WO1985003948A1 - Facteur d'activation de macrophages - Google Patents

Facteur d'activation de macrophages Download PDF

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Publication number
WO1985003948A1
WO1985003948A1 PCT/GB1985/000088 GB8500088W WO8503948A1 WO 1985003948 A1 WO1985003948 A1 WO 1985003948A1 GB 8500088 W GB8500088 W GB 8500088W WO 8503948 A1 WO8503948 A1 WO 8503948A1
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Prior art keywords
antigen
activating factor
cell
macrophage activating
cells
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PCT/GB1985/000088
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English (en)
Inventor
Ann Dorothy Mary Rees
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Celltech Limited
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Publication of WO1985003948A1 publication Critical patent/WO1985003948A1/fr

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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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/57—IFN-gamma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to a macrophage activating factor (referred to herein also as MAF) and to cell lines producing same.
  • MAF macrophage activating factor
  • T lymphocytes screte a heterogeneous mixture of substances , known collectively as macrophage activating factors which induce macrophages to kill tumours, bacteria, fungi and parasites.
  • T lymphocytes produce interferon- ⁇ (IFN- ⁇ ) which is known to activate macrophages and is the only identified and characterised macrophage activating factor.
  • IFN- ⁇ interferon- ⁇
  • a macrophage activating factor characterised in that the macrophage activating factor is antigenically distinct from interferon- ⁇ .
  • the macrophage activating factor is separable from interferon- ⁇ by high performance liquid chromatography.
  • the macrophage activating factor is antigenically the same as or similar to a macrophage activating factor produced by cloned human T cell line TB 68.2.1 (referred to later as Clone 1), TB 68.2.2 (referred to later as Clone 2) or TB 68.2.6 (referred to later as Clone 6) .
  • a cloned T cell line selected from TB 68.2.1, TB 68.2.2 and TB 68.2.6 and mutants and derivatives thereof.
  • the term 'mutants and derivatives thereof includes any human T cell line derived from a cell line as defined above which exhibits the characteristic of producing a macrophage activating factor which is antigenically distinct from interferon- ⁇ .
  • Macrophage activator factor according to the invention may be prepared by cloning T cells which have been prestimulated with an appropriate antigen. We have discovered that a purified antigen of
  • M. tuberculosis (hereinafter referred to as the TB 68 antigen) prepared from immunoadsorbants coupled to a monoclonal antibody TB 68 is particularly useful for generating T cell clones.
  • Other antigenic preparations which contain the TB 68 antigen for example M. tuberculosis strain H37v, M.bovis strain BCG and tuberculin purified protein derivative (PPD) may also be used.
  • PPD tuberculin purified protein derivative
  • We further provide a process for producing macrophage activating factor of the invention comprising the steps of culturing a cloned human T cell which has been stimulated prior to cloning with a TB 68 antigen and isolating the macrophage activating factor from the culture supernatant.
  • the cell lines are those designated TB 68.2.1, TB 68.2.2 and TB 68.2.6 referred to above.
  • the cloned T cell line is cultured in a culture medium which includes a cell growth factor such as, for example, interleukin 2.
  • a cell growth factor such as, for example, interleukin 2.
  • the cloned human T cell line is cultured in the presence of an antigen which stimulates secretion of macrophage activating factor, such as, for example, the TB 68 antigen and autologous feeder cells such as, for example, fresh identical HLA DR-identcal or part identical cells (monocytes/macrophages).
  • an antigen which stimulates secretion of macrophage activating factor such as, for example, the TB 68 antigen
  • autologous feeder cells such as, for example, fresh identical HLA DR-identcal or part identical cells (monocytes/macrophages).
  • the feeder cells act to present the antigen to the growing cell line.
  • the cloned human T cell line is cultured in the presence of a monoclonal antibody having specificity for the T3 cell surface antigen.
  • a suitable such monoclonal antibody is that designated OKT-3 (Ortho Diagnostics Systems Inc.).
  • the macrophage activating factor of the invention has therapeutic uses in the treatment of tumours and the prophylaxis or treatment of infection, for example, by bacteria, fungi or parasites.
  • a pharmaceutical composition comprising macrophage activating factor of the invention and a pharmaceutically acceptable excipient.
  • We also provide a process for preparing such a composition comprising bringing macrophage activating factor of the invention into association with a pharmaceutically acceptable excipient.
  • Figure 1 shows a graph indicating the enhancement of hydrogen peroxide release from human macrophage-like cells by recombinant DNA-derived interferon- ⁇ (circles) , native interferon- ⁇ (squares) and supernatant from a T cell clone (triangles).
  • Figure 2 shows the fractionation of macrophage activating factor from different sources.
  • Yield of antigen was estimated to be 50 ⁇ g/10 mg of expressate (approx 0.5% of total protein in M tuberculosis strain H37Rv expressate).
  • Immunoblotting indicates the native molecular weight of the antigen to be 120 K daltons.
  • 8 M urea treatment reduces this protein to 4 bands of molecular weights of 69, 46, 43 and 30 K daltons. These bands are immunoprecipitated by monoclonal antibody TB 68 and not by any other monoclonal antibody.
  • PBMC Peripheral blood mononuclear cells
  • Clones were allowed to grow for 4 days after the addition of IL2 and feeders before testing in proliferative assays. The above procedure gave rise to 3 cloned T cell lines designated TB 68.2.1, TB 68.2.2 and TB 68.2.6.
  • TB 68 antigen was prepared as described in Example 1. TB 72 antigen was similarly prepared.
  • mycobacterial pressates Other antigenic preparations of mycobacteria used were mycobacterial pressates; the non-particulate fraction of a bacterial homogenate passed through a press as described by Hewitt e t al.. , 1982. Tuberculin purified protein derivative (PPD) was obtained from Evans Medical Supplies Limited) .
  • Proliferative responses were determined using a microterasaki method as described by O'Brien and Knight et. al. , 1979. Briefly, cloned cells at 2.5 x 10 5 /ml in maintenance medium with 20% heat inactivated autologous serum were added in 20 ⁇ l aliquots to microterasaki plates containing antigen in 2 1.
  • the clones referred to as Clone 1, 2 and 6 are the Clones TB 68.2.1. TB 68.2.2 and TB 68.2.6 respectively.
  • the clones referred to as Clones 7 and 13 in Example 4 are not included within the scope of the invention.
  • T lymphocytes secrete macrophage activating factors (MAF) which induce macrophages to kill tumours 1,2 bacteria 3,4 , fungi 5 and parasites 6,7 . These lymphocytes also produce interferon- ⁇ (IFN- ⁇ ) 8 .
  • IFN- ⁇ interferon- ⁇ 8 .
  • a crucial question is whether macrophage activation by T cell supernatants is due entirely or partly to IFN- ⁇ . Both human and murine IFN- ⁇ have been produced in high purity by recombinant DNA techniques 1 1-1 3 . However, the existence of MAF antigenically distinct from IFN- ⁇ in T cell supernatants has not been established.
  • MAF anti-IFN- ⁇ monoclonal antibody
  • IFN- ⁇ activates macrophages to kill intracellular parasites, to lyse tumour cells and to release the microbicidal agent hydrogen peroxidase 6 it is not known whether srtigen-stimulated T lymphocytes secrete MAF distinguishable from IFN- ⁇ .
  • IFN- ⁇ is one of several MAFs which may function independently or synergistically. The finding of MAF activity but not IFN- ⁇ activity in supernatants from murine T cell clones 2 and murine T cell hybridomas 14,15 suggests the existence of several MAFs.
  • Cells of the human macrophage-like line U937 can be immunologically activated to express anti-microbial activity 16 and we used enhancement of hydrogen peroxide releasel? from these cells to assay MAF.
  • T cell supernatants and cloned IFN- ⁇ activated the cells for peroxide release but the T cell supernatants were about 50-fold more potent than would be expected if their activity was solely due to their interferon content.
  • Anti-IFN- ⁇ MAB 12:20 obliterated the effect of up to 100 units of cloned IFN- ⁇ . Natural IFN- ⁇ also activated U937 cells for peroxide release and this activity too was substantially reduced by MAB 12:20.
  • the MAF activity of the T cell clone supernatants was only slightly reduced by MAB 12:20, a finding compatible with the neutralisation of the 10-60 units interferon (anti-viral) activity per ml in these supernatants.
  • Physiochemical characterisation of a supernatant from a murine T cell line EL-4 has revealed two MAFs, one of which is distinct from IFN- ⁇ and is unaffected by anti-IFN- ⁇ serum 19,20 .
  • molecular filtration by HPLC revealed that the MAF in T cell clone supernatants was distinguishable from IFN- ⁇ ( Figure 2) .
  • T cell clone supernatant Enhancement of hydrogen peroxide from human macrophage-like cells by exposure to T cell clone supernatant or IFN- ⁇ and the effects of monoclonal anti-IFN- ⁇ antibody.
  • T cell clone supernatant was collected during clone maintenance on irradiated feeder cells with interleukin 2 and antigen 26 .
  • From an exponentially replicating culture of human macrophage-like lymphoma cell line U937 16 in RPMI 1640 medium containing 10% foetal calf serum, aliquots of 5 x 10 5 cells were dispensed into plastic tubes (12 x 75 mm; Falcon). The tubes were gently centrifuged and the supernatants removed.
  • T cell clone supernatant or IFN- ⁇ were made in U937 growth medium and added to the tubes either directy or after mixing with antibody (100 ⁇ g ml -1 ) and incubating for 2 hours at 37°C. Each tube contained a final volume of 500 ⁇ l. The tubes were incubated for 3 days at 37°C with daily centrifugation and replacement of medium and supplements. Hydrogen peroxide release from the cells during 1-h stimulation with phorbol myristate acetate (1 ⁇ g ml -1 ) was then measured and the number of cells in each tube assessed by DNA estimation 17 .
  • Controls included tubes containing either no supplements or sham supernatants prepared identically to T cell clone supernatants but without using T cells. Peroxide release in these controls (2-6 nmol 10 0 cells -1 ) was subtracted from the relevant test values and the difference was plotted as increment in peroxide release versus units of interferon in the test supplements. Interferon was assayed as inhibition of nucleic acid synthesis in SFV-infected WISH fibroblast cells 27 .
  • results obtained in a representative experiment which included recombinant DNA-derived IFN- ⁇ (o, ⁇ ), native IFN- ⁇ (from PHA-stimulated human blood lymphocytes, Finnish Red Cross; ⁇ , ⁇ ) , supernatant from T cell Clone 1 ( ⁇ , ⁇ ) used either alone (open symbols) or after treatment with anti-IFN- ⁇ MAB 12:20 C 8 (closed symbols). Resnlts with recombinant DNA-derived IFN- ⁇ treated with MAB NB10 are also shown Supernatants from 3 discrete T cell clones (1, 2 and 6) gave similar results and for clarity only data from one of these is shown. Regressions were fitted by the least squares method.
  • lymphocytes respond with immunological specificity to the invading microorganism little is known of the importance of individual antigens. It is not known, for example, whether one antigen may preferentially generate one particular, or several of the responses known to follow stimulation wtih bacterial or their antigens.
  • the clones described were prepared from a single prestimulation of normal peripheral blood mononuclear cells (PBMC) with TB 68 antigen, by a modification 6 of a method previously described 7 .
  • PBMC peripheral blood mononuclear cells
  • Plating efficiency (the proportion of cells proliferating) was estimated to be 20% and, therefore clonality was established by subcloning. Plating efficiency at subcloning was 95% and subclones were, by our criteria, identical to the parent clone.
  • the clones generated were screened initially for the capacity to respond to the eliciting antigen. The majority of the clones (75%) failed to respond. Of the 25% which did respond 5 of the clones were selected for futher investigation. The phenotype of these clones is described in Table 1.
  • the antigenic specificity of individual clones was determined by co-culturing clones with irradiated autologous PBMC and a variety of antigenic preparations some of which were known to contain, at lease in part, determinant(s) of the eliciting antigen, and some which did not 4,9 .
  • the MAB TB 68 has also been shown to bind to PPD 10 .
  • Table 2 shows that all clones responded vigorously to the TB 68 antigen.
  • the clones also responded to other antigenic preparations. Indeed Clone 13 also responded to a number of antigens which did not contain the eliciting antigen, particularly TB 72, which was purified in a similar fashion to TB 68.
  • Clones 1, 2, 6 and 7 on the other hand proliferated only to those antigenic preparations, which contained TB 68 antigen i.e. Mycobacterium tuberculosis strain H37Rv. Mycobacterium bovis strain BCG and PPD. Not all clones responded identically. In particular. Clone 2 did not respond to PPD or to M bovis BCG antigenic preparations, indicating that this clone may recognise a different epitope of the antigen than either Clones 1, 6 or 7. In its native state the TB 68 antigen is large with a molecular weight of 120 K. On SDS treatment 4 major chains are found. Clone 2 may, therefore recognise a different chain to Clones 1, 6 and 7. All clones were responsive to IL2 (lymphocult T, lectin free, Biotest Folex Limited) alone, although to a lesser extent than antigen alone. Optimal proliferation was achieved in the presence of both antigen and IL2.
  • IL2 lymphocult T, lectin free, Biotest
  • U937 is a macrophage cell line that can be immunologically activated to express antimicrobial activity 12 .
  • Table 3 shows that all supernatants from clones with helper/ inducer phenotypes, irrespective of the pattern of antigen specificity in the clone proliferative response, increased H 2 O 2 production.
  • the clone supernatants were 10-fold more effective than a whole phytohaemaglutinin A-activated (PHA) spleen cell supernatant (SCF), indicating that the production of macrophage activating factor(s) (MAF) is an important constituitive function of these clones. This activity does not appear to be due to interferon!3. Clone 7 supernatant did not have MAF activity.
  • PHA phytohaemaglutinin A-activated
  • SCF phytohaemaglutinin A-activated
  • MAF macrophage activating factor
  • This activity does not appear to be due to interferon!3.
  • Clone 7 supernatant did not have MAF activity.
  • This clone is currently being tested to determine whether it is functionally a suppressor or a cytotoxic T cell. If it is a suppressor T cell clone, this would suggest that this particular antigen may also stimulate the proliferation of T ceils involved in the regulation of the macrophage activating response.
  • helper/inducer clones cultured with U937 cells, were as good, or frequently better, than supernatants in increasing H 2 O 2 release.
  • Cloned cells as well as lymphokine could also enhance H 2 O 2 release from conventional macrophages matured from peripheral blood monocytes , indicating that this activity was not dependent on using U937 cells.
  • Sham supernantants prepared from identical cultures with autologous feeders, but in the absence of cloned cells, had a small, but measurable effect on H 2 O 2 production. This was not due to Interleukin 2, which even at 50% concentration did not increase H 2 O 2 production above control levels .
  • the TB 68 antigen is not alone in stimulating MAF production by lymphocytes, a variety of stimuli have been used 14,15 .
  • T cell cloning we have demonstrated that helper/inducer but not suppressor/cytotoxic T cells secrete MAF, although cells of both phenotypes specifically proliferate in vitro to TB 68 antigen.
  • Previously lymphokine production and proliferation to soluble antigens were thought to be the function of distinct populations of T cells 16,17 . Whilst the exact relationship between the release of H 2 O 2 and microbicidal functions remains to be clarified, H 2 O 2 appears to kill M microti in mouse macrophages 18 . Therefore, these T cell clones, either by cell to cell contact, or through lymphokines, may enhace the microbicidal function of the macrophage which is the main effector cell of immunity to Mycobacterium tuberculosis.
  • U937 cells at 10 6 cells/tube were cultures in RPMI 1640 medium (Gibco Biocult Limited). 10% foetal calf serum in the presence and absence of various concentrations of cloned T cell supernatants, sham control (a supernatant prepared from identical cultures but in the absence of cloned T cells) and spleen cell factor (SCF) produced by mitogen activated human spleen cells cultured with PHA for 72 hours. Medium and clone supernatants and SCF in U937 cultures were replaced at 24 hour intervals. At 72 hours the cells were rinsed in Hanks balanced salt solution.

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Abstract

Facteur d'activation de macrophages qui est antigénétiquement distinct de l'interféron - gamma. De tels facteurs d'activation de macrophages sont produits par culture des lignées de cellules T humaines clonées TB 68.2.1, TB 68.2.2 et TB 68.2.6.
PCT/GB1985/000088 1984-03-02 1985-03-04 Facteur d'activation de macrophages WO1985003948A1 (fr)

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GB848405555A GB8405555D0 (en) 1984-03-02 1984-03-02 Macrophage activating factors
GB8405555 1984-03-02

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5316763A (en) * 1991-07-10 1994-05-31 The United States Of America As Represented By The Department Of Health And Human Services Short-term anti-CD3 stimulation of lymphocytes to increase their in vivo acitivity
WO1994026876A1 (fr) * 1993-05-14 1994-11-24 Dr. L. Willems-Instituut Cellule t humaine monoclonale, procede pour sa production et son utilisation dans le diagnostic des maladies infectieuses, des maladies auto-immunes, des allergies induites par des cellules t et le cancer
US5443983A (en) * 1986-08-08 1995-08-22 Regents Of The University Of Minnesota Method of culturing lymphocytes and method of treatment using such lymphocytes
US5607917A (en) * 1991-12-31 1997-03-04 Zymogenetics, Inc. Methods for reducing blood loss
US5650152A (en) * 1988-10-27 1997-07-22 Regents Of The University Of Minnesota Liposome immunoadjuvants containing IL-2

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075886A2 (fr) * 1981-09-25 1983-04-06 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé d'obtention du facteur activant les macrophages
EP0094317A2 (fr) * 1982-05-12 1983-11-16 Shionogi & Co., Ltd. Préparation d'interleucine et de ses facteurs immunorégulateurs analogues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075886A2 (fr) * 1981-09-25 1983-04-06 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé d'obtention du facteur activant les macrophages
EP0094317A2 (fr) * 1982-05-12 1983-11-16 Shionogi & Co., Ltd. Préparation d'interleucine et de ses facteurs immunorégulateurs analogues

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biological Abstracts/Reports, Reviews, Meetings, Vol. 28, issued in 1985 (Philadelphia, US) P.W. ANDREW et al.: "Secretion of a Macrophage-Activating Factor Distinct from Interferon-gamma by Human T Cell Clones", see Abstract No. 28915, & European Journal of Immunology (West Germany) 1984, Vol. 14, No. 10, 962-964 *
CHEMICAL ABSTRACTS, Vol. 102, No. 9, 4 March 1985 (Columbus, Ohio, US) R. MATTHEWS et al.: "Mycobacterial Antigen-Specific Human T-Cell Clones Secreting Macrophage Activating Factors", see Abstract No. 77030s, & Immunology, 1985, 54(1), 17-23 *
CHEMICAL ABSTRACTS, Vol. 97, No. 19, 8 November 1982 (Columbus, Ohio, US) Y. YAMAMOTO et al.: "Macrophage Activating Factor is not Identical with Immune Interferon or a Factor Inducing Differentiation of Mouse Mycloid Leukemic Cells", see page 534, Abstract No. 160856q, & Gann. 1982, 73(4), 557-64 *
The Journal of Immunology, Vol. 119, No. 3, September 1977, The Williams & Wilkins Co. (Baltimore, US) L.P. RUCO et al.: "Macrophage Activation for Tumor Cytotoxicity: Induction of Tumoricidal Macrophages by Supernantants of PPD-Stimulated Bacillus Calmette-Guerin-Immune Spleen Cell Cultures", see pages 889-896, especially page 889, right-hand column, line 28 - page 890, left-hand column, line 5 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5443983A (en) * 1986-08-08 1995-08-22 Regents Of The University Of Minnesota Method of culturing lymphocytes and method of treatment using such lymphocytes
US5650152A (en) * 1988-10-27 1997-07-22 Regents Of The University Of Minnesota Liposome immunoadjuvants containing IL-2
US5773006A (en) * 1988-10-27 1998-06-30 Regents Of The University Of Minnesota Lipsome containing IL-2
US5316763A (en) * 1991-07-10 1994-05-31 The United States Of America As Represented By The Department Of Health And Human Services Short-term anti-CD3 stimulation of lymphocytes to increase their in vivo acitivity
US5607917A (en) * 1991-12-31 1997-03-04 Zymogenetics, Inc. Methods for reducing blood loss
WO1994026876A1 (fr) * 1993-05-14 1994-11-24 Dr. L. Willems-Instituut Cellule t humaine monoclonale, procede pour sa production et son utilisation dans le diagnostic des maladies infectieuses, des maladies auto-immunes, des allergies induites par des cellules t et le cancer

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JPS61501563A (ja) 1986-07-31
EP0175705A1 (fr) 1986-04-02

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