WO2002076500A1 - Vaccine for the treatment of tubercolosis and other intracellular infections diseases - Google Patents
Vaccine for the treatment of tubercolosis and other intracellular infections diseases Download PDFInfo
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- WO2002076500A1 WO2002076500A1 PCT/IN2001/000047 IN0100047W WO02076500A1 WO 2002076500 A1 WO2002076500 A1 WO 2002076500A1 IN 0100047 W IN0100047 W IN 0100047W WO 02076500 A1 WO02076500 A1 WO 02076500A1
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- vaccine
- tuberculosis
- cells
- macrophages
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
- A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
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- 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
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- 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 process for the preparation of a vaccine against tuberculosis and other intracellular pathogens.
- This vaccine is targeted against intracellular pathogens, more particularly the pathogen Mycobacterium tuberculosis and Salmonella in this case.
- the utility of the present invention is to develop a vaccine against the intracellular pathogens, which are causative agent of tuberculosis, brucellosis, leishmaniasis, anceriosis, leprosy, malaria, typhoid, trypanosomiasis and streptococcus and HTV- infection.
- the pathogen Mycobacterium tuberculosis (M. tuberculosis) the subject matter of this invention is a causative agent of tuberculosis.
- M. tuberculosis was allowed to grow in the allogeneic and syngeneic macrophages and macrophage cell lines.
- the macrophages- tuberculosis complex was then irradiated to kill the macrcphag ⁇ s as well as the mycobacterium.
- Tuberculosis is a chronic infectious disease that continues to kill some 3 million people a year. About 8 million new cases arise every year and the number continues to increase. About one-third of the world population is infected with M. tuberculosis. The emergence of AIDS has reactivated tuberculosis in millions of dormant individuals, causing a sharp rise in the number of cases and deaths. M. tuberculosis is therefore responsible for the highest morbidity rate among all infectious agents. The only available vaccine BCG is both unpredictable and highly variable. Doubtful efficacy of BCG vaccination has put the scientific community to urgently develop effective means of vaccination against the M. tuberculosis (Bloom, B.R. et. al., Annu. Rev. Immunol. 10:1992:453).
- BCG has been extensively used as a vaccine world over.
- Several hundred million children and new born have been the recipient of BCG vaccine.
- tuberculosis has still become the fastest spreading disease not only in developing countries but also in the industrialized world.
- the protective efficacy of the current BCG vaccine is both unpredictable and highly variable and it remains the most controversial of all currently used vaccines. Its doubtful efficacy in controlled trials have increased the concern about its use as a vaccine (Bloom and Fine, Tuberculosis In B. Bloom (ed.), 1994:531, Bloom, B.R. et. al., Annu. Rev. Immunol. 10:1992:453).
- BCG's performance is based on a hypothesis that BCG is effective against primary infection in children and endogenous reactivation of long-standing infections but not against exogenous infection (ten Dam, H.G. Adv. Tuberc. Res. 21:1984:79; ten Dam, H.G. and A. Pio. Tubercle 63:1988:226).
- Epidemiological data suggest that BCG vaccination imparts greater or more consistent protection against systemic disease, in particular miliary tuberculosis and tuberculosis meningitis in children, than against pulmonary disease (Rodrigues, et.al., it J epidemiol. 22:1993:1154). Lurie's studies indicated that the number of CFU of M. tuberculosis isolated from lungs of BCG-immunized versus unimmunized rabbits showed no difference in the number of organisms reaching and capable of being cultured from lung and other tissues.
- MHC Major Histocompatibility Complex
- the effective resistance to M. tuberculosis infection will require participation both of specific CD8 CTL to lyse macrophages or parenchymal cells unable to restrict their infection and of specific CD4 + T cells able to produce IL-2, TFN- ⁇ , TNF- ⁇ , and other lymphokines involved in macrophage activation.
- specific CD8 CTL to lyse macrophages or parenchymal cells unable to restrict their infection and of specific CD4 + T cells able to produce IL-2, TFN- ⁇ , TNF- ⁇ , and other lymphokines involved in macrophage activation.
- the applicants have taken advantage of the fact that the vaccine will be used as an irradiated preparation and has no fear of inoculating in AIDS patients and immunocompromised children.
- BCG is given as an attenuated preparation and is not recommended in these subjects because it causes disseminated BCG-osis.
- Another insight is provided by the intracellular location of the mycobacterium.
- BCG remains essentially entirely within the phagolysosome of macrophages, whereas virulent M. tuberculosis can escape from the phagolysosome and enter the cytoplasm (McDonough, K.A., Y. Kress, and B.R. Bloom. 1993. Infect. Immun. 61:2763-2773).
- the antigens in the endosomal compartment of antigen-presenting cells are presented in conjunction with MHC class II determinants to CD4 + T helper cells, whereas cytoplasmic antigens are presented in association with the Major Histocompatibility Complex (MHC) class 1 determinants to CD8 + Cytotoxic T cells.
- MHC Major Histocompatibility Complex
- tuberculosis is more dependent for its elimination on MHC class I-restricted CTL.
- BCG is not effective in eliciting MHC class I- restricted CTL (Stover, et.al., Nature 351:1991:456).
- the present vaccine contains the irradiated preparation of M. tuberculosis grown in macrophages. M. tuberculosis infected macrophages are reported to effectively generate CTL (Stover, et.al., Nature 351:1991:456).
- irradiated cells undergo apoptosis and can be phagocytosed by the dendritic cells (Albert, M ., et.al., Nature 392:1998:86) and it leads to the generation of antigen specific CD4 + and CD8 + T cell response.
- This apoptosis-dependent pathway may not only have potential in vaccination studies but also for therapeutically manipulating immune system to induce T-helper and CTL response in vivo to a variety of antigens including tumor, and possibly to modulate favourable immune response.
- tuberculosis grown in the natural environment of the macrophages that secrete the unique antigens responsible for the induction of protective immune response and can generate CD4 + T-helper cells and CD8 + CTL.
- the effective resistance to M. tuberculosis infection will require participation of both specific CD8 CTL to lyse macrophages or parenchymal cells unable to restrict their infection and of specific CD4 + T cells able to produce IL-2, IFN- ⁇ , TNF- ⁇ , and other lymphokines involved in macrophage activation.
- Allo-macrophages in the system generate allo-reaction as a result large amount of cytokines like IL-2, IL-12, IFN- ⁇ , etc., are produced which promote the Thl response and cell mediated immune response. It is known that Thl -type of response provides protection against tuberculosis. Hence the main utility of the process was to produce a potent and specific vaccine against M. tuberculosis.
- the main object of the present invention thus is to develop a vaccine against tuberculosis and other intracellular diseases like leprosy, leishmaniasis, typhoid, trypanosomiasis, malaria, brucellosis, anceriosis, AIDS, streptococcal infection and cancer.
- Another object of the present invention is to culture the pathogen inside the syngeneic and allogeneic macrophages and allow them to secrete antigens within the cells. Yet another object is to develop a method whereby the pathogen are killed by the already known drugs and further will be gamma irradiated before use; the gamma irradiated cells are known to undergo apoptosis and are engulfed by the dendritic cells. Dendritic cells are potent activator of Thl cells and CD8+ cytotoxic cells.
- Still another objective of the present invention is to develop a vaccine based on entrapment of pathogen in the allogeneic cells that would elicit immune response irrespective of the genetic background i.e. it will work as a promiscuous vaccine, and hence it will work irrespective of the genetic diversity in the human subjects.
- the present invention relates to a process for the preparation of a vaccine against tuberculosis and other intracellular pathogens.
- This vaccine is targeted against intracellular pathogens, more particularly the pathogen Mycobacterium tuberculosis and Salmonella in this case.
- the novelty in the present invention is that the protective antigens secreted by the mycobacterium inside the macrophages can be used as a vaccine without isolating them from the macrophages.
- the vaccine was used after irradiation and the irradiated cells are known to undergo apoptosis.
- the cells undergoing apoptosis were engulfed by the dendritic cells.
- Dendritic cells activated na ⁇ ve T cell to differentiate into Thl cells and cytotoxic cells.
- the cells known to be cardinal in imparting protective immunity against intracellular infections and cancer.
- the allogeneic cells used in the construction of vaccine would elicit immune response irrespective of the genetic background i.e. it will work as a promiscuous vaccine. Hence it can used in human subjects irrespective of the genetic diversity.
- the aim of the present invention is to develop a vaccine against tuberculosis, salmonella and other intracellular infections.
- M. tuberculosis and Salmonella typhimurium was cultivated in allogeneic (AMTV) and syngeneic (SMTV) macrophages and was killed by ⁇ -irradiation and was used as a vaccine.
- the AMTV in vivo will preferably be engulfed by dendritic cells ( ⁇ -irradiation causes cells to undergo apoptosis and dendritic cells engulf apoptotic cells) and will then activate the m y cobacterium reactive na ⁇ ve T cells.
- Allogeneic macrophages being used for immunization worked as an adjuvant and elicited allogeneic reactive T cells that produced huge amount of IL-2, IFN- ⁇ , IL-12. These cytokines are vital for the growth and differentiation of na ⁇ ve T cells to CD4 + and CD8 + effector T cells.
- Dendritic cells are the preferred Antigen Presenting Cells (APC) for Thl and cytotoxic T cells (CTL).
- Thl and CD8 + CTL are principal cells in generating effective and protective immunity against M. tuberculosis. The tuberculosis resistant and susceptible strains of mice were inoculated with the vaccine.
- FIG 1 represents schematically the process of how Allo-Macrophage Tuberculosis (AMTV) works.
- AMTV Allo-Macrophage Tuberculosis
- Dendritic cells are the preferred Antigen Presenting Cells (APC) for Thl and cytotoxic T cells (CTL). They cause stimulation of na ⁇ ve T cells to differentiate into antigen reactive Thl cells and cytotoxic T lymphocytes. Moreover, dendritic cells trap foreign antigen (in this case mycobacterium antigen) and act as a reservoir, slowly releasing the antigen in the system for the activation of T cells and for the maintenance of memory cells.
- APC Antigen Presenting Cells
- CTL cytotoxic T cells
- IL-2, IFN- ⁇ and IL-12 secreted by alloreactive T cells will engineer the clonal expansion of mycobacterium reactive Thl and cytotoxic T cells.
- Thl and CD8 + CTL are cardinal in generating effective and protective immunity against M. tuberculosis.
- the tuberculosis resistant and susceptible strains of mice were inoculated with the vaccine.
- the rationale behind the process of how Allo-Macrophage Tuberculosis (AMTV) works has been demonstrated by cultivating M. tuberculosis cultivating in MHC-mismatched (allogeneic) and syngeneic macrophages. This preparation was ⁇ -irradiated ana used as vaccine.
- the AMTV in vivo will preferably be engulfed by dendritic cells (as it is known that ⁇ -irradiation causes cells to undergo apoptosis and dendritic cells engulf apoptotic cells) and will then activate the mycobacterium reactive na ⁇ ve T cells.
- dendritic cells as it is known that ⁇ -irradiation causes cells to undergo apoptosis and dendritic cells engulf apoptotic cells
- macrophages loaded with mycobacterium cannot activate na ⁇ ve T cells directly. Allo- macrophages being used for immunization will elicit allo-reactive T cells that produce huge amount of IL-2, IFN- ⁇ , IL-12.
- cytokines are vital for the growth and differentiation of na ⁇ ve T cells to CD4 + and CD8 + effector T cells.
- Dendritic cells are the preferred Antigen Presenting Cells (APC) for Thl and cytotoxic T cells (CTL). They cause stimulation of na ⁇ ve T cells to differentiate into antigen reactive Thl cells and cytotoxic T lymphocytes. Moreover, dendritic cells trap foreign antigen (in this case mycobacterium antigen) and act as a reservoir, slowly releasing the antigen in the system for the activation of T cells and for the maintenance of memory cells. IL-2, IFN- ⁇ and IL-12 secreted by alloreactive T cells will engineer the clonal expansion of mycobacterium reactive Thl and cytotoxic T cells. Thl and CTL are cardinal in generating effective and protective immunity against M.
- APC Antigen Presenting Cells
- CTL cytotoxic T cells
- tuberculosis (Albert, M ., et. al., Nature 392:1998:86; Wang, B. et. al., Proc. Natl. Acad. Sci. USA 90:1993:4156).
- the tuberculosis resistant and susceptible strains of mice were vaccinated with AMTV and SMTV.
- the efficacy of the vaccine was monitored by infecting the mice with live M. tuberculosis and monitoring their mortality and viable counts of the bacteria in the lungs, spleen and liver.
- the vaccinated (4-12 weeks) mice were challenged with 10 5 -10 6 viable M. tuberculosis H37Rv.
- the lungs, spleens and livers of the infected mice were removed after an additional period of 3-4 weeks and serial dilutions of organ homogenate was plated on agar plates to establish the number of viable tubercle bacilli residing in these organs.
- the vaccinated animals were also monitored for the generation of Thl and Th2 cells by measuring IFN- ⁇ and IL-4.
- the vaccine was inoculated in the mouse footpad and the induction of delayed type hypersensitivity reaction was monitored by measuring the thickness of the footpa ⁇ .
- tuberculosis vaccine comprise M. tuberculosis cultivated in MHC- matched and mismatched-macrophages.
- the preparations are irradiated and used as distinct vaccines.
- the vaccine fulfill all the requirements necessary for generating favourable immune response against M. tuberculosis, it has been anticipated that such preparations should work effectively against tuberculosis.
- the vaccine AMTV works in a promiscuous manner, since it does not follow the rules of MHC-restriction and is based on allo-stimulation and engulfment of foreign-apoptotic cells by dendritic cells. Whereas the vaccine SMTV works in MHC-restriction fashion.
- the infected cells were grown in sufficient quantity and stored after isoniazid treatment and ⁇ -irradiation. The preparation was thoroughly checked for viable mycobacterium by viability counting. None of the bacteria were viable in the vaccine.
- the mice were vaccinated intraperitoneally or subcutaneously with vaccine and were challenged with viable M. tuberculosis H37Rv. The viability of the tubercle bacilli residing in lungs, spleens and livers was monitored. The animals were immunized with the vaccine and the uptake of the apoptotic cells by dendritic cells was documented by immuno fluorescence.
- the animals were vaccinated with SMTV and AMTV and the proliferation and differentiation of na ⁇ ve CD4 + Th cells into effector Thl and Th2 subtype was studied.
- M. tuberculosis entrapped in syngeneic macrophages was also used.
- the ability of SMTV and AMTV to generate CD8 + cytotoxic T cells was monitored by the standard Cr 51 - release assay.
- mice were immunized with ovalbumin entrapped in mitomycin C treated allogeneic and syngeneic APC.
- IA k CBA mice
- Antigen-specific-T cell proliferation and predominant Thl response were noticed, as evidenced by mainly the production of IL- 2 and IFN- ⁇ and IgG2a-isotype.
- High production of IL-2 in allo-response was noticed which indicates that the immunization with the antigen entrapped in allo-APC treated with mitomycin C undergoes apoptosis.
- the apoptotic cells are engulfed by dendritic cells that then evokes mycobacterium specific and the allo-reactive T cells response.
- the allo-T cells are >10% of the total T cell population and are known to induce high secretion of IL-2.
- IL- 2 produced by allo-T cells then engineers the proliferation of antigen specific T cell.
- M. tuberculosis was cultivated in the macrophage cell line viz. J77.4 or allogeneic and syngeneic macrophages.
- the infected macrophages were isoniazid treated and irradiated and then used for vaccination studies in protection against M. tuberculosis.
- Allo-Macrophage Tuberculosis (AMTV) works has been demonstrated by cultivating M. tuberculosis cultivating in MHC-mismatched (allogeneic) and syngeneic macrophages. This preparation was ⁇ -irradiated and used as vaccine.
- the AMTV in vivo will preferably be engulfed by dendritic cells (as it is known that ⁇ -irradiation causes cells to undergo apoptosis and dendritic cells engulf apoptotic cells) and will then activate the mycobacterium reactive na ⁇ ve T cells.
- dendritic cells as it is known that ⁇ -irradiation causes cells to undergo apoptosis and dendritic cells engulf apoptotic cells
- macrophages loaded with mycobacterium cannot activate na ⁇ ve T cells directly. Allo- macrophages being used for immunization will elicit allo-reactive T cells that produce huge amount of IL-2, IFN- ⁇ , IL-12.
- cytokines are vital for the growth and differentiation of na ⁇ ve T cells to CD4 + and CD8 + effector T cells.
- Dendritic cells are the preferred Antigen Presenting Cells (APC) for Thl and cytotoxic T cells (CTL). They cause stimulation of na ⁇ ve T cells to differentiate into antigen reactive Thl cells and cytotoxic T lymphocytes. Moreover, dendritic cells trap foreign antigen (in this case mycobacterium antigen) and act as a reservoir, slowly releasing the antigen in the system for the activation of T cells and for the maintenance of memory cells. IL-2, IFN- ⁇ and IL-12 secreted by alloreactive T cells will engineer the clonal expansion of mycobacterium reactive Thl and cytotoxic T cells. Thl and CTL are cardinal in generating effective and protective immunity against M.
- APC Antigen Presenting Cells
- CTL cytotoxic T cells
- tuberculosis (Albert, MX., et. al., Nature 392:1998:86; Wang, B. et. al., Proc. Natl. Acad. Sci. USA 90:1993:4156).
- the tuberculosis resistant and susceptible strains of mice were vaccinated with AMTV and SMTV.
- the efficacy of the vaccine was monitored by infecting the mice with live M. tuberculosis and monitoring their mortality and viable counts of the bacteria in the lungs, spleen and liver.
- the vaccinated (4-12 weeks) mice were challenged with 10 5 -10 6 viable M. tuberculosis H37Rv.
- the lungs, spleens and livers of the infected mice were removed after an additional period of 3-4 weeks and serial dilutions of organ homogenate was plated on agar plates to establish the number of viable tubercle bacilli residing in these organs.
- the vaccinated animals were also monitored for the generation of Thl and Th2 cells by measuring IFN- ⁇ and IL-4.
- the vaccine was inoculated in the mouse footpad and the induction of delayed type hypersensitivity reaction was monitored by measuring the thickness of the footpad.
- the present invention provides a vaccine against tuberculosis and other intracellular pathogens selected from the group consisting of Mycobacterium leprae, leishmania, salmonella, trypanosoma, plasmodium, brucella, leisteria, HIV, streptococc s and cancer.
- the invention also provides a mthod for the development of the said vaccine, comprising the steps of: i) culturing pathogens selected from the group comprising Mycobacterium tuberculosis, Mycobacterium leprae, leishmania, salmonella, trypanosoma, plasmodium, brucella, leisteria, HIV, streptococcas ii) culturing syngeneic (same strain), allogeneic (different strain) and xenogeneic (different species like sheep and goat) macrophages and macrophage cell lines selected from the group consisting of J774A, P388D1, RAW, BMC-2, THP-1, etc., iii) infecting macrophages and cell lines with a pathogen, iv) treating the infected cells with known drugs followed by gamma irradiation to obtain the vaccine, v) immunizing disease resistant and susceptible strains of animals with the vaccine obtained above.
- pathogens selected from
- the invention further provides a process for the preparation of a vaccine against tuberculosis, wherein the said process comprising the steps of: i) culturing of Mycobacterium tuberculosis H37Rv, ii) culturing of syngeneic and allogeneic macrophages and macrophage cell lines selected from the group consisting of J774A, P388D1, RAW, BMC-2, THP-1, etc., iii) infecting macrophages and cell lines (J774, P388D1, RAW, BMC-2, THP-1) with M.
- tuberculosis iv) treating the infected cells with isoniazid and gamma irradiation to obtain the vaccine, v) immunizing tuberculosis resistant and susceptible strains of mice with allogeneic macrophage tuberculosis vaccine (AMTV) and syngeneic macrophage tuberculosis vaccine (SMTV) obtained above, vi) infecting the mice with live M.
- AMTV allogeneic macrophage tuberculosis vaccine
- SMTV syngeneic macrophage tuberculosis vaccine
- tuberculosis and monitoring their mortality and viable counts of bacteria in lungs, spleen and liver
- the invention also provides a process for the preparation of a vaccine against salmonella, wherein the said process comprising the steps of: i) culturing of. Salmonella typhimurium, ii) culturing of syngeneic and allogeneic macrophages and macrophage cell lines selected from the group consisting of J774A, P388D1, RAW, BMC-2, THP-1, etc., iii) infecting macrophages and cell lines (J774, P388D1, RAW, BMC-2, THP-1) with
- S. typhimurium iv) treating the infected cells with mitomycin C and gamma irradiation to obtain vaccine, v) immunizing tuberculosis resistant and susceptible strains of mice with vaccine obtained above, vi) infecting the mice with live S. typhimurium and monitoring their mortality and viable counts of bacteria in lungs, spleen and liver, vii) monitoring the vaccinated animals for proliferation and generation of CD4 + Thl and Th2 cells and CD8 + cytotoxic T cells indicating the generation of cell mediated immunity, and viii) inoculating the vaccine in the mouse footpad and examining the delayed type hypersensitivity reaction by measuring the swelling in the footpad for protective immunity.
- the invention provides a vaccine by entrapment of M. tuberculosis, Salmonella and other intracellular pathogens in the allogeneic and syngeneic macrophages and using it for the protection against the infectious agent.
- Examplel A process for the preparation of a vaccine against tuberculosis End other intracellular pathogens.
- the intracellular pathogens viz. Mycobacterium tuberculosis, Mycobacterium leprae, leishmania, salmonella, trypanosoma, p.' modiu , brucella, leisteria, HIV, streptococcas were cultured in the macrophages of syngeneic and allogeneic mice, macrophages cell lines J774, P338D1, RAW, BMC-2, THP-1 (ATCC, Rockville). The infected cells were treated with isoniazid (20 ⁇ g/ml) for 48h at 37°C/5% CO 2 and irradiated at 0.05 kGy. i.
- Example2 A process for the preparation of a vaccine against tuberculosis.
- Mycobacterium tuberculosis H37Rv obtained from Central JALMA Institute for Leprosy, Agra, was cultured in the macrophages of syngeneic and allogeneic mice, macrophages cell lines J774, P338D1, RAW, BMC-2, THP-1 (ATCC, Rockville). The infected cells were treated with isoniazid (20 ⁇ g/ml) for 48h at 37 °C/5% CO 2 and irradiated at 0.05 kGy. i.
- Example3 A process for the preparation of a vaccine against salmonella.
- Salmonella typhimurium (MTCC98) was cultured in the macrophages obtained from syngeneic and allogeneic mice and macrophages cell lines J774, BMC-2 and RAW.
- the infected cells were treated with mitomycin C (50 ⁇ g/ml) and gamma irradiated (0.05 kGy).
- mitomycin C 50 ⁇ g/ml
- gamma irradiated 0.05 kGy
- the resultant infected cells were treated with the drug and irradiated and were used as a vaccine and their efficacy was monitored by challenging the vaccinated mice with 10 5 - 10 6 viable bacteria. The animals were observed for mortality for 21 days.
- the lungs, spleens and livers of the infected mice were removed and serial dilutions of organ homogenates was plated on agar plates to establish the number of viable salmonella bacilli residing in these organs.
- the unvaccinated animals were challenged with live bacteria and were monitored for their mortality and viable counts in lungs, spleens and livers.
- M. tuberculosis (i) About one-third of the world population is infected with M. tuberculosis. About 5-10% only develop active tuberculosis and the 90% of the individual develop effective immunity against the M. tuberculosis. M. tuberculosis present in the host macrophages secretes unique antigens, which are the effective inducers of long lasting protective immunity. In contrast, M. tuberculosis when cultured in vitro in artificial medium, secrete antigens that do not induce optimum level of protection and the immunity generated is short lived. The outstanding feature in the process is that the protective antigens of mycobacterium secreted inside the macrophages were utilized without isolating them from the macrophages.
- the advantage of the invention is that the ⁇ -irradiated mycobacterium infected macrophages were engulfed by dendritic cells.
- the ⁇ -irradiated cells are known to undergo apoptosis.
- Apoptotic cells taken up by the dendritic cells induce the activation of CD4 Thl and CD8 + cytotoxic T cells.
- Cytotoxic T cells are responsible for the killing of macrophages infected with mycobacterium. Lysis of target is essential in the case of diseases like tuberculosis, typhoid, leprosy, leishmaniasis, AIDS, etc., where the pathogen reside and multiplies within the macrophages.
- Dendritic cells express high level of B7-1 and secrete IL-12 and are only potent APC that can activate na ⁇ ve T cells. Moreover, dendritic cells can differentiate na ⁇ ve T cells to Thl and CD8 + cytotoxic T cells. Thl and cytotoxic T cells are vital for induction of protective immunity against tuberculosis (Wakeham, et. al., J. Immunol., 160:1998:6101).
- dendrites on dendritic cells trap the foreign antigens and work as a reservoir. This antigen is slowly released from the dendrites, and is responsible for the maintenance of memory cells.
- the AMTV vaccine works in MHC-unrestricted manner, because it is based on allo- stimulation and engulfment of apoptotic cells by dendritic cells. It will work for all human, irrespective of the genetic diversity.
Abstract
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BR0107058-4A BR0107058A (en) | 2001-03-23 | 2001-03-23 | Process for preparing a vaccine for the treatment of tuberculosis and other intracellular diseases and infections and the vaccine produced by such a process |
CNB01802209XA CN100496605C (en) | 2001-03-23 | 2001-03-23 | Vaccine for treatment of tubercolosis and other intracellular infections diseases and preparing process thereof |
PCT/IN2001/000047 WO2002076500A1 (en) | 2001-03-23 | 2001-03-23 | Vaccine for the treatment of tubercolosis and other intracellular infections diseases |
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CN108743931B (en) | 2018-05-02 | 2022-08-16 | 成都威斯克生物医药有限公司 | Vaccine against tuberculosis and its preparation method and use |
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US4064007A (en) * | 1975-03-03 | 1977-12-20 | Institut National De La Sante Et De La Recherche Medicale | Process for obtaining an active product from mammalian macrophages |
EP0223218A2 (en) * | 1985-11-22 | 1987-05-27 | Christiane Prof. Dr. Stang-Voss | Conditioned macrophages and process for their preparation |
-
2001
- 2001-03-23 WO PCT/IN2001/000047 patent/WO2002076500A1/en active Application Filing
- 2001-03-23 BR BR0107058-4A patent/BR0107058A/en not_active Application Discontinuation
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US4064007A (en) * | 1975-03-03 | 1977-12-20 | Institut National De La Sante Et De La Recherche Medicale | Process for obtaining an active product from mammalian macrophages |
EP0223218A2 (en) * | 1985-11-22 | 1987-05-27 | Christiane Prof. Dr. Stang-Voss | Conditioned macrophages and process for their preparation |
Non-Patent Citations (2)
Title |
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DAS GOBARDHAN ET AL: "Leishmania donovani infection of a susceptible host results in apoptosis of Th1-like cells: Rescue of anti-leishmanial CMI by providing Th1-specific bystander costimulation.", MICROBIOLOGY AND IMMUNOLOGY, vol. 42, no. 11, 1998, pages 795 - 801, XP001011602, ISSN: 0385-5600 * |
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