WO1996001120A1 - Produits thymiques et applications - Google Patents

Produits thymiques et applications Download PDF

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Publication number
WO1996001120A1
WO1996001120A1 PCT/GR1994/000016 GR9400016W WO9601120A1 WO 1996001120 A1 WO1996001120 A1 WO 1996001120A1 GR 9400016 W GR9400016 W GR 9400016W WO 9601120 A1 WO9601120 A1 WO 9601120A1
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WO
WIPO (PCT)
Prior art keywords
thymus
cells
hla
mhc
immune
Prior art date
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PCT/GR1994/000016
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English (en)
Inventor
Panagiotis N. Gerolymatos
Original Assignee
P.N. Gerolymatos S.A.
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 P.N. Gerolymatos S.A. filed Critical P.N. Gerolymatos S.A.
Priority to PCT/GR1994/000016 priority Critical patent/WO1996001120A1/fr
Priority to AU72360/94A priority patent/AU7236094A/en
Publication of WO1996001120A1 publication Critical patent/WO1996001120A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/26—Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0271—Chimeric animals, e.g. comprising exogenous cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance

Definitions

  • New-born human embryonic crude thymus is obtained from fresh cadavers or stili births and is used either as a crude preparation or the thymus is processed and the cells are separated and further processed.
  • HLA haplotypes of the new-born are identified and the material is grouped according to the HLA specificity (A, C, B, DR, DQA, DQB and DP).
  • the crude thymus cells are separated by activated sorting and are placed in sealed in gas/02 flame and cooled slowly till -70 degrees centigrade. After 2-6 hours the material is transferred rapidly to a liquid N2 freezer, recorded and preserved as long as necessary. Cell lines from these cells are established and propagated in vitro.
  • the thymus cell bank maintains for each specific HLA histocompatibility group preparations for each type of thymus cell..
  • Each HLA specific EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is either crude thymus extract or a mixture of cell lines of thymocytes (at different stages of development and maturity) added to an equal number of nursing cells (epithelial, dendritic or other thymus cells).
  • the established thymus cell lines are grafted with MHC I and MHC II genes in order to produce cell lines that are marked with one or more antigenic HLA specificity.
  • HLA specificity also constitutes an EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • the MHC I and MHC II genes are grafted using a virus based vector and a constructed replication defective retrovirus that contains complementary DNA encoding of one or more of human MHC I and MHC II antigens.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is used to transform the miniature swine and the Pan Troglodytes (or other animal species) to chimeras of the human HLA specific histocompatible individual(s).
  • the genetically engineered to one or more MHC I and MHC II genes EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is used in an equivocal manner to transform strains of homozygotic donor animals to human HLA chimeras.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is implanted in the thymus at birth or preferably one to three weeks (pending to the animal species) prior to the estimated delivery date by intraplacental surgery.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is implanted in the bone marrow or in the spleen or is injected intravenously or in the thymus artery.
  • the cell types that are implanted or injected belong to one or more of the established thymus cell lines and to one or more HLA specificities.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is also used in the TUMOUR IMMUNE SUPPRESSION PROJECT, in the T CELL IMMUNE DEFICIENCY PROJECT and in the AUTO IMMUNE PROJECT.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is introduced to the cancer, HIV immune deficient and auto immune patient in the thymus or in the
  • MHC I and MHC II genes are grafted on the animal strain's spermatozoids or oocytes prior to fertilisation establishing a new inbred strain expressing one or more human MHC I and MHC II antigens for HLA specificity. 4.
  • Each individual animal is grouped according to the human HLA specificity to which it has been transformed chimerical to the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • the donors species are bred as laboratory animals and processed to the next two procedures (THYMUS DONOR INDIVIDUAL PREPARATION and XENOTRANSPLANTS FROM GROWN CHIMERICAL HLA - SPECIFIC ANIMALS).
  • Table 1 are shown the combination of possibilities of the different EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION and THYMUS DONOR INDIVIDUAL PREPARATION in outbred COLONY OF CHIMERICAL ANIMALS.
  • Table 2 are shown the combinations for inbred homozygotic animals and in Table 3 and Table 4 for MHC I and MHC II grafted transgenic animal strains.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION used is universal (for the corresponding histocompatlble MHC I and MHC II included in the graft) and there is no need that the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is specific for each HLA - human specificity Steps #1, #2, #3 and #4 are described in PROCEDURES TO BE FOLLOWED in the chapter 1.XENOTRANSPLANT PROJECT.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION used is universal (for the corresponding histocompatible MHC I and MHC II included in the graft) and there is no need that the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is specific for each HLA - human specificity.
  • THYMUS DONOR INDIVIDUAL PREPARATION is universal for all HLA histocompatible animals in relation to the histocompatibility specificity of EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION they received at birth.
  • THYMUS DONOR INDIVIDUAL PREPARATION there is no need for specific THYMUS DONOR INDIVIDUAL PREPARATION to be prepared from each animal : the human recipient is treated prior to the xenotransplantation with a universal THYMUS DONOR INDIVIDUAL PREPARATION HLA compatible to the MHC I and MHC II antigens of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • any strain from the inbred colony can be used for xenotransplantation provided that the grafted MHC I and MHC II of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is histocompatible to the HLA specificity of the human recipient.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION used is universal (for the corresponding histocompatible MHC I and MHC II included in the graft) and there is no need that the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is specific for each HLA • human specificity
  • the THYMUS DONOR INDIVIDUAL PREPARATION is universal and there is no need for specific THYMUS DONOR INDIVIDUAL PREPARATION to be prepared from each animal : the human recipient is treated prior to the xenotransplantation with a universal THYMUS DONOR INDIVIDUAL PREPARATION compatible to the MHC I and MHC II antigens of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • EET any strain from the inbred colony can be used for xenotransplantation provided that the grafted MHC I and MHC II of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is histocompatible to the HLA specificity of the human recipient.
  • the THYMUS DONOR SPECIFIC PREPARATION is introduced to the human recipient and is recognised because of the MHC I and MHC II antigen histocompatibility as self.
  • the reaction or rejection of the THYMUS DONOR SPECIFIC PREPARATION is minimal and the human candidate recipient becomes CHIMERIC to the MHC I and MHC II of the donor homozygotic inbred animal strain. Any xenotransplants from the corresponding animal colony MHC I and MHC II compatible can be transplanted and recognised as self both by the donor and the recipient.
  • THYMUS DONOR INDIVIDUAL PREPARATION is crude thymus, or cell lines from thymus from outbred or inbred homozygotic or transgenic donor animals.
  • the HLA specificity of the THYMUS DONOR INDIVIDUAL PREPARATION corresponds to the chimerical histocompatibility of the donor animal from which the crude thymus was extracted from. 4.
  • the crude thymus cells are separated by activated sorting and are placed in sealed in gas/02 flame and cooled slowly till -70 degrees centigrade. After 2-6 hours the material is transferred rapidly to a liquid N2 freezer, recorded and preserved as long as necessary until the bred animal is grown up and a candidate human recipient is selected for receiving a xenotransplant from the individual animal.
  • crude thymus is cooled, frozen and preserved without prior cell, activated sorting and used in an equivocal manner as THYMUS DONOR INDIVIDUAL PREPARATION.
  • crude thymus extract from inbred strain of donor miniature swine or Pan Troglodytes is used for the preparation of cell lines of thymocytes, epithelial and dendritic cells and other thymus cell lines after selection and sorting. These cell lines are propagated in vitro, stored and used in an equivocal manner as THYMUS DONOR INDIVIDUAL PREPARATION.
  • Each one of these thymus cell lines corresponds to the HLA specificity of the
  • THYMUS DONOR INDIVIDUAL PREPARATION contains thymus cells (precursor and mature thymocytes), epithelial cells and dendritic or other thymus cells.
  • the THYMUS DONOR INDIVIDUAL PREPARATION is thawed rapidly at 37 degrees centigrade, checked for viability and implanted or injected to the candidate human recipient for xenotransplantation.
  • the implantation or injection is in the thymus or in the bone marrow or in the spleen or intravenously or in the thymus artery.
  • THYMUS DONOR INDIVIDUAL PREPARATION is administered to the candidate human recipient alone or if a reaction occurs concurrently with immune suppressive treatment.
  • THYMUS DONOR INDIVIDUAL PREPARATION originates from an inbred homozygotic colony that received at birth or intraplacentally EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION that was by genetic engineering grafted with one or more of MHC I and MHC II genes.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION used is the corresponding to the HLA specificity of the MHC I and MHC II antigens included in the graft.
  • THYMUS DONOR INDIVIDUAL PREPARATION is universal and there is no need for specific THYMUS DONOR INDIVIDUAL PREPARATION to be prepared from each animal : the human recipient is treated prior to the xenotransplantation with a universal THYMUS DONOR INDIVIDUAL PREPARATION compatible to the MHC I and MHC II antigens of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • any strain from the inbred colony can be used for xenotransplantation provided that the grafted MHC I and MHC II of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is histocompatible to the HLA specificity of the human recipient.
  • the same preparation is used for all MHC I and MHC II histocompatible candidate human recipients who in turn will receive transplants from any animal of the colony that belongs to the same homozygotic inbred chimerical strain having the same MHC I and MHC II antigens as the donor animal (Table 4).
  • THYMUS DONOR SPECIFIC PREPARATION is introduced to the human recipient and is recognised because of the MHC I and MHC II antigen histocompatibility as self.
  • the reaction or rejection of the THYMUS DONOR SPECIFIC PREPARATION is minimal and the human candidate recipient becomes chimerical to the MHC I and MHC II of the donor homozygotic inbred animal strain. Any transplants from the corresponding animal homozygotic inbred colony MHC I
  • ⁇ and MHC II compatible can be transplanted and recognised as self both by the donor and the recipient.
  • the procedure followed is the same as with inbred homozygotic strains in THYMUS DONOR SPECIFIC PREPARATION the same procedures as with homozygotic inbred strains are followed (Table 4).
  • THYMUS DONOR INDIVIDUAL PREPARATION from transgenic inbred homozygotic strains described in COLONY OF CHIMERICAL ANIMALS constitutes a special situation.
  • the animal strains are not introduced at birth or by transplacental surgery with EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • These animals are chimeras by genetic engineering on their spermatozoids or oocytes to one or more MHC I and MHC II antigen HLA specificity and therefore can be given to all corresponding candidate human recipients, that are HLA histocompatible to the grafted MHC I and MHC II genes.
  • the xenotransplantation is performed without the human recipient candidate to have to be prepared with THYMUS DONOR INDIVIDUAL PREPARATION.
  • Xenotransplants used are extracted from any animal of the inbred homozygotic colony without the need to use the same xenotransplant that originates from the same individual animal's THYMUS DONOR PREPARATION (Table 3).
  • the THYMUS DONOR INDIVIDUAL PREPARATION from inbred homozygotic strains is used as a universal vaccine for certain life threatening neonatal conditions in which the patient is liable to absolute need of transplantation during life. In such cases the THYMUS DONOR INDIVIDUAL PREPARATION is implanted or injected to the new-born human patient in preparation of a future transplantation.
  • the patient is prepared for xenotransplantation by the administration of THYMUS DONOR INDIVIDUAL PREPARATION that corresponds to the patient's HLA specificity (except in the case of a transgenic donor).
  • the xenotransplantation is performed without immune suppressive treatment. If a reaction occurs immune suppressive measures are initiated.
  • T cells from peripheral blood, lympnatic ganglia or from the tumour site are typed for HLA specificity using allogeneic antisera or by mixed lymphocyte reaction.
  • T cell cytotoxic effect against tumoral and non tumoral cells is evaluated by the mixed lymphocyte tumour interaction test.
  • T cells of histocompatible HLA healthy volunteers are tested in the mixed lymphocyte tumour interaction test and their cytotoxic effect against tumour cells is compared to that of the putative patient's T cells.
  • T cells from healthy volunteers are separated, sorted and typed according to their CD4+ CD8+ clone specificity, their autologus anti tumour effect and the HLA specificity.
  • T cells are established as cell lines and propagated in vitro. 3.
  • a T cell bank is established containing several or all HLA specificity cell lines. 4. T cells are preserved and used for suitable histocompatible patients showing a low putative anti tumour cytotoxic effect and a high T cell line effect.
  • New-born human embryonic crude thymus is obtained from fresh cadavers or still births and is to be used either as a crude preparation or the thymus cells are separated and processed.
  • HLA haplotypes of the new-born are identified and the material is grouped according to the HLA specificity (A, C, B, DR, DQA, DQB and DP).
  • the thymus cell bank maintains for each specific HLA histocompatibility group preparations for each type of thymus cells.
  • Each HLA specific EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is either crude thymus extract or a mixture of cell lines of thymocytes (at different stages of development and maturity) added to an equal number of nursing cells (epithelial, dendritic or other thymus cells). 7.
  • the established thymus cell lines are grafted with MHC I and MHC II genes in order to produce cell lines that are marked with more than one antigenic HLA specificity.
  • These genetically engineered thymus cell lines representing groups of HLA specificity also constitute an EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is used in addition to the TUMOUR IMMUNE SUPPRESSION PROJECT, in the XENOTRANSPLANT PROJECT, in the T CELL IMMUNE DEFICIENCY PROJECT and in the AUTO IMMUNE PROJECT.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is implanted to the patient in the thymus or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery.
  • the patients are typed as to their paternal and maternal HLA haplotypes and are diagnosed if they have allogeneic T cells or other cells established in their body.
  • T cells from healthy volunteers are separated, sorted and typed according to their HLA specificity and to their cytotoxic effect against allogeneic T cells and constitute the T CELLS FROM HEALTHY INDIVIDUALS WITH HISTOCOMPATIBLE
  • T CELLS FROM HEALTHY INDIVIDUALS WITH HISTOCOMPATIBLE HLA HAPLOTYPES are transfused to HIV patients in which allogeneic T cells or other cells are shown to have been established in the body. 4. Selected T cells that show cytotoxic effect against the allogeneic T cells are established as cell lines and propagated in vitro to constitute the T CELL LINES OF SPECIFIC HLA HAPLOTYPES. 5. A T cell bank is established containing all or as many as possible T CELLS FROM HEALTHY INDIVIDUALS WITH HISTOCOMPATIBLE HLA HAPLOTYPES and used
  • monoclonal antibodies specific against the HLA allogeneic haplotypes are administered for a treatment period of two to six weeks.
  • the allogeneic T cells are selected and sorted and are used for the preparation of the specific syngeneic monoclonal antibodies.
  • Specific monoclonal antibodies against several T cells of specific HLA haplotypes are preserved, stocked and used for suitable histocompatible patients having an allogeneic tolerance. 4. Monitoring of the rate of elimination of the allogeneic cells from the patient will determine the length of treatment.
  • T cells from healthy volunteers are separated, sorted and typed according to their CD4+ CD8+ clone specificity, their cytotoxic effect against allogeneic T cells effect and the HLA specificity.
  • HISTOCOMPATIBLE HLA HAPLOTYPES are selected, propagated and established as cell lines in vitro.
  • a T cell bank is established containing several or all HLA specificity cell lines
  • T cells are preserved and used for suitable histocompatible patients having an allogeneic tolerance.
  • T CELL LINES OF SPECIFIC HLA HAPLOTYPES with cytocytic effect against allogeneic T cells are selected.
  • MHC I and MHC II genes are grafted by genetically engineering 2.
  • These GENETICALLY ENGINEERED T CELL LINES WITH GRAFTED MHC I AND MHC II GENES are used to MHC I and MHC II histocompatible patients with HIV infections under the same clinical conditions as the T CELL LINES OF SPECIFIC HLA - HAPLOTYPES.
  • New-born human embryonic crude thymus is obtained from fresh cadavers or still births and is used either as a crude preparation or the thymus cells are separated and processed.
  • HLA haplotypes of the new-born are identified and the material is grouped according to the HLA specificity (A, C, B, DR, DQA, DQBand DP).
  • the thymus cell bank maintains for each specific HLA nistocompatibility group preparations for each type of thymus cells.
  • Each HLA specific EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is either crude thymus extract or a mixture of cell lines of thymocytes (at different stages of development and maturity) added to an equal number of nursing cells
  • the established thymus cell lines are grafted with MHC I and MHC II genes in order to produce cell lines that are marked with more than one antigenic HLA specificity.
  • These genetically engineered thymus cell lines representing groups of HLA specificity will also constitute an EARLY HUMAN HLA SPECIFIC THYMUS
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is used in addition to the T CELL IMMUNE DEFICIENCY PROJECT in the XENOTRANSPLANT PROJECT, in the HUMAN TUMOUR IMMUNE SUPPRESSION PROJECT, and in the AUTO IMMUNE PROJECT.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is implanted to the patient in the thymus or in the bone marrow or in the spleen or injected intravenously or in the thymus artery.
  • the patients are typed as to their paternal and maternal HLA haplotypes.
  • T cells from healthy volunteers are separated, sorted and typed according to their HLA specificity and to their cytotoxic effect against auto reactive T cells and
  • a T cell bank is established containing all HLA specificity cell lines or as many as possible.
  • T cells are preserved and used for suitable histocompatible patients having auto reactive T cell population. 6. From T CELLS FROM SYNGENEIC HEALTHY INDIVIDUALS WITH
  • HISTOCOMPATIBLE HLA HAPLOTYPES T CELL LINES HLA.-.
  • HAPLOTYPE SPECIFIC are prepared.
  • T cell lines constitute the T CELLS LINES HLA - HAPLOTYPES SPECIFIC.
  • a T cell bank is established containing several or all of the T CELLS LINES HLA HAPLOTYPES SPECIFIC. 4. The T CELLS LINES HLA - HAPLOTYPES SPECIFIC are preserved and used for suitable histocompatible patients.
  • SHEET 1 In established and confirmed of their activity against auto reactive T CELLS LINES HLA - HAPLOTYPES SPECIFIC, MHC I and MHC II genes are grafted by genetically engineering.
  • monoclonal antibodies specific against the HLA auto reactive T cells are administered for a treatment period of two to six weeks.
  • the auto reactive T cells are selected and sorted and are used for the preparation of the specific syngeneic monoclonal antibodies.
  • New-born human embryonic crude thymus is obtained from fresh cadavers or still births and is used either as a crude preparation or the thymus cells are separated and processed.
  • HLA haplotypes of the new-born are identified and the material is grouped according to the HLA specificity (A, C, B, DR, DQA, DQB and DP).
  • the thymus cell bank maintains for each specific HLA histocompatibility group preparations for each type of thymus cells.
  • Each HLA specific EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is either crude thymus extract or a mixture of cell lines of thymocytes (at different stages of development and maturity) added to an equal number of nursing cells (epithelial, dendritic or other thymus cells).
  • the established thymus cell lines are grafted with MHC I and MHC II genes in order to produce cell lines that are marked with more than one antigenic HLA specificity.
  • These genetically engineered thymus cell lines representing groups of HLA specificity will also constitute an EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is used in addition to the AUTO IMMUNE PROJECT in the XENOTRANSPLANT PROJECT, in the TUMOUR IMMUNE SUPPRESSION PROJECT and in the T CELL IMMUNE DEFICIENCY PROJECT.
  • the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is implanted to the patient in the thymus or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery.
  • the methodology used for the extraction of thymus, preservation of crude thymus, sorting of thymus cells, preservation in cell banks of thymus cell lines and genetic engineering for grafting MHC I and MHC II genes to thymus cells is the same for all four projects.
  • the patent describes a novel approach to achieve successful discordant xenograft transplants from miniature swine, primate Pan Troglodytes, or other animal species to human recipients.
  • the methodology described aims to limit the complications observed up to now in transplantation surgery and to offer an abundant source of donor organs and tissues.
  • XENOTRANSPLANTATION PROJECT allows the transplantation of organs and tissues from one human to another (allogeneic transplantation).
  • the overall objective is to develop a colony (outbred or inbred homozygotic or transgenic) of donor animals that is used as an abundant reserve of organs and tissues for xenograft transplantation to humans.
  • Specific project objectives are:
  • HLA haplotypes specific thymus extracts from human new-borns to transform outbred or inbred animals to human specific HLA chimeras
  • Allogeneic transplants from human donors and xenografts are liable to rejection due to an immunologic response that has to be eliminated in order to achieve tolerance of a transplant.
  • Immunologic response can be eliminated by finding matching donor-recipient combinations of identical histocompatibility antigens as is the case of identical twins.
  • Another way to overcome the rejection response is by immune suppression.
  • a third way to overcome the response is by creating a specific immunologic tolerance. The method described in this patent aims in creating positive and negative selection tolerance and generate a new T cell chimerical repertoire in the human recipient that will be transplanted with a xenograft from a discordant donor (miniature swine, Pan Troglodytes or other animals).
  • Pan Troglodytes is a difficult species to be used - at least at the beginning - as a laboratory animal, on the contrary outbred or inbred miniature swine have clear-cut and well described advantages as to their size, physiology, anatomy and breeding. The method described is equally applicable to both Pan Troglodytes and to miniature swine or outbred animals that are used as donors to human recipients.
  • Crude thymus is obtained from new-born or still birth human cadavers as early as possible and the thymus extract is either preserved to be used as crude or it is processed and thymus cells are prepared.
  • Epithelial, dendritic, precursor and mature thymocyte and other cell lines from the crude thymus are contained in the crude extracts and are separated, sorted, established and propagated in vitro in order to obtain specific HLA - haplotypes cell lines.
  • the thymus tissue extracted from the new-bom is used: a) crude b) or is processed for the preparation of cell lines c) or the cell lines are grafted by genetic engineering with MHC I and MHC II genes .
  • All three thymus preparations are used in an equivocal manner as alternative constituents of the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION. Each preparation is HLA - haplotypes' specific.
  • the EARLY HUMAN HLA - SPECIFIC THYMOCYTE PREPARATION is implanted in the thymus or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery of inbred homozygotic or outbred new-bom donor animals or is implanted or injected by transplacental surgery to the embryo.
  • the EARLY HUMAN HLA - SPECIFIC THYMOCYTE PREPARATION is also used in the HUMAN IMMUNE TUMOUR SUPPRESSION PROJECT, in the IMMUNE DEFICIENCY PROJECT and in the AUTO IMMUNE PROJECT.
  • the same preparation is also used for the preparation of patients to receive allogeneic transplants.
  • the human recipient is prepared with EARLY HUMAN HLA - SPECIFIC THYMOCYTE PREPARATION histocompatible to the donor human prior to the transplantation and thereafter the same procedure is followed as in xenotransplantations.
  • Miniature swine or Pan Troglodytes or other animals are transformed to chimeras to human HLA specificities and used as donors of organs and tissues to histocompatible human recipient patients.
  • the donor animals receive during the late gestation period by transplacental surgery or as new-borns, human thymus crude cells or ceil lines or genetically engineered thymus cells (EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION).
  • the successful implantation or injection of such material transforms the animals to chimeras to one specific or groups of human HLA - haplotypes in concordance to the constituents of the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION that they have received in their early life.
  • Crude thymus, thymus cell lines or thymus cell lines are processed and preserved in a THYMUS DONOR INDIVIDUAL PREPARATION bank. From the cell lines MHC I and MHC II genes are grafted and cell lines are prepared that have HLA specificity antigen markers on their surface. The preparations maintained in the bank are identifiable as
  • THYMUS DONOR SPECIFIC PREPARATION prepared from homozygotic inbred animals having received at birth MHC I and MHC II grafted EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION and also having been grafted with corresponding MHC I and MHC II genes constitute a separate situation.
  • the candidate recipient patient will receive syngeneic THYMUS DONOR SPECIFIC PREPARATION and will recognise it as self without reaction or need of immune suppressive treatment.
  • the THYMUS DONOR SPECIFIC PREPARATION in a similar manner recognises as self the human recipient.
  • the candidate patient recipient is treated with the specific THYMUS DONOR INDIVIDUAL PREPARATION.
  • the THYMUS DONOR INDIVIDUAL PREPARATION is implanted in the thymus or bone marrow or spleen or is injected intravenously or in the thymus artery.
  • the xenotransplantation of the histocompatible donor organ or tissues follows.
  • THYMUS DONOR INDIVIDUAL PREPARATION is used in conjunction with plasmophoresis, monoclonal anti-human T cells, irradiation or pharmaceutical immune suppression, if required, pending on the human recipient's condition, immune status and concomitant diseases.
  • Organ or tissue xenotransplants are extracted and transplanted to the human recipient patient that is HLA - haplotype compatible to the specific donor chimerical animal (more precisely to the HLA - haplotypes to which the individual animal had been rendered chimerical at birth).
  • Each animal is identifiable and corresponds to the EARLY HUMAN HLA DONOR THYMUS PREPARATION to which it was induced at birth and to the THYMUS DONOR INDIVIDUAL PREPARATION that was extracted from the animal in early life.
  • each animal is identifiable by the MHC I and MHC II genes to which it was rendered transgenic to.
  • THYMUS DONOR INDIVIDUAL PREPARATION is universal and there is no need for specific THYMUS DONOR INDIVIDUAL PREPARATION to be prepared from each animal : the human recipient is treated prior to the xenotransplantation with a universal THYMUS DONOR INDIVIDUAL PREPARATION compatible to the MHC I and MHC II antigens of the EARLY HUMAN HLA SPECIFIC THYMUS CELL PREPARATION. Furthermore in this situation there is no need to use separate individual animals, any strain from the inbred colony can be used for xenotransplantation provided that the grafted MHC I and MHC II of the EARLY
  • HUMAN HLA SPECIFIC THYMUS CELL PREPARATION is histocompatible to the HLA specificity of the human recipient.
  • the same preparation is used for all MHC I and MHC II histocompatible candidate human recipients who in turn will receive transplants from any animal of the colony that belongs to the same homozygotic
  • the THYMUS DONOR SPECIFIC PREPARATION is introduced to the human recipient and is recognised because of the MHC I and MHC II antigen histocompatibility as self.
  • the reaction or rejection of the THYMUS DONOR SPECIFIC PREPARATION is minimal not requiring immune suppressive measures and the human candidate recipient becomes chimerical to the MHC I and MHC II of the donor homozygotic inbred animal strain. Any transplants from the corresponding animal homozygotic inbred colony MHC I and MHC II compatible can be transplanted and recognised as self both by the donor and the recipient (Table 4)).
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION is extracted from new-born human cadavers or from still births.
  • the crude thymus is typed to identify the HLA haplotypes specificity and is either used crude or thymus cell lines are prepared and propagated in vitro as HLA specific cell lines.
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION can either be crude thymus or thymus cell lines or genetically engineered cell lines
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION is preserved and maintained in a bank for future introduction to animal strains. 6.
  • the number of EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION will be either one or more preparation or groups of HLA specificities according to the number of genes that have been successfully grafted to the thymus cells.
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION bank maintains and has on stock as many as possible HLA haplotypes of thymus or thymus cell lines.
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION is introduced or implanted to the donor animal in the thymus ally (or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery).
  • the introduction to the new-bom or embryo animal of the new-born human thymus material is performed by transplacental surgery or immediately after birth 10.
  • the future xenotransplant donor animals becomes a chimera and is tolerant to human HLA - haplotypes specific.
  • the introduction consists of a graft of crude thymus or of cell lines of the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION.
  • the introduction or implantation is performed by a multisite micro- injection, or implantation.
  • EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION is specific HLA-A, B, C, E, F, G, H for class I and HLA-D for class II MHC specific.
  • This material contains precursor and mature thymocytes, epithelial nursing cells, dendritic, or other thymus cells.
  • the chimerical donor animals are used as a reservoir of organs and tissues that will be used in transplantation to human recipients. 16.
  • the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION due to the early stage of life of the donor animal is established in the donor animal and will process donor thymocytes and T cell by positive and negative selection.
  • the donor animal becomes chimerical and its T cells recognise as self both the original donor animal cells as well as the cells of the human HLA - haplotype to which it was exposed.
  • the restriction repertoire of the donor animal's T cells is determined by the chimerical environment in which they have matured which will represent a positive and negative selection compatible to the human HLA - haplotypes and of the inbred animal donor strain's histocompatibility specificity. 18.
  • MHC I and MHC II grafted genes on the human new-bom thymus cell lines the methodology is simplifies and there will be less need for use of cadavers and still births.
  • the animals are under control for a period of one to four weeks before part of their thymus is extracted and THYMUS ANIMAL DONOR INDIVIDUAL MATERIAL from each individual animal is processed and preserved till the time when the animals will be sacrificed and serve as donors for candidate human recipients. 2. From the extracted crude thymus the THYMUS DONOR INDIVIDUAL PREPARATION is processed.
  • THYMUS DONOR INDIVIDUAL MATERIAL corresponds to the specific human HLA - specificity or specificities to which the animal was transformed chimerical to at birth. 6. Banks of THYMUS DONOR INDIVIDUAL PREPARATION are organised that maintain the following: a.
  • the human recipient is transplanted later with a transplant originating from the same individual animal b.
  • INBRED HOMOZYGOTIC COLONIES Genetically grafted cell lines with MHC 1 and MHC II genes from these animal strains are used as THYMUS DONOR INDIVIDUAL PREPARATION for the individual or groups of
  • HLA SPECIFIC THYMUS PREPARATION with genetically engineered thymus cells with grafted MHC I and MHC II genes compatible to the MHC I and MHC II markers of the recipient patient.
  • the candidate recipient patient will receive the histocompatible xenotransplant THYMUS DONOR INDIVIDUAL PREPARATION (grafted with MHC I and MHC II genes) and will recognise it as self without reaction or need of immune suppressive treatment.
  • THYMUS DONOR INDIVIDUAL PREPARATION is introduced to the human recipient patient who is a candidate for xenotransplantation prior to the transplant intervention.
  • the tolerability is higher in the case that compatible MHC I and MHC II grafted cells are used in both the EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION and the THYMUS DONOR INDIVIDUAL PREPARATION.
  • DONOR INDIVIDUAL PREPARATION is rendered chimerical to the individual donor animal.
  • the human recipient's chimerical thymus educates and nurses accordingly the thymocytes that will be appropriately positively and negatively selected in order to recognise as self both the "human" self haplotype as well as the individual donor animal's haplotypes.
  • the chimerical animal used for xenotransplantation is the same one from which the THYMUS DONOR INDIVIDUAL MATERIAL was prepared from, and implanted (or injected) to the human recipient candidate (or alternatively thymus cell lines or genetically engineered thymus cell lines).
  • the histocompatibility sequence of events corresponds to one or more of the following situations : a. EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION and candidate recipient patient share the same HLA specificity as to the marker MHC I and MHC II antigens. b. New-born donor animal, THYMUS DONOR INDIVIDUAL PREPARATION and Xenotransplants belong to the same individual animal.
  • New-born donor animal, THYMUS DONOR INDIVIDUAL PREPARATION and Xenotransplants do not belong to the same individual animal however are originating from homozygotic inbred strains.
  • New-born donor animal and Xenotransplant are transgenic homozygotic inbred strains grafted possessing MHC I and MHC II antigen markers identical to the human recipient's corresponding MHC I and MHC II markers.
  • the xenotransplant being a chimera of the same specific HLA - haplotype as the human recipient candidate recognises the human recipient's cells as self and is tolerated. 5.
  • THYMUS DONOR INDIVIDUAL PREPARATION is omitted.
  • the MHC I and MHC II markers of the transgenic strain should include the MHC I and MHC II markers of the human recipient. 6.
  • Step #2 and step #3 will also be omitted in the case of difficulties in achieving tolerance of the THYMUS DONOR INDIVIDUAL PREPARATION by the human recipient candidate. 7. In all these situations the xenotransplant will be directly transplanted to the human recipient.
  • the patent describes a novel approach in the therapy of human tumours.
  • a specific HLA - haplotypes preparation of mature T cells will be transfused in order to restore the immune surveillance system and by an enhanced cytotoxic effect destroy the tumour c cells.
  • the patient's histocompatibility profile is determined and the paternal and maternal HLA - haplotypes is identified by serology or mixed lymphocyte culture. This will allow to administer to the patient the suitable histocompatible healthy T cells or cell line or genetically engineered HLA - haplotypes specific anti tumour T cells.
  • the cytotoxic anti tumour effect of the patient's T cells and T cells of histocompatible healthy subjects or cell line T cells is compared.
  • Tumour cells are tested in a mixed cell culture system with histocompatible lymphocytes from normal donors and their anti-neoplastic cell cytotoxicity is determined in comparison to that of the patient's putative lymphocytes. This will allow to test the natural cytotoxic effect of the "healthy" lymphocytes that should be significantly more potent than the putative patient's T cells in order to justify the therapeutic T cell transfusion which is described in this patent.
  • I Lymphocytes from histocompatible individuals of the same HLA - haplotype is transfused to patients with human tumours to revitalise the patient's lacking immune surveillance suppressive capacity against the tumour cells.
  • T cells of specific HLA - haplotypes will be established and propagated in vitro allowing an abundant resource of suitable T cells that can be propagated in vitro.
  • the selection of the T cells clones for in vitro propagation will be based on the anti tumour cytotoxic effect profile as determined by the mixed lymphocyte tumour inactivation.
  • a T cell bank will be established in which in vitro propagated and preserved T cells of different HLA specificities will be available for transfusion to suitable patients.
  • the T cells are transfused in monotherapy or in combination with surgery, chemotherapy and or radiotherapy.
  • MHC I and MHC II genes will be grafted on the propagated T cells to render them universal donors or at least compatible with large groups of HLA - haplotypes. Such a genetic manipulation will allow to limit the number of T cell lines and obtain T cells suitable for large groups of HLA - haplotypes.
  • the preparation will be the same as the one in the Xenotransplant Project.
  • Cell lines or genetically engineered cells are developed in addition to crude thymus extracts.
  • Implantation is made in the thymus or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery. The aim is to restore and re-educate the putative Tcells of the patient in the immune surveillance of the self cells of the body and in the destruction of neoplastic cells.
  • HLA histocompatible lymphocyte treatment can be combined with other chemotherapeutic, radiotherapeutic or surgical approaches. Re-education of the patient's thymocytes in order to restore in the long term the immune surveillance system. Another dimension of the same project and using the same products and systems is its expansion to treat infections due to virus, bacteria, fungi and parasites.
  • the patent describes a set of systems, tests and cell products and preparations that will allow to diagnose immune deficiencies and treat HIV infection based on the concept that HIV infection is secondary to an allogeneic immune condition.
  • the project aims in providing means to allow the patient to restore and re-establish the immunologic status of self and non-self recognition of the immune deficient state, and by an indirect way attack the HIV infection through the antigen presenting cells.
  • the project is based on the assumption that immune deficiency is a consequence of the introduction of allogeneic T cells in the individual that is rendered a chimera.
  • the allogeneic thymocytes could have been introduced by transfusion, introduction of sperm in the circulation, accidental injection, trauma or bite. In the case that the allogeneic cells have not been destroyed as non - self cells and have managed to become tolerant, then the individual is a chimera to the donor's thymocyte material to which he or she has been exposed.
  • T cells from healthy individuals with compatible HLA - haplotypes are transfused in order to potentate the self thymocytes and enhance the infectious control.
  • These T cells by being HLA compatible to the original putative T cells of the patient will supply the eliminated or reduced patient's T cells and destroy the allogeneic T cells.
  • the transfused T cells will also recognise and inactivate the processed HIV in antigen presenting cells.
  • Monoclonal antibodies against the HLA - haplotypes of the allogeneic donor T cells in order to destroy the non - self population and allow the patient to repopulate and re ⁇ establish the initial original paternal and maternal haplotypes self T cells.
  • T cell lines of specific HLA - haplotypes are developed propagated in vitro and preserved. Banks of T cells of many HLA haplotypes will increase the availability of specific T cells for suitable patients
  • the treatment of HIV immune deficient patients with T cell transfusions and monoclonal antibodies will increase the putative T cells and restore the natural immune antiviral and anti allogeneic T cell activity of the host.
  • the allogeneic T cells and the HIV infection can recover and the disease continue. More radically the condition is controlled by the restoration of the thymus that can be restored and re-educated in order to develop normal putative T cells.
  • the restoration of the normal T cell production is achieved by implantation of EARLY HUMAN HLA SPECIFIC THYMUS PREPARATION in the thymus (or in the bone marrow).
  • This preparation will revitalise the thymus, and allow the "nursing" and maturation of thymocytes.
  • T cells will recognise self body cells of the host including putative T cells and also recognise as non "self allogeneic T cells and other donor allogeneic cells and eliminate them.
  • the preparation is the same as the one in the Xenotransplant Project and contains thymus cell lines or genetically engineered cells or crude thymus extracts, implanted in the thymus or bone marrow or in the spleen or injected intravenously or in the thymus artery.
  • the donor T cell manage to survive a dynamic condition will occur that will end with the exhaustion of the specific T cells of the host that recognise the donor T cells.
  • the donor's T cells will continue proliferating and the host's specific T cell population will continue being reduced in population numbers due to the destruction by the donor's T cells.
  • the dynamics of the two T cell populations will determine the clinical condition that will evolve in the individual. In the situation in which the donor T cells are established the individual will become a chimera.
  • the destruction or deletion of certain T cell clones by the established donor T cells in the host individual will have as a consequence immunologic gaps in the recognition of viral and other antigens on antigen presenting cells.
  • the infection by HIV virus might be in such a situation a consequence of non-response of the individual's T cells to the recognition of HIV processed antigen on the antigen presenting cells.
  • HIV infection is considered as secondary to the events associated to the introduction and establishment of allogeneic T cells in the host. HIV infection occurring in such allogeneic chimerical individuals will follow the natural history of the disease as described. In parallel and concurrently the individual will be suffering from the consequences of the ongoing pathology of the chimerical condition due to the allogeneic T cells.
  • the model can be further complicated in the case of incidental introduction of allogeneic T cells from a third or fourth donor individual.
  • the patent describes a novel approach for the treatment of auto immune disease based on the elimination of T cells in the periphery that are auto reactive and the restoration of the proper selection of T cells in the thymus.
  • Auto immune disease caused by auto reactive cells that were not adequately selected in the thymus will be the target of this project : aiming to overcome the deficiencies in the negative selection process in the thymus, and to eliminate auto reactive T cells.
  • the HLA profile of each patient is evaluated by determining the paternal and maternal initial haplotypes of the subject and determining if the patient has auto reactive T cells From the patient's peripheral blood lymphocytes are separated and sorted and auto reactive T cells collected.
  • T CELLS FROM SYNGENEIC HEALTHY INDIVIDUALS WITH HISTOCOMPATIBLE HLA HAPLOTYPES are tested as to their cytotoxic effect against the putative patient's auto reactive T cells. Cytotoxicity tested in a mixed cell culture system will determine the need for treatment with T CELLS FROM SYNGENEIC HEALTHY INDIVIDUALS WITH HISTOCOMPATIBLE HLA HAPLOTYPES for each patient
  • T CELLS LINES HLA HAPLOTYPE SPECIFIC T cell lines of specific HLA - haplotypes are developed propagated in vitro and preserved. Banks of T cells of many HLA haplotypes will increase the availability of specific T cells for suitable patients
  • thymus or cell lines of dendritic cells, epithelial cells, precursor thymocytes, mature thymocytes and other thymus ceils related to the T cell "education" with specific histocompatible HLA - haplotypes and propagated in vitro will be prepared.
  • This syngeneic material or cells will be implanted in the thymus (or in bone marrow) in order to re-establish and enforce the proper negative selection of the developing thymocytes.
  • Thymus cell lines or genetically engineered cells are developed in addition to crude thymus
  • Implantation is made in the thymus or in the bone marrow or in the spleen or is injected intravenously or in the thymus artery.
  • the aim is to restore and re-educate the putative Tcells of the patient in properly selecting T cells and eliminate auto reactive thymocytes.

Abstract

Les données expérimentales en immunologie ont déjà mis en évidence que le thymus joue un rôle important dans la sélection et le développement des lymphocytes thymiques et dans la surveillance des cellules 'saines' de l'organisme. L'hétérogreffe (greffe hétéroplastique), la surveillance et l'élimination des cellules tumorales, l'infection par VIH, la dépression immunitaire et les cellules autoréactives en auto-immunité sont associées au thymus et au développement, à l''éducation' ou à la maturation des lymphocytes thymiques. Les quatre projets décrits dans ce brevet sont de nouvelles applications méthodologiques basées sur le rôle immunologique essentiel que jouent le thymus et les lymphocytes thymiques dans l'immunotolérance, dans la surveillance des cellules cancéreuses, dans la tolérance allogénique et dans la libération de lymphocytes T autoréactifs dans les maladies auto-immunes. L'utilisation de différentes approches visant l'activité du thymus, en fonction de l'état clinique, et consistant à restaurer, supprimer, améliorer ou contourner cet organe, permet d'assurer des effets thérapeutiques utilisables dans la transplantation clinique, en cancérologie et dans le traitement des maladies infectieuses et auto-immunes.
PCT/GR1994/000016 1994-07-03 1994-07-03 Produits thymiques et applications WO1996001120A1 (fr)

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EP0842266A1 (fr) * 1995-08-04 1998-05-20 The General Hospital Corporation Porc transgenique et cellules de porc possedant des genes hla de l'homme
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EP0517199A1 (fr) * 1991-06-04 1992-12-09 Yeda Research And Development Company, Ltd. Transplantation durable de cellules et de tissu humain dans des mammifères normaux
WO1993009815A1 (fr) * 1991-11-22 1993-05-27 The General Hospital Corporation Tolerance specifique lors d'une transplantation

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B.A.E. VANDEKERCKHOVE ET AL.: "HUMAN HEMATOPOIETIC CELLS AND THYMIC EPITHELIAL CELLS INDUCE TOLERANCE VIA DIFFERENT MECHANISMS IN THE SCID-hu MOUSE THYMUS.", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 175, no. 4, April 1992 (1992-04-01), NEW YORK, N.Y., US, pages 1033 - 1043 *
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EP0842266A1 (fr) * 1995-08-04 1998-05-20 The General Hospital Corporation Porc transgenique et cellules de porc possedant des genes hla de l'homme
EP0842266A4 (fr) * 1995-08-04 1999-07-21 Gen Hospital Corp Porc transgenique et cellules de porc possedant des genes hla de l'homme
US6030833A (en) * 1995-08-04 2000-02-29 The General Hospital Transgenic swine and swine cells having human HLA genes
US6558663B1 (en) 1995-08-04 2003-05-06 The General Hospital Corporation Transgenic swine & swine cells having human HLA genes
US9420770B2 (en) 2009-12-01 2016-08-23 Indiana University Research & Technology Corporation Methods of modulating thrombocytopenia and modified transgenic pigs

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