, a sizable percentage of T cells. It is also possible that the ability of these and other microbial-derived superantigens to stimulate populations of T cells bearing particular V ⁇ s may be related to the differential resistance of
  • the cell surface antigen which is the V ⁇ molecule.
  • Enhanced presence of the VA molecules means that there has been enhanced expression of the DNA coding for the particular molecule.
  • the following experiments deal with the measurement of the aforementioned T-cell subsets via analysis of the DNA expressing a particular V ⁇ subtype.
  • PCR polymerase chain reaction
  • Total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T cells as described supra. Two ⁇ g of total RNA was prepared from anti-CD3 stimulated peripheral T
  • One twentieth of each cDNA samples was co-amplified using a V ⁇ -specific primer with a C ⁇ primer and two C ⁇ primers as set forth at Table 2 with final concentration of 0.3 ⁇ M in each reaction.
  • the amplification was performed with 2.5 U of Taq polymerase (Perkin-Elmer) and a Cetus Perkin Elmer thermocycler under the following conditions; 95°C melting, 55°C annealing, and 72°C extension for 1 minute each.
  • coamplification was performed with 5' 3 2 P-labelled reverse primers (about 5x10 5 cpm each).
  • the amplified products were separated on 2% agarose gels, dried and exposed to X-ray film. The autoradiograms were used to identify and cut out the V ⁇ -C ⁇ and C ⁇ bands.
  • V ⁇ bands The size of amplified products (V ⁇ bands) by V ⁇ and 3'C ⁇ primers ranged from about 170 to 220 bp.
  • the 3'C ⁇ primer used in this study matches exactly both C ⁇ 1 and C ⁇ 2 DNA.
  • the sequences of V ⁇ , C ⁇ , and C ⁇ are from previously published reports.
  • V ⁇ 13.1, c V ⁇ 13.2, and d V ⁇ 14.1 have also been called V ⁇ 12.3, 12.4, and 3.3, by Toyonaga, et al., Ann. Rev. Immunol. 5: 585-620 (1987), Kimura, et al., Eur. J. Immunol. 17: 375-383 (1987).
  • V ⁇ -specific oligonucleotides for use as 5' sense primers for PCR were synthesized. Their sequences, and the V ⁇ 's which they would be expected to amplify, are shown in Table 2. All the V ⁇ 's indicated as
  • V ⁇ 6 primer matches V ⁇ 6.4 except for one nucleotide, and further experiments will be needed to find out if V ⁇ 6.4 is amplified using this primer. Altogether, all these primers would be expected to cover at least 39 of the 46 sequenced human genes. Each V ⁇ specific oligomer was picked to have roughly the same G+C content and to be located at relatively the same position in V ⁇ .
  • Total RNA was prepared from human peripheral T cells stimulated by anti-CD3 antibody or one of 5 different S. aureus toxins (SEB, SEC2, SEE, exfoliating toxin
  • ExT toxic shock syndrome toxin 1
  • TSST toxic shock syndrome toxin 1
  • a single strand complementary DNA was prepared for mRNA phenotyping, following Buus, et al., Science 235: 1353-1358 (1987); Townsend, et al., Cell 44: 959-968 (1986), and aliquots of cDNA from each sample were amplified with each of the 22 5' V ⁇ specific sense primers and the 3' C ⁇ specific antisense primer.
  • TCR ⁇ chain mRNA was co-amplified in the same tube. Amplification was performed with 25 cycles, a limited number used to ensure that the amount of product synthesized was
  • V ⁇ specific primer was determined by the size of its amplified product and hybridization to the amplified products of specific probes (not shown).
  • the amplification efficiencies of four of the primer sets (5'C ⁇ -3' ⁇ , V ⁇ s 2 , 3, and 8-3' C ⁇ ) were determined as described by Chelly, et al., supra. The average efficiency ranged about 46-48% . For each sample the number of counts in the V ⁇ band were
  • the PCR methodology was used to analyze the
  • T cells stimulated with anti-CD3 were used as a control, because Examples 1 and 2 show that stimulation with anti-CD3 did not significantly change the percentages of T cells bearing particular V ⁇ 's from that seen in the starting population. Results are shown in Figure 4. The results of a complete
  • V ⁇ families were used more abundantly than others by normal peripheral T cells. Members of the V ⁇ 2 , 3, 6, 7 and 8 families and V ⁇ 13.1 were expressed by more than 50% of total T cells. Such a finding was perhaps not unexpected for VA6 and VA8 which are part of large families of V ⁇ 's (although the V ⁇ 6
  • V ⁇ 13.1 which appears to be the product of a single gene.
  • the uneven expression of V ⁇ 's by human peripheral T cells did not appear to be idiosyncratic for this individual or determined by MHC, since similar frequencies were seen for 2 other unrelated human donors tested (see discussion, infra, and Figure 5).
  • the related toxin, SEC2 also stimulated T cells expressing V ⁇ 12, V ⁇ 14, V ⁇ 15, V ⁇ 17 and V ⁇ 20, but not those expressing V ⁇ 3 .
  • SEE stimulated T cells bearing members of the V ⁇ 8 family, as we have previously shown, but also increased the proportion of V ⁇ 5.1 + , V ⁇ 6.1-3 + , and V ⁇ 18 + cells.
  • mice and humans in the T cell response to these toxins in striking. In both cases T cells bearing particular V ⁇ 's dominate the response to each toxin. In both cases the discriminatory powers of the toxins can be particularly dramatic. For example, in humans V ⁇ 5.1 T cells responded to SEE, whereas cells bearing V ⁇ 5.2/3 did not. Similarly, it has been
  • Mls-1 superantigen, which stimulates T cells bearing V ⁇ 8.1 but not those expressing V ⁇ 8 .2 or V ⁇ 8.3. See Kappler, et al., Nature 332; 35-40 (1988).
  • V ⁇ genes from mouse and man shows that there are some homologues, both by primary sequence, and by their relative location in the V ⁇ gene complex. See Toyonaga, et al., Ann. Rev. Immunol. 5: 585-620 (1987); Concannon, et al., Proc. Natl. Acad. Sci. USA 83: 6598-6602 (1986); Lai, et al., Nature 331: 543-546 (1988). The stimulation patterns by the
  • mice V ⁇ stimulation by toxins was compared, following White, et al., Cell 56: 27-35 (1989).
  • T cells bearing homologous V ⁇ 's show a similar pattern of response to the toxins.
  • ExT and especially TSST stimulated T cells bearing human V ⁇ 2 and mouse T cells bearing the most analogous V ⁇ 15.
  • Human T cells expressing members of the V ⁇ 12, 14, 15 and 17 families all showed a tendency to respond to SEB and SEC2, but not ExT or TSST. This property was shared by their closest murine relatives , mouse V ⁇ ' s 8 .1 , 8 .2 and 8.3.
  • V ⁇ gene elements are often inactivated by point mutations. See Wade, et al., J.
  • hypotension systolic blood pressure ⁇ 90 mmHg for adults and/or orthostatic syncope or dizziness.
  • hyperemia decreased renal function or pyuria, elevated liver enzymes, platelet count ⁇ 100,000/mm 3 , and
  • S. aureus was cultured from
  • Major criteria include fever (>102°F), a characteristic erythematous rash that subsequently is followed by
  • Minor criteria include A, gastrointestinal symptoms
  • D renal functional impairment or pyuria
  • E laboratory evidence of hepatic dysfunction
  • F
  • thrombocytopenia platelet count ⁇ 100,00/mm 3
  • G disorientation or altered state of consciousness. #Patient 3 had at least 10 prior episodes of toxic shock syndrome. Several of these had been associated with
  • enterotoxins A,B,C 1 ,C 2 ,C 3 ,D and E, and TSST-1. ⁇ Not done.
  • Peripheral blood mononuclear cells taken from the patients were isolated from heparinized blood following Ficoll hypaque gradient centrifugation. Stimulation of T cells were accomplished as described supra in plastic flasks coated with purified anti-CD3 antibody. Cells were cultured at 1x10 6 cells per ml in media containing RPMI 1640 supplemented with 2 mM glutamine, 10 mM hepes buffer, 100 u/ml penicillin, 100 ug/ml streptomycin, and 10% fetal calf serum. After three days of culture, live cells were harvested and cultured for an additional 24 hours in 25 ⁇ /ml recombinant human IL-2 to expand cells expressing the receptor for IL-2 while allowing
  • Total RNA was prepared from anti-CD3 stimulated cells as described and total RNA was used for the synthesis of first strand cDNA using reverse
  • cDNA was amplified using the polymerase chain reaction as described in Example 3.
  • peripheral blood mononuclear cells were isolated from patients and controls, and T cells were stimulated in culture with anti-CD3 antibody and IL-2.
  • T cell receptor gene segments encoding V ⁇ 2 , V ⁇ 5 (5.2 and 5.3), V ⁇ 8 (8.1 and 8.2), and V ⁇ 12 were amplified and quantitated.
  • a C ⁇ gene segment was also amplified in each reaction.
  • Figure 6 shows results with T cells from Patient 1 and a concomitantly-studied normal individual. A striking increase in amplified C ⁇ 2 DNA is apparent in the patient compared with control, whereas little
  • V ⁇ 2 expansion in toxic shock syndrome It should be noted that among the patients not demonstrating increased V ⁇ 2/C ⁇ ratios (Patients 4,6,8,9), one (Patient 4) was studied a relatively long period after the acute disease such that an increased level could have been missed.
  • T cells isolated from patients and controls were also analyzed for subset alterations by indirect
  • V ⁇ 2 levels elevated V ⁇ 2 levels.
  • the ranges of CD4 and CD8 + T cell percentages were 30-84% and 14-60%, respectively, in patients compared with means ( ⁇ SE) values of 64 ⁇ 5.1% and 29 ⁇ 4.6% for control individuals. Cells from 7 of the patients were also stained for the expression of V ⁇
  • Examples 1-6 show that the efficiency of V ⁇ 2 amplification is similar to that for V ⁇ 5 and V ⁇ 8, supporting the validity of estimating the percentage of circulating T cells expressing V ⁇ 2 by the polymerase chain reaction method.
  • the results suggest that V ⁇ 2 + T cells in normal individuals are approximately 10% of the peripheral blood T cell population.
  • peak values for patients 1 and 2 may be as great as 70% and
  • a pathological condition such as an infection
  • a pathological condition can be diagnosed by assaying a sample from a patient to determine levels of particular V ⁇ molecules in the sample. Increased levels of specific subtypes have been found to be linked to particular antigens, as the results show.
  • pathological condition is not limited to an infection; rather, it refers to any condition where an abnormal immune response has occurred. This includes, e.g., autoimmune diseases where, as has been shown supra, specific V ⁇ type molecules are present where they should not be, or are present in quantities above those found in normal individuals.
  • V ⁇ quantities are not the only way to diagnose pathological conditions in accordance with this invention.
  • the art is familiar with various diseases and pathological states, such as HIV infection, where T cell levels are below those normally encountered. Correlation of particular V ⁇ types to conditions characterized by T cell depletion are also embraced herein.
  • Examples 7 and 8 shows that a selective increase in circulating T cells expressing V ⁇ 2 is frequently
  • T cell subsets studied including those expressing V ⁇ 5, V ⁇ 8, and V ⁇ 12 were not increased above normal levels and did not fluctuate over time. Thus, measurement of the proportion of T cells expressing V ⁇ 2 in peripheral blood could be used as a diagnostic test for this disease.
  • aureus enterotoxins stimulate T cells bearing particular V ⁇ segments almost regardless of the composition of the rest of the T cell receptor on these cells.
  • Other variable elements D ⁇ , J ⁇ , V ⁇ , J ⁇
  • D ⁇ , J ⁇ , V ⁇ , J ⁇ do not appear to contribute much to the recognition of these V ⁇ -specific superantigens as they do for conventional antigens.
  • V ⁇ 2 levels One patient was studied nearly five months after the acute illness, and elevated levels could have been missed. This possibility is corroborated by the serial changes in two patients, in which a return to near-normal levels occurred within one to two months after presentation. Examples 1-6 indicated that S.
  • aureus toxins other than TSST-1 do not stimulate V ⁇ 2 + T cells but do stimulate other sets of T cells in a v ⁇ - specific fashion.
  • V ⁇ 2 are likely to detect abnormalities only in TSST-1 mediated disease. Future studies that include the
  • T cell subsets likely to be expanded by these other toxins may increase the frequency of positive tests. As predicted, the patient with fatal shock
  • T cell stimulation occurs on a scale not observed in response to conventional antigens, and it is proposed that this massive T cell activation is a critical event in the development of disease.
  • These activated T cells are likely to be releasing IL-2, interferon-gamma, lymphotoxin (TNF- ⁇ ), and a variety of other less
  • T cell activation process and/or release of IL-2 could also greatly enhance or be required for the release of IL-1 and TNF by macrophases. Nedwin, et al., J. Immunol. 135: 2492-7 (1985). If T cell activation is required for expression of toxic shock syndrome, T cell depletion or functional inactivation should interrupt the cascade of events in S. aureus toxin mediated disease. This may be partially supported by studies suggesting that
  • corticosteroids early in the disease course may produce beneficial effects in some patients. See Todd, et al., JAMA 252: 3399-3402 (1984).

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Abstract

Méthode pour la détermination des niveaux d'antigènes de surface de cellules en T chez les humains, plus particulièrement, des molécules Vβ. La mesure de ces niveaux permet le diagnostic de conditions pathologiques, telles que des infections.
PCT/US1990/006613 1989-11-15 1990-11-13 Methode de mesure d'antigenes de surface de cellules en t chez les humains WO1991007508A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019920701151A KR920703844A (ko) 1989-11-15 1990-11-13 사람에 있어 t-세포 표면 항원의 측정방법
AU77873/91A AU651346B2 (en) 1989-11-15 1990-11-13 Method for measuring T-cell surface antigens in humans
NO92921879A NO921879L (no) 1989-11-15 1992-05-13 Fremgangsmaate til maaling av t-celleoverflateantigener i mennesker
FI922197A FI922197A (fi) 1989-11-15 1992-05-14 Foerfarande foer bestaemning av ytantigener hos maenskans t-celler.

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US437,370 1989-11-15
US07/437,370 US5336598A (en) 1989-11-15 1989-11-15 Method for diagnosing a superantigen caused pathologial condition via assay of T-cells
US48835390A 1990-03-02 1990-03-02
US488,353 1990-03-02

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EP0602178A1 (fr) * 1991-08-28 1994-06-22 The Wistar Institute Therapie de la polyarthrite rhumatoide basee sur le recepteur de lymphocytes t
FR2736831A1 (fr) * 1995-07-19 1997-01-24 Centre Nat Rech Scient Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
WO1998054575A2 (fr) * 1997-05-27 1998-12-03 University Of Wales College Of Medicine Procede permettant d'evaluer la cicatrisation d'une plaie
US10858760B2 (en) 2015-06-01 2020-12-08 Medigene Immunotherapies Gmbh T cell receptor library
US10882891B2 (en) 2015-12-23 2021-01-05 Medigene Immunotherapies Gmbh Dendritic cell composition
US11292838B2 (en) 2015-06-01 2022-04-05 Medigene Immunotherapies Gmbh Method for generating antibodies against T cell receptor

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CN108026171A (zh) * 2015-06-01 2018-05-11 基因医疗免疫疗法有限责任公司 T细胞受体特异性抗体

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EP0602178A1 (fr) * 1991-08-28 1994-06-22 The Wistar Institute Therapie de la polyarthrite rhumatoide basee sur le recepteur de lymphocytes t
EP0602178A4 (en) * 1991-08-28 1995-10-25 Wistar Inst T cell receptor-based therapy for rheumatoid arthritis.
FR2736831A1 (fr) * 1995-07-19 1997-01-24 Centre Nat Rech Scient Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
WO1997004093A1 (fr) * 1995-07-19 1997-02-06 Centre National De La Recherche Scientifique Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
WO1998054575A2 (fr) * 1997-05-27 1998-12-03 University Of Wales College Of Medicine Procede permettant d'evaluer la cicatrisation d'une plaie
WO1998054575A3 (fr) * 1997-05-27 1999-03-11 Univ Wales Medicine Procede permettant d'evaluer la cicatrisation d'une plaie
US10858760B2 (en) 2015-06-01 2020-12-08 Medigene Immunotherapies Gmbh T cell receptor library
US11292838B2 (en) 2015-06-01 2022-04-05 Medigene Immunotherapies Gmbh Method for generating antibodies against T cell receptor
US10882891B2 (en) 2015-12-23 2021-01-05 Medigene Immunotherapies Gmbh Dendritic cell composition
US11155589B2 (en) 2015-12-23 2021-10-26 Medigene Immunotherapies Gmbh Generation of antigen-specific TCRs

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CA2068888A1 (fr) 1991-05-16
AU7787391A (en) 1991-06-13
FI922197A0 (fi) 1992-05-14
AU651346B2 (en) 1994-07-21
FI922197A (fi) 1992-05-14
EP0500780A1 (fr) 1992-09-02
EP0500780A4 (en) 1993-03-10
JPH05504621A (ja) 1993-07-15
KR920703844A (ko) 1992-12-18

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