WO1993015759A1 - Autoantibody assay and usage in the control of human disease - Google Patents
Autoantibody assay and usage in the control of human disease Download PDFInfo
- Publication number
- WO1993015759A1 WO1993015759A1 PCT/US1993/000886 US9300886W WO9315759A1 WO 1993015759 A1 WO1993015759 A1 WO 1993015759A1 US 9300886 W US9300886 W US 9300886W WO 9315759 A1 WO9315759 A1 WO 9315759A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ataa
- cells
- autoantibody
- cell
- target
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/24—Immunology or allergic disorders
Definitions
- This invention relates generally to the field of biological cellular antigen assay and, specifically, to establishing a method of assay for autoantibodies in relation to regulation of the immune system.
- ATAA demonstrable antibody
- autoantibodies specific antibodies which react with almost any tissue or organ in the body, i.e. brain, skin, various serum proteins (including antibody molecules), all blood cells (including lymphocytes), intestinal tissues, heart cells, etc.]. It has never been clear whether these antibodies cause resultant disease or are the result of the disease, but in some cases they are interpreted as being causal.
- thymocytes There are many different types of thymocytes which originate in the thymus and are the precursors of T-lymphocytes which are found in blood and various lymphoid and non-lymphoid organs of the body. T- lymphocytes are concerned with cellular immunity, as differentiated from B-lymphocytes which produce antibodies and are responsible for the humoral immune response. The T-lymphocytes recognize antigens by recognition sites and accessory molecules which are of various types and which define each type of T-lymphocyte. The recognition sites are associated with the major histocompatibility complex.
- T-lymphocytes are of many different types, each identifiable by distinct antigenic differences and many of which have distinct functions.
- the development (ontogeny) of the various T-lymphocytes occur within the thymus gland and are present in various percentages, at various times, within the thymus. (See: Molecular and Cellular Events of T-Cell Development; B.J. Fowlkes and Drew M. Pardoll; Adv. In Immunology; Vol. 44, pp. 201-217; 1989).
- T-lymphocytes Aside from classification of T-lymphocytes by their recognition sites and accessory molecules, there are several different functional subsets of T-lymphocytes: helper cells; suppressor cells; killer cells; etc. therefore, it is no surprise that investigators have been unable to understand the nature or the functional significance of the thymocyte autoantibody. It has been said that the serum levels of ATAA do not show etiological significance to disease (Eisenberg et al . , J . Immunology 722, p. 2272, 1979).
- Perper et al disclose an IgG thymolytic autoantibody in rats which has specificity for a sub-population of T-cells (R.J. Perper, A.L. Oronsky and Maria Sanda; Immunology, paper 312; 1976). These researchers present an interesting disclosure wherein a cytotoxic anti-thymocyte IgG autoantibody is found present in Lewis rats which, in the presence of autologous complement, destroys (in vi tro) 12-28% of isologous or aubologous thymocytes, a small number of lymph node cells and splenocytes, but not bone marrow or circulating lymphocytes.
- the labile cells in the thymus represent a finite subpopulation which is autologous anti-thymocyte antibody sensitive and steroid resistant.
- the presence of the autoantibody is randomly distributed in outbred animals, whereas inbred Lewis rats, a strain in which the induction of some autoimmune reactions is under genetic control, the antibody is almost always present. In this strain, the susceptible T-cells and the quantity of circulating autoantibody is significantly depressed during the productive phase of the T-cell mediated disease (adjuvant polyarthritis) and returns to normal after the disease becomes stabilized.
- 4,937,071 teaching a METHOD FOR AUGMENTING IMMUNE RESPONSE, discloses a method for enhancing the ability for humoral immune response in a mammal which comprises exposure of lymphocytes histocompatible with the lymphocytes of the mammal to the presence of delta-immunoglobulin at a concentration higher than that at which the lymphocytes would have been exposed while in the lymph or blood stream of the mammal and, thereafter introducing these lymphocytes to the blood stream of lymph of the mammal.
- This is clearly a method of augmentation, and no one suggests the use of a naturally occurring (or monoclonal replicate of an) autoantibody to regulate the immune response mechanism.
- the target cell of ATAA regulates the development of the disease and the level of ATAA serves as a marker and may control the number of these (target) cells.
- I use the amount of ATAA to predict susceptibility/resistivity to disease and to regulate the quantity of these target cells so as to be able to manipulate body susceptibility/resistivity and the cause of both autoimmune diseases and malignancies.
- the quantitation of ATAA in circulation using the appropriate target cell (a subpopulation of thymocytes, the antigen of which might be present on various other cell types and detailed, but not limited to those mentioned earlier) predicts susceptibility to the development of allergic hypersensitivity reactions and autoimmune disease or resistance to tumor development.
- modification may be had of the course of either tumor development or autoimmune disease/allergic hypersensitivity diseases.
- Figure 1 is a graphical representation showing the effect of pre-existing autoantibody titer on the severity of adjuvant disease (re: swelling) in Lewis rats;
- Figure 2 is a graphical representation contrasting the level of pre-existing anti-thymocyte autoantibody (ATAA) with the change in body weight (day 8- 18) after the induction of EAE; and
- Figure 3 is a graphical display which illustrates that, when the target cell of ATAA is eliminated, there exists an enhanced immune reactivity of the surviving cells.
- the target cell of ATAA is able to suppress the cellular immune response (a suppressor cell in, and derived from, the thymus).
- High levels of ATAA reduce the number of suppressor cells and allow the development of autoimmune diseases.
- low levels of ATAA result in high levels of suppressor cells which prevent cellular immunity from rejecting malignancies.
- an inverse relationship between vulnerability to malignancy and autoimmunity exists. This relationship is regulated by the presence of ATAA.
- Figure 3 shows the popliteal lymph node Graft versus Host (GVH) of Lewis rat thymocytes preincubated with isologous serum (naturally occurring ATAA) .
- isologous serum naturally occurring ATAA
- L/BN F.Hybrids
- Thymocytes were preincubated with either complement sufficient isologous serum (120 CH 50 units) or the same serum heat inactivated (0 CH 50 units).
- the control experiment in which 5.0 x 10 7 F.Hybrid cells were preincubated with complement sufficient is shown as a single point (L/BN ⁇ * L/BN) .
- I apply the same type of assay system as has been used in rats to a human situation.
- I use various human sera and fetal human thymocytes as target cells.
- I measured, in several human samples, the presence of ATAA which reacts with (kills) a small percentage of human fetal thymocytes.
- ATAA which reacts with (kills) a small percentage of human fetal thymocytes.
- the quantitation of ATAA in circulation while using the appropriate target cell predicts susceptibility to the development of allergic hypersensitivity reactions and autoimmune disease (high level) or resistance to tumor development (low level).
- Table B outlines methods for altering the in vivo levels of ATAA or the susceptible cell. This is simply an outline without excluding other possibilities currently known or which may become available, and the reader should be cautioned not to attribute arbitrary bounds to these methods.
- vi tro delete other ly phoid cell types resulting in functional increase in susceptible cell.
- serum from an individual animal is mixed with a pool of living thymocytes from about five to about ten donors.
- inbred animals Lewis rats
- outbred animals Wistar or Sprague Dawley rats
- the pool of thymocytes is derived from about five to about ten individual donors all presumably with different histocompatibility antigens. The latter was preferred since it mimics the human situation where the amount of anti-thymocyte antibody (ATAA) will differ in each individual and it is tested against a common thymocyte antigen present in all individuals within the species.
- AAA anti-thymocyte antibody
- the assay involves mixing a vital dye (trypan blue) with the live thymocytes.
- the live cells will exclude the dye and will remain unstained (clear) when viewed under a microscope.
- the dead cells will allow the passage of dye internally so that they stain and appear blue.
- This assay therefore, reflects the ability of the added serum to kill the target cells.
- There are innumerable other methods to measure the reaction of antibody in the serum (anti-thymocyte antibody) with the relevant target cells i.e. (1) labeling the target cells with radioactive molecules and observing the release of radioactivity as a function of cell death; (2) measuring binding of antibody with cells such as using an ELISA assay; (3) measuring binding of antibody with target cells using the consumption of secondary serum molecules (complement), and so forth.
- the end result is the measurement of the reaction of antibody in serum with target thymocytes.
- Thymus glands were obtained from either Lewis, Wistar or Sprague Dawley rats anaesthetized with ether. The cells were teased into cold Hanks balanced salt solution, washed twice in the same solution and resuspended at concentration of 5x10° cells per ml. in RPMI 1640 media. After warming at 37°C, 100 microliters of cell suspension was placed in each well of 300 microliter plates to which was added 50 microliters of serum at a 1:3 dilution at 37°C. All samples were tested in quadruplicate. Plates were incubated in a stirred water bath at 37°C for 30 minutes. Fifty microliters of cell suspension were mixed with 50 microliters of 0.2% trypan blue and the number of dead and live cells were counted in a hemocytometer plate. One hundred cells from each sample were separately counted.
- EAE was induced by described methods [J. Neurosci. Res. 24 -. 222-230 (1989)] and the end point of disease development as a function of weight gain is described in detail elsewhere [J. Pharmacal. Exp. Therap., 242: 614-620 (1987)].
- Adjuvant arthritis was induced as described elsewhere in the art [Proc. Soc. Exp. Biol., 737: 506 (1971)]. The aforementioned methods only are herein incorporated by these references.
- the assay system used although accurate, is simplistic and economically feasible. Increased sensitivity is also achieved by employing radioactive labeled cells or various types of binding measurement techniques.
- the most important assay development technique is to identify the target cell type, and then purify the relevant antigenic determinant. Once this is accomplished, the target cell (or antigen) suspension will be so enriched that, instead of identifying a small number of relevant cells, most or all will be reactive with the ATAA-containing serum. Thus, a more accurate quantitation of the amount of ATAA is made.
- the relevant antigen is purified, the probability is higher that it will be found in more easily accessible cells or tissues, rather than having to use thymus cells.
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Abstract
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93904802A EP0625909A4 (en) | 1992-02-12 | 1993-02-01 | Autoantibody assay and usage in the control of human disease. |
JP5514133A JPH07504495A (en) | 1992-02-12 | 1993-02-01 | Autoantibody assay method and its use in human disease control |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83569692A | 1992-02-12 | 1992-02-12 | |
US835,696 | 1992-02-12 |
Publications (1)
Publication Number | Publication Date |
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WO1993015759A1 true WO1993015759A1 (en) | 1993-08-19 |
Family
ID=25270231
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/000886 WO1993015759A1 (en) | 1992-02-12 | 1993-02-01 | Autoantibody assay and usage in the control of human disease |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0625909A4 (en) |
JP (1) | JPH07504495A (en) |
AU (1) | AU3603893A (en) |
CA (1) | CA2129895A1 (en) |
WO (1) | WO1993015759A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0725239D0 (en) * | 2007-12-24 | 2008-02-06 | Oncimmune Ltd | Calibrator for autoantibody assay |
-
1993
- 1993-02-01 JP JP5514133A patent/JPH07504495A/en active Pending
- 1993-02-01 CA CA 2129895 patent/CA2129895A1/en not_active Abandoned
- 1993-02-01 AU AU36038/93A patent/AU3603893A/en not_active Abandoned
- 1993-02-01 EP EP93904802A patent/EP0625909A4/en not_active Withdrawn
- 1993-02-01 WO PCT/US1993/000886 patent/WO1993015759A1/en not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
Immunology, Volume 31, issued 1976, R.J. PERPER, "A IgG Thymolytic Autoantibody in Rats which has Specificity for a Sub-Population of T-Cells", pages 1-8, Appendix paper 312, see entire document. * |
Science, Vol. 252, issued 21 June 1991, T.A. WALDMANN, "Monoclonal Antibodies in Diagnosis and Therapy", pages 1657-1661, see entire document. * |
See also references of EP0625909A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP0625909A4 (en) | 1997-03-05 |
EP0625909A1 (en) | 1994-11-30 |
JPH07504495A (en) | 1995-05-18 |
AU3603893A (en) | 1993-09-03 |
CA2129895A1 (en) | 1993-08-13 |
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