WO1993017708A1 - Procede permettant de traiter les infections dues aux pathogenes des macrophages - Google Patents

Procede permettant de traiter les infections dues aux pathogenes des macrophages Download PDF

Info

Publication number
WO1993017708A1
WO1993017708A1 PCT/US1993/002017 US9302017W WO9317708A1 WO 1993017708 A1 WO1993017708 A1 WO 1993017708A1 US 9302017 W US9302017 W US 9302017W WO 9317708 A1 WO9317708 A1 WO 9317708A1
Authority
WO
WIPO (PCT)
Prior art keywords
tgf
infection
macrophage
mice
leishmania
Prior art date
Application number
PCT/US1993/002017
Other languages
English (en)
Inventor
Steven G. Reed
Original Assignee
Reed Steven G
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reed Steven G filed Critical Reed Steven G
Priority to CA002130995A priority Critical patent/CA2130995C/fr
Publication of WO1993017708A1 publication Critical patent/WO1993017708A1/fr

Links

Classifications

    • 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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a method of treating an individual infected with a macrophage pathogen comprising administering an effective amount of a Transforming Growth Factor- ⁇ (TGF- ⁇ ) antagonist.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • Macrophage pathogens include any microorganism that replicates or proliferates within host macrophage cells as their exclusive or primary host cells.
  • One such macrophage pathogen is Leishmania.
  • Leishmania is an obligate intracellular macrophage parasite.
  • a variety of species of Leishmania infect man, and most or all of such species can cause experimental infection but do not always cause disease in a predictive model such as mice.
  • MostL. brasiliensis strains cause infection in mice but not disease symptoms.
  • Leishmania are intracellular protozoan parasites of macrophages which cause a variety of human diseases, characterized by visceral, cutaneous, or mucosal lesions. Leishmania are transmitted to humans and other mammals by the bite of a sandfly. Different species and isolates of Leishmania vary in their ability to infect and replicate in macrophages both in vivo and in vitro. For example, L. major and L. amazonensis multiply rapidly in human and mouse macrophages in vitro, and readily infect mice. L. brasiliensis is mildly to non-infectious for cultivated macrophages or mice.
  • T. cruzi The hemoflagellate protozoan Trypanosoma cr zi (T. cruzi) causes Chagas' disease, a major public health problem in many countries of Latin America. Infection with this parasite may be acute or chronic, and frequently involves development of progressive pathology in tissues of the heart, esophagus and colon. The parasites infect a variety of nucleated cells, including macrophages. In both human and laboratory animals, T. cruzi infection is accompanied by a non-specific immune- suppression mediated by T cells and macrophages, which results in reduced T cell function, including helper T cells for antibody production and cytotoxicity. Mechanisms which control parasite replication during the acute and chronic phases and which maintain low but persistent numbers of circulating parasites during the chronic phase are not well understood. However, several publications point to a key role played by cytokines for regulating both parasite replication and immune responses in infected individuals.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • This 24 kD protein is produced by many cells, including B cells, T cells and activated macrophages.
  • TGF- ⁇ has been implicated as a mediator or immunosuppression, as inhibiting Interleukin-2 (D -2) receptor induction, as mediating Interleukm ⁇ l QL-1) induced th ' ymocyte proliferation, and other activities.
  • D -2 Interleukin-2
  • QL-1 Interleukm ⁇ l QL-1 induced th ' ymocyte proliferation
  • TGF- ⁇ has the ability to inhibit cytokine- induced macrophage activation, and to suppress production of reactive oxygen and nitrogen intermediates.
  • the potent effects of TGF- ⁇ on cellular immune responses often resemble those accompanying acute T. cruzi infection.
  • the present invention relates to a method of treating an individual infected with a macrophage pathogen, comprising administering an effective amount of a TGF- ⁇ antagonist.
  • TGF- ⁇ antagonists comprise any pharmaceutical composition capable of blocking activity of the cytokine TGF- ⁇ - Macrophage pathogens comprise microorganisms that replicate within macrophages as their exclusive or primary host cells.
  • pathogens include, for example, Leishmania, Listeria, Mycobacteria,
  • TGF- ⁇ antagonists include, for example, blocking antibodies specific for a human TGF- ⁇ , soluble TGF- ⁇ receptors, membrane-bound TGF- ⁇ receptors, protease inhibitors that inactivate a protease responsible for activating a precursor TGF- ⁇ into an active, mature TGF- ⁇ , antibodies specific to TGF- ⁇ receptors (Types I, II or IE) and which prevent TGF- ⁇ binding to the receptor, and combinations thereof.
  • BRTFF DESCRIPTION OF THE DRAWINGS include, for example, blocking antibodies specific for a human TGF- ⁇ , soluble TGF- ⁇ receptors, membrane-bound TGF- ⁇ receptors, protease inhibitors that inactivate a protease responsible for activating a precursor TGF- ⁇ into an active, mature TGF- ⁇ , antibodies specific to TGF- ⁇ receptors (Types I, II or IE) and which prevent TGF- ⁇ binding to the receptor, and combinations thereof.
  • FIG. 1 illustrates a comparison of TGF- ⁇ production in vitro induced by Leishmania.
  • Active TGF- ⁇ was produced by murine macrophages upon infection with L. amazonensis.
  • Data represent the mean plus standard error of the mean of the peak response (obtained 72 hours post-infection) of three different isolates of L. amazonensis, compared to uninfected cells. Details of this experiment are presented in Example 1 herein.
  • FIG. 2 shows an in vivo effect of TGF- ⁇ on the course of cutaneous Leishmaniasis.
  • panel A C57BL/6 mice were infected with L. amazonensis. TGF- ⁇ was injected at 24 hours and at 6, 7, 8 and 9 weeks post infection (open circles). Control animals were injected similarly and at the same time periods with the same amount of saline (close circles).
  • panel B BALB/c mice were infected with L. brasiliensis and recombinant TGF- ⁇ was injected subcutaneously into the lesion at 24 hours and at weeks 1, 2, 3, 5, 12, and 13 post infection (open circles). Saline treated controls are shown with closed circles.
  • Figure 3 illustrates a protective effect caused by an anti-TGF- ⁇ monoclonal antibody as a TGF- ⁇ antagonist on the course of cutaneous Leishmaniasis.
  • Panel A describes BALB/c mice infected with L. amazonensis and treated six times (three times per week during the first two weeks post-infection) with 1D11.16 (anti-murine TGF- ⁇ monoclonal antibody, open circles) or a similar amount of an irrelevant antibody
  • FIG. 4 is a graph showing production of active TGF- ⁇ by Leishmania- infected macrophages. Cultures of mouse peritoneal macrophages were infected with L. brasiliensis (BA-92 or BA-331) and supematants were collected three days later. Data are shown as the mean plus standard error of the mean from triplicate cultures.
  • FIG. 5 shows a comparison of TGF- ⁇ or a TGF- ⁇ antagonist (monoclonal antibody ID 11.16) on in vitro replication of Leishmania in mouse peritoneal macrophages infected with BA-92 and cultured with 2 ng/ml TGF- ⁇ (open bars), 200 ⁇ g ml of 1D11.16 (hatched bars) 24 hours before and continuously after infection, or in medium alone (control bars). The numbers of intracellular parasites were determined at 2, 24, and 48 hours after infection.
  • Figure 6 shows the effects of exogenous TGF- ⁇ on the course of L. brasiliensis infections in BALB/c mice.
  • Infections were made with BA-92 (5 x 10 ⁇ stationary- phase promastigotes) diluted in control saline or in saline containing TGF- ⁇ at 40 ⁇ g ml, for a total dose of l ⁇ g/mouse. Treatments were followed with TGF- ⁇ (1 ⁇ g/dose, open circles) or saline (closed circles) injected into the infected footpad one time per week for ten weeks.
  • FIG 7 shows an experiment designed similarly to Figure 6 except the BALB/c mice were infected with B A-331 instead of B A-92 in Figure 6.
  • FIG 8 shows the effect of TGF- ⁇ on a previous infection with L. brasiliensis.
  • BALB/c mice were infected with either B A-92 (close circles) or BA-331 (open circles) and maintained without treatment for 15 weeks. The mice were then treated with TGF- ⁇ (1 ⁇ g/injection) or saline for a three week period for three injections per week. Saline-injected controlled mice (triangles) did not develop lesions.
  • the present invention relates to a method of treating an individual infected with a macrophage pathogen comprising administering an effective amount of a TGF- ⁇ antagonist.
  • the present invention was conceived by the research finding that mice infected with the macrophage pathogen Leishmania can be treated with a blocking monoclonal antibody specific to murine TGF- ⁇ . This finding, in a predictive animal model, provides data to fully enable the inventive method of treating individuals infected with any macrophage pathogen with a pharmaceutical composition comprising a substance with TGF- ⁇ antagonist activity.
  • TGF- ⁇ antagonists include antibodies or monoclonal antibodies that are blocking for human TGF- ⁇ , soluble TGF- ⁇ receptors, membrane-bound TGF- ⁇ receptors, protease inhibitors that inactivate a protease responsible for activating precursor TGF- ⁇ into an active, mature TGF- ⁇ form, and combinations thereof.
  • the course of infection with the protozoa and macrophage pathogen Leishmania is determined, in part, by their early replication in macrophages, the exclusive host cells for these organisms. Although factors contributing to the inhibition or proliferation of Leishmania are not well understood, certain cytokines can influence the course of infection. We have found that Leishmania infection induces production of active TGF- ⁇ both in vivo and in vitro, and that TGF- ⁇ plays an essential role in determining in vivo resistance and susceptibility to Leishmania infection in an experimental mouse model.
  • TGF- ⁇ is a 24 kD protein produced by many cells, including B and T lymphocytes and activated macrophages, as well as by many other cell types. TGF- ⁇ is generally secreted as latent precursor, requiring enzymatic cleavage of carbohydrate groups or transient acidification to release the active cytokine. Among the effects of TGF- ⁇ on the immune system are inhibitions of IL-2-receptor induction, IL-1 -induced thymocyte proliferation and blocking of gamma interferon-induced macrophage activation.
  • TGF- ⁇ The potential role of TGF- ⁇ during infection, in vivo, of a macrophage pathogen was investigated. Leishmania lesions were examined using a murine TGF- ⁇ - specific monoclonal antibody. There was local TGF- ⁇ production in mouse footpads following Leishmania infection but there was no detectable TGF- ⁇ in uninfected footpads of the same mouse. Therefore, increased TGF- ⁇ production was associated with Leishmania infection both in vitro and in vivo.
  • TGF- ⁇ is able to reverse genetic resistance to Leishmaniasis in C57BL/6 mice.
  • TGF- ⁇ also influences infection withL. brasiliensis. This parasite does not produce lesions even in BALB/c mice, which are susceptible to infection with other Leishmania species.
  • TGF- ⁇ treatment led to replication of L. brasiliensis and to production of lesions in BALB/c mice ( Figure 2B).
  • lesions in the BALB/c mice were investigated histologically, lesions from saline-treated animals were composed of predominately lymphocytic infiltrate, whereas lesions from TGF- ⁇ -treated BALB/c mice exhibited a large number of heavily vacuolated and parasitized macrophages among the lymphocytes. Therefore, local administration of TGF- ⁇ led to production of acute disease in two different animal models of resistance.
  • TGF- ⁇ was increased during Leishmania infection and that exogenously-administered recombinant TGF- ⁇ could produce exacerbated infections in resistant mice
  • Highly susceptible BALB/c mice were treated with a neutralizing antibody specific for murine TGF- ⁇ during the course of infection withL. amazonensis.
  • Control mice were similarly injected with an irrelevant immunoglobulin.
  • In vivo treatment with anti-TGF- ⁇ arrested development of lesions resulting fromL. amazonensis infection in susceptible BALB/c mice (Figure 3). Inhibition of lesion development was noted by the 5th week post-infection and was maintained thereafter. Therefore, endogenous TGF- ⁇ production was directly associated with susceptibility to a macrophage pathogen such as Leishmania.
  • anti-TGF- ⁇ antibody is a TGF- ⁇ antagonist that will have similar biological and pharmacological properties to other TGF- ⁇ antagonists, such as other blocking monoclonal antibodies specific for a human TGF- ⁇ , soluble TGF- ⁇ receptors that bind and inactivate active TGF- ⁇ , and protease inhibitors that inactivate a protease responsible for activating a precursor TGF- ⁇ into an active, mature TGF- ⁇ .
  • TGF- ⁇ Production of active TGF- ⁇ requires infection by live macrophage pathogens or other parasites, and represents an important parasite virulence mechanism.
  • exogenously-administered TGF- ⁇ was shown to have profound effects on the course of macrophage parasite infection.
  • Genetically resistant mice became susceptible to macrophage parasite infection following TGF- ⁇ treatment, and avirulent Leishmania produced disease in conjunction with TGF- ⁇ .
  • these data demonstrate a unique role for TGF- ⁇ in mediating resistance and susceptibility to a parasitic protozoan, and represent an important mechanism by which macrophage pathogens avoid destruction by host macrophages. The data further predict and enable the full scope of the claimed invention.
  • TGF- ⁇ active TGF- ⁇ is produced in vitro by macrophages infected with Leishmania.
  • Macrophages are both host cells for Leishmania and other macrophage parasites and important producers of the cytokine TGF- ⁇ .
  • I analyzed the production of TGF- ⁇ during in vitro infection of peritoneal macrophages from normal mice.
  • Thioglycolate-stimulated mouse peritoneal macrophages were plated in 24- well plates at 5 x 105 cells/well in RPMI1640 supplemented with antibiotics, glutamine, and 10% heat-inactivated fetal calf serum. After three days in culture, macrophages were infected with stationary-phase L.
  • brasiliensis promastigotes (2.5 x 106 parasites/well) for three hours. Extracellular parasites were removed by extensive washing with wash culture medium, followed by further incubation for up to 72 hours. Cell-free supernatants were collected at 24, 48, or 72 hours after infection. Replicate monolayers were washed with phosphate buffered saline (PBS), fixed in acetone- methanol, and stained with Giemsa. The percentage of infected macrophages, and the number of amastigotes per 100 macrophages were determined by microscopic examination as described in Reed et al., J. Exp. Med. 166:1734, 1987.
  • PBS phosphate buffered saline
  • TGF- ⁇ was assayed for presence and activity by taking supernatants from uninfected and Leishmania-infected macrophage cultures and assaying for TGF- ⁇ activity using CCL-64 mink lung epithelial cells as described in Collinsalis et al., Biochem. Biophys. Res. Commun. 148:1 3, 1987. Cells were plated at 105 cells/well into 96- well microtiter plates for one hour at 37° C in volume of 100 ⁇ l of DMEM
  • TGF- ⁇ standards ranging in concentration from 2 ng to 0.00049 ng
  • test supernatants were added at appropriate dilutions to a final volume of 200 ⁇ l/well.
  • the standards were diluted by 2x serial dilutions in DMEM containing 10% heat-inactivated fetal calf serum.
  • the cultures were incubated for 22 hours at 37° C and tritiated ( ⁇ H) thymidine was added during the final four hours at a concentration of 0.25 ⁇ Ci well.
  • TGF- ⁇ released in its latent or precursor form will not inhibit CCL-64 cell cultures (Twardzik et al, in Transforming Growth Factors-Chemistry, Biology, and Therapeutics, Ann. N.Y. Acad. Sci.593:216, 1990).
  • Hydrochloric acid (IN) was added to each culture supernatant to adjust the pH to 3.0-3.5 for 10 minutes at room temperature and immediately neutralized to pH 7.0-7.6 by adding IN NaOH.
  • the concentration of TGF- ⁇ in each sample was determined by comparison with a curve generated from the TGF- ⁇ standards. A sample regression curve was computed using a Microsoft GB STAT® program.
  • TGF- ⁇ The production of TGF- ⁇ in the supernatant of infected macrophages was determined at several time points after infection. Two interesting observations came from these experiments. The first was that biologically active TGF- ⁇ was produced by mouse peritoneal macrophages following in vitro infection with Leishmania ( Figure 4). The second was that the levels of TGF- ⁇ induced differed between two individual isolates of L. brasiliensis (BA-92 and BA-331).
  • Example 2 This example illustrates the effect of TGF- ⁇ to exacerbate in vitro infection by
  • L. brasiliensis In vitro infection of mouse macrophages by L. brasiliensis is characterized by static numbers of intracellular parasites. However, when macrophages were treated with recombinant TGF- ⁇ prior to infection, a progressive increase in numbers of intracellular amastigotes occurred ( Figure 5). Therefore, explanted macrophages were capable of limiting the intracellular replication of Leishmania, and the mechanism responsible for this control was inhibited by exogenous TGF- ⁇ . Regulation of intracellular parasite replication was resisted due to progressive reduction of amastigotes in macrophages treated with a neutralizing monoclonal antibody (mAb) specific for TGF- ⁇ . This observation suggests a role for Leishmania-mduced TGF- ⁇ in the persistence of intracellular macrophage parasites.
  • mAb neutralizing monoclonal antibody
  • This example illustrates the exacerbation of in vivo Leishmania infection by TGF- ⁇ .
  • in vitro observations suggested a differential ability of Leishmania isolates to induce active TGF- ⁇ production as well as a role for TGF- ⁇ in control of Leishmania infection.
  • This example illustrates in vivo experiments in which two L. brasiliensis isolates were used to infect mice with and without administering TGF- ⁇ .
  • mice (Jackson Laboratories, Bar Harbor, ME) were infected in the left hind footpad with 5 x 10 6 stationary-phase promastigotes of Leishmania in 25 ⁇ l of saline.
  • the parasites were resuspended in saline containing 40 ⁇ g ml rTGF- ⁇ (1 ⁇ g/mouse).
  • Recombinant TGF- ⁇ treatments were at doses of 1 ⁇ g/mouse injected into each infected footpad.
  • Control mice were injected with the same volume of saline. Lesion progression was evaluated during the course of infection by measuring footpad thickness with a dial gauge caliper (C.
  • BA-331 was a relatively weak inducer of TGF- ⁇ in vitro and produced no measurable lesion, while BA-92 induced measurable but self-limiting lesions as well as significantly higher in vitro levels of TGF- ⁇ .
  • TGF- ⁇ production in Leishmania infectivity and/or intracellular replication in vivo.
  • Exogenous TGF- ⁇ was administered to groups of mice infected with either of these two L. brasiliensis isolates. Recombinant TGF- ⁇ treatment led to a dramatic increase in mean lesion size in all mice ( Figures 6 and 7). Histologically, the lesions were characterized by large numbers of heavily parasitized macrophages.
  • Example 4 This example illustrates activation of latent L. brasiliensis infections by administration of exogenous TGF- ⁇ .
  • L. brasiliensis infection in intact mice is characterized by transient or no lesion development as illustrated in Figure 6.
  • BALB/c mice were treated with recombinant TGF- ⁇ for a three week period, beginning 15 weeks after initial infection. When recombinant TGF- ⁇ was administered there were no visible lesions present characteristic of disease. Animals were treated with recombinant TGF- ⁇ (l ⁇ g/mice/dose) or saline, three times a week during a three week period.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un procédé qui permet de traiter un individu infecté par le pathogène d'un macrophage, consiste à administrer une quantité efficace d'un antagoniste du TGF-β (facteur de croissance transformant β). Ces pathogènes des macrophages incluent tout micro-organisme pathogène qui se réplique dans les cellules hôtes macrophages considérées comme leurs cellules hôtes exclusives ou primaires. Les antagonistes du TGF-β incluent des anticorps bloquants spécifiques d'un TGF-β humain, des récepteurs solubles du TGF-β, des inhibiteurs de protéases qui inactivent celle chargée d'activer un TGF-β précurseur pour le transformer en TGF-β actif et mature, ainsi que leurs combinaisons.
PCT/US1993/002017 1992-03-06 1993-03-04 Procede permettant de traiter les infections dues aux pathogenes des macrophages WO1993017708A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002130995A CA2130995C (fr) 1992-03-06 1993-03-04 Methode pour le traitement d'infections par des agents pathogenes macrophages

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84744192A 1992-03-06 1992-03-06
US07/847,441 1992-03-06

Publications (1)

Publication Number Publication Date
WO1993017708A1 true WO1993017708A1 (fr) 1993-09-16

Family

ID=25300634

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/002017 WO1993017708A1 (fr) 1992-03-06 1993-03-04 Procede permettant de traiter les infections dues aux pathogenes des macrophages

Country Status (3)

Country Link
CA (1) CA2130995C (fr)
MX (1) MX9301135A (fr)
WO (1) WO1993017708A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669833A1 (fr) * 1992-10-29 1995-09-06 Celtrix Pharmaceuticals, Inc. UTILISATIONS D'UN FRAGMENT DE RECEPTEUR DU TGF-$g(b) COMME AGENT THERAPEUTIQUE
US7151169B2 (en) 1999-04-30 2006-12-19 Cambridge Antibody Technology Limited Specific binding members for TGFβ1
EP1741780A2 (fr) * 1995-06-02 2007-01-10 Gilead Sciences, Inc. Ligands oligonucléotidiques ayant une affinité élevée pour les facteurs de croissance
US7368111B2 (en) 1995-10-06 2008-05-06 Cambridge Antibody Technology Limited Human antibodies specific for TGFβ2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF EXPERIMENTAL MEDICINE, Volume 174, Number 3, issued 01 September 1991, SILVA et al., "Regulation of Trypanisoma Cruzi Infections In Vitro and In Vivo by Transforming Growth Factor Beta", pages 539-545. *
SCIENCE, Volume 257, Number 5069, issued 24 July 1992, BARRAL-NETTO et al., "Transforming Growth Factor Beta, in Leishmanial Infection: A Parasite Escape Mechanism", pages 545-548. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669833A1 (fr) * 1992-10-29 1995-09-06 Celtrix Pharmaceuticals, Inc. UTILISATIONS D'UN FRAGMENT DE RECEPTEUR DU TGF-$g(b) COMME AGENT THERAPEUTIQUE
EP0669833A4 (fr) * 1992-10-29 1996-07-31 Celtrix Pharma UTILISATIONS D'UN FRAGMENT DE RECEPTEUR DU TGF--g(b) COMME AGENT THERAPEUTIQUE.
US5693607A (en) * 1992-10-29 1997-12-02 Segarini; Patricia R. Uses of TGF-β receptor fragment as a therapeutic agent
EP1741780A2 (fr) * 1995-06-02 2007-01-10 Gilead Sciences, Inc. Ligands oligonucléotidiques ayant une affinité élevée pour les facteurs de croissance
EP1741780A3 (fr) * 1995-06-02 2007-03-28 Gilead Sciences, Inc. Ligands oligonucléotidiques ayant une affinité élevée pour les facteurs de croissance
US7368111B2 (en) 1995-10-06 2008-05-06 Cambridge Antibody Technology Limited Human antibodies specific for TGFβ2
US7151169B2 (en) 1999-04-30 2006-12-19 Cambridge Antibody Technology Limited Specific binding members for TGFβ1

Also Published As

Publication number Publication date
CA2130995A1 (fr) 1993-09-16
CA2130995C (fr) 1998-12-29
MX9301135A (es) 1993-09-01

Similar Documents

Publication Publication Date Title
Huffnagle et al. The role of monocyte chemotactic protein-1 (MCP-1) in the recruitment of monocytes and CD4+ T cells during a pulmonary Cryptococcus neoformans infection.
Kwiatkowski et al. Tumour necrosis factor production in Falciparum malaria and its association with schizont rupture.
Eckmann et al. Entamoeba histolytica trophozoites induce an inflammatory cytokine response by cultured human cells through the paracrine action of cytolytically released interleukin-1 alpha.
Rolfe et al. Pulmonary fibroblast expression of interleukin-8: a model for alveolar macrophage-derived cytokine networking
Scharton et al. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice.
Standiford et al. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung.
Vilcek et al. Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors.
Franitza et al. TGF‐β1 enhances SDF‐1α‐induced chemotaxis and homing of naive T cells by up‐regulating CXCR4 expression and downstream cytoskeletal effector molecules
Rolfe et al. Expression and regulation of human pulmonary fibroblast-derived monocyte chemotactic peptide-1
Kadi et al. Differential effects of chemokines on oligodendrocyte precursor proliferation and myelin formation in vitro
US5730976A (en) Method for treating macrophage pathogen infections by TGF-B antagonists
Darville et al. Mouse strain-dependent chemokine regulation of the genital tract T helper cell type 1 immune response
Tracey et al. Cachectin/tumor necrosis factor and other cytokines in infectious disease
Jensen et al. Lactic acidosis increases tumor necrosis factor secretion and transcription in vitro
EA009125B1 (ru) Применение ингибиторов il-18 для лечения и/или предупреждения заболеваний, характерных для синдрома системной воспалительной реакции
EP0131789A2 (fr) Composition contenant le facteur de nécrose de tumeurs purifié en association avec l'interféron humain et son application
Foex et al. The cytokine response to critical illness.
US5208018A (en) Treatment of cachexia with interleukin 2
Kudo et al. Inhibition of IL-8-induced W3/25+(CD4+) T lymphocyte recruitment into subcutaneous tissues of rats by selective depletion of in vivo neutrophils with a monoclonal antibody.
JP2023064023A (ja) 乾癬を治療／抑制するための医薬の製造における試薬の使用
Millar et al. Production of tumor necrosis factor-a by blood and lung mononuclear phagocytes from patients with human immunodeficiency virus-related lung disease
UA77950C2 (en) Use of mutants of cc chemokines for treatment of multiple sclerosis
WO1993017708A1 (fr) Procede permettant de traiter les infections dues aux pathogenes des macrophages
Onogawa Local delivery of soluble interleukin-6 receptors to improve the outcome of alpha-toxin producing Staphylococcus aureus infection in mice
Umeda et al. Inhibition of natural killer activity by calcitonin gene-related peptide

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): BB BR CA JP KP KR LK MG MW SD

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2130995

Country of ref document: CA

122 Ep: pct application non-entry in european phase