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WO2001056379A1 - Methode permettant de reduire une reaction inflammatoire corneenne - Google Patents

Methode permettant de reduire une reaction inflammatoire corneenne Download PDF

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Publication number
WO2001056379A1
WO2001056379A1 PCT/US2001/003960 US0103960W WO0156379A1 WO 2001056379 A1 WO2001056379 A1 WO 2001056379A1 US 0103960 W US0103960 W US 0103960W WO 0156379 A1 WO0156379 A1 WO 0156379A1
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WO
WIPO (PCT)
Prior art keywords
corneal
cornea
epithelial cells
immunogenic
living
Prior art date
Application number
PCT/US2001/003960
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English (en)
Other versions
WO2001056379A9 (fr
Inventor
Junko Hori
Wayne J. Streilein
Original Assignee
The Schepens Eye Research Institute, Inc.
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 The Schepens Eye Research Institute, Inc. filed Critical The Schepens Eye Research Institute, Inc.
Priority to AU2001236740A priority Critical patent/AU2001236740A1/en
Publication of WO2001056379A1 publication Critical patent/WO2001056379A1/fr
Publication of WO2001056379A9 publication Critical patent/WO2001056379A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • A61F2/142—Cornea, e.g. artificial corneae, keratoprostheses or corneal implants for repair of defective corneal tissue
    • 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
    • A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0621—Eye cells, e.g. cornea, iris pigmented cells
    • 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
    • A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses

Definitions

  • LC Langerhans cells
  • corneal stimuli e.g., trauma, infection, cauterization
  • centripetal migration of LC into the cornea from the limbus, the border between cornea and conjunctiva, where they may initiate antigen processing (Williamson et al.; McLeish et al.).
  • Non-corneal solid organs sensitize their hosts primarily through the direct pathway of sensitization where "passenger cells” from the donor emigrate to the host's lymphoid organs and activate T cells.
  • passenger cells two features of the cornea, (1) its depressed expression of class II antigens, and (2) its lack of "passenger cells,” make this pathway less operative in the setting of corneal transplantation.
  • sensitization of the host in corneal grafting requires the participation of host antigen-presenting cells, in a process known as indirect sensitization (Sano et al., 1997a) .
  • the "indirect" pathway for corneal allograft recognition may involve activation of migration of recipient LC from the limbus to the donor corneal tissue where they can acquire foreign antigen (Sano et al . , 1997b) .
  • migration of limbal LC into the cornea has been associated with loss of ocular immune privilege (Dana et al.) and other immunoinflammatory events in the cornea such as development of herpetic keratitis (Jager et al., 1991, 1992a, 1992b, 1995; Hendricks et al . ) .
  • the invention is directed to a method for treating donor corneal tissue, e.g., allografts or xenografts, so as to reduce or prevent corneal graft rejection, and to a method for generally treating corneal inflammation so as to reduce or prevent an immune or inflammatory response of the eye.
  • One aspect of the invention includes the creation of a non-allogenic epithelial layer (e.g., from living epithelial cells from the recipient or from living, commercially available non- immunogenic epithelial cells) to cover a donor corneal stroma (with associated endothelium) and the use of this composite cornea as the grafted entity.
  • living epithelial cells from a patient can be used in general to prepare a protective barrier layer, e.g., a "bandage,” to quiet a corneal inflammatory response.
  • the method of the invention is used to prolong transplant survival in corneal allograft recipients.
  • the method of the invention would also be useful for therapeutic intervention in immunogenic inflammatory diseases of the cornea and ocular surface, such as keratoconjunctivitis sicca and other dry eye states including Sj ⁇ gren's syndrome, allergic conjunctivitis and other atopic conditions of the ocular surface, corneal neovascularization, and immune or infectious keratitis states.
  • the method of the invention would be useful for suppressing intraocular inflammatory diseases such as uveitis and post-surgical inflammation within discrete compartments (e.g., anterior chamber, vitreous cavity) .
  • Fig. 1A is a graphic representation of the various layers in a normal cornea
  • Fig. IB is a micrograph showing the normal corneal layers in si tu; Figs. 2A and 2B show day 14 clinical and histologic findings for an epithelium deprived syngeneic graft implanted beneath the kidney capsule.
  • Fig. 2A arrows point to graft margins. The grafts were found to be clear by clinical inspection through a dissecting microscope. Histologic examination revealed the stroma to be free of infiltrating cells, and the donor endothelium appeared to be intact.
  • the arrow points to nuclei of stromal cells, and the arrowhead points to a nucleus of endothelium with intact Descemet's membrane.
  • K kidney
  • CS corneal stroma. Section stained with hematoxyline and eosin.
  • Fig. 3A shows clinical findings at 14 days for a CD95 ligand-deficient corneal allograft (B ⁇ -gld) without an epithelial layer implanted beneath the kidney capsule. These grafts were opaque. Neovessels were also observed emerging from the kidney and penetrating into these grafts. Arrows point to the margins of the graft; arrowheads point to the neovessels that have formed in the periphery of the graft bed.
  • Fig. 3B shows histological findings at day 4.
  • Inset shows a high power image of stromal infiltrating cells.
  • Figs. 4A and 4B show clinical and histologic findings at 4 weeks for a reconstituted cornea with syngeneic epithelium and allogeneic stroma plus endothelium.
  • Fig. 4A shows by clinical inspection that the graft was clear.
  • histologic examination revealed the graft to be free of infiltrating cells or neovessels. Section stained with hematoxyline and eosin.
  • Fig. 5 shows histologic findings for a reconstituted cornea with allogeneic epithelium and allogeneic stroma plus endothelium at 4 weeks. Histologic examination showed the graft was swollen, infiltrated, and neovascularized. Section stained with hematoxyline and eosin.
  • the method of the invention was developed during experiments designed to answer the question: to what extent is the normal high rate of acceptance that is observed for corneal transplants due to properties of the graft itself and to what extent is this rate of acceptance due to the immune-privileged status of the eye.
  • the goal of the relevant experiments was to determine the possible sources of immunogenicity among the different layers of the cornea following corneal transplantation and to determine the mechanism by which the cornea provides its own immune privilege through constitutive expression of CD95 ligand.
  • a normal cornea consists of three cellular layers.
  • an outer layer of epithelial cells rests on an acellular membrane, called Bowman's membrane.
  • This membrane separates the epithelium from the internal bulk layer, or second layer, of the cornea, called the stroma.
  • the posterior (inner surface of the cornea) is lined by endothelial cells, the third layer, which rest on an acellular membrane (Descemet's membrane) separating the stroma from the endothelium.
  • acellular membrane acellular membrane
  • Corneas for experimentation were obtained from normal or cauterized eyes (i.e., containing Langerhans cells) of syngeneic and allogeneic mouse donors, denuded of epithelium or endothelium, divided in half (1x2 mm), and then grafted beneath the kidney capsule of recipient mice as (a) full-thickness corneas, (b) endothelium- deprived corneas, (c) isolated epithelial layers, (d) composite grafts of epithelium from one donor and stroma- endothelium from a different donor, (e) stroma alone and (f) stroma with attached endothelium.
  • the fate of the graft including the integrity of the corneal endothelial layer, was assessed clinically, histologically and immunohistochemically . Acquisition of systemic T-cell mediated immune responses in the recipient was evaluated by Delayed Hypersensitivity (DH) assessment.
  • DH Delayed Hypersensitivity
  • endothelial cells protected stroma allografts from rejection unless the tissue lacked CD95L expression.
  • CD95L protected allogeneic endothelial cells, but not stroma, from rejection.
  • epithelium-deprived cornea stroma and endothelium
  • Viable allogeneic corneal epithelium eliminates the immune-suppressive effects of CD95L-bearing corneal endothelial cells, presumably due to its capacity to secrete factors that are proinflammatory and angiogenic.
  • corneal epithelium was peeled as an intact sheet from full-thickness normal or cauterized (2 weeks previously) corneas of BALB/c (recipient) or C57BL/6 (donor) mice.
  • a two mm diameter corneal stroma button plus endothelium components prepared from full-thickness normal corneas of C57BL/6 mice was gently covered by a similarly-sized epithelium sheet under the dissecting microscope.
  • the following reconstituted corneas were used for grafting: syngeneic (BALB/c recipient derived) epithelium and allogeneic (C57BL/6 donor derived) stroma plus allogeneic endothelium. Penetrating keratoplasty was performed with these reconstituted grafts, using normal BALB/c mice as recipients. Reconstituted corneas were placed in recipient eyes with 8 interrupted sutures
  • the survival rates of these control groups at 8 weeks were (a) 43 % (10 out of 23), (b) 44 % (4 out of 9), and (c) 50 % (5 out of 10), respectively.
  • All rejector mice in each group acquired allo-specific DH at 8 weeks.
  • 85 % (11 out of 13) of reconstituted cornea grafts comprised of syngeneic epithelium and allogeneic stroma plus endothelium survived, and failed to induce DH at 8 weeks, less than 50% of normal allogeneic corneas survived, and all mice acquired DH.
  • reconstituted corneal allografts that are devoid of allogeneic epithelium, but are covered with a syngeneic epithelial layer, fail to sensitize their recipients, because the typical immigration of Langerhans cells from the limbus into the graft does not take place. As a consequence, the ability of the recipients to become sensitized to donor alloantigens is curtailed. Histological examination of accepted, reconstituted grafts revealed little evidence of scarring or fibrosis secondary to the surgical reconstruction. However, as evident in Fig. 5, a reconstituted cornea with allogenic epithelium and allogenic stroma plus endothelium became swollen, infiltrated and neovascularized after 4 weeks.
  • this new method of corneal transplantation in which a syngeneic epithelial layer acts as a "bandage" to cover the surface of the graft until recipient epithelium replaces it, is a safe and effective method of preventing recipient sensitization to donor alloantigens and of protecting the graft from eventual immune rejection.
  • a few epithelial cells from an intended recipient e.g., a recipient with a damaged cornea who is in need of a corneal transplant
  • the epithelial cells are obtained from the ocular area of the intended recipient or from another, non-ocular area of the body.
  • the cells can be obtained from, e.g., a commercial source of non-immunogenic epithelial cells.
  • This composite cornea is then used as the grafted entity for a corneal transplant into the recipient.
  • the epithelial layer from a recipient, or from a non-immunogenic external source acts as a "bandage" to keep the stroma from sending out the signals that would result in its own death.
  • the method of the invention would be particularly useful for high risk corneal transplant recipients.
  • Possible uses of the method of the invention other than in the arena of corneal transplant from a human donor to a human recipient include the use of xenografts, where the donor cornea is taken from a mammal other than human, e.g., from a pig.
  • Other, non-grafting, uses for the method of the invention include quieting of the corneal inflammatory response in general, such as in Steven-Johnson Syndrome or in wound heali g failure or stromal keratitis.
  • Other exemplary conditions that would benefit from the method of the invention are listed in Table 2.
  • Vernal keratoconjunctivitis (Giant papilla keratoconjunctivitis)
  • the outer epithelial layer of the cornea is not generally thought of as a "skin, " we have shown here that living epithelial cells from a patient or from, e.g., a commercial non-immunogenic epithelial cell source can be used as an active "bandage” to reduce the transmission of inflammatory cell signaling and thus improve healing following a corneal inflammatory response .

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Genetics & Genomics (AREA)
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  • Organic Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Ophthalmology & Optometry (AREA)
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Abstract

L'invention concerne une méthode destinée au traitement d'un tissu cornéen provenant d'un donneur, une allogreffe, par exemple, de façon à réduire ou à prévenir un rejet de greffe cornéenne, ou au traitement globale d'une inflammation cornéenne, de façon à prévenir une réponse immune ou une réaction inflammatoire de l'oeil. Un aspect de l'invention comprend la création d'une couche épithéliale non allogénique (à partir de cellules épithéliales vivantes provenant du receveur ou de cellules épithéliales vivantes, non immunogènes, disponibles sur le marché, par exemple) destinée à recouvrir un stroma cornéen provenant d'un donneur (avec endothélium associé) et l'utilisation de cette cornée composite comme entité greffée. Dans d'autres aspects de cette invention, les cellules épithéliales vivantes d'un patient peuvent être utilisées en général pour préparer une couche de protection, un « bandage », par exemple, pour réduire une réaction inflammatoire cornéenne.
PCT/US2001/003960 2000-02-07 2001-02-06 Methode permettant de reduire une reaction inflammatoire corneenne WO2001056379A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001236740A AU2001236740A1 (en) 2000-02-07 2001-02-06 A method of quieting a corneal inflammatory response

Applications Claiming Priority (2)

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US18051300P 2000-02-07 2000-02-07
US60/180,513 2000-02-07

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WO2001056379A1 true WO2001056379A1 (fr) 2001-08-09
WO2001056379A9 WO2001056379A9 (fr) 2002-10-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100333702C (zh) * 2004-04-28 2007-08-29 浙江大学医学院附属邵逸夫医院 一种无细胞的异种角膜基质及制备方法和用途
WO2021053609A1 (fr) 2019-09-20 2021-03-25 Niios-Usa Inc. Superposition provenant d'un donneur pour le traitement ou le soulagement de troubles cornéens antérieurs
WO2021094780A1 (fr) * 2019-11-13 2021-05-20 The University Of Nottingham Tissu cornéen

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827641A (en) * 1992-11-13 1998-10-27 Parenteau; Nancy L. In vitro cornea equivalent model

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827641A (en) * 1992-11-13 1998-10-27 Parenteau; Nancy L. In vitro cornea equivalent model

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HE ET AL.: "Experimental transplantation of cultured human limbal and amniotic epithelial cells into the corneal surface", CORNEA, vol. 18, no. 5, 1999, pages 570 - 579, XP002938774 *
MAGUIRE ET AL.: "Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies", OPHTHALMOLOGY, vol. 101, no. 9, September 1994 (1994-09-01), pages 1536 - 1547, XP002938776 *
TRESELER ET AL.: "The relative immunogenicity of corneal epithelium, stroma and endothelium", TRANSPLANTATION, vol. 41, no. 2, February 1986 (1986-02-01), pages 229 - 234, XP002938775 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100333702C (zh) * 2004-04-28 2007-08-29 浙江大学医学院附属邵逸夫医院 一种无细胞的异种角膜基质及制备方法和用途
WO2021053609A1 (fr) 2019-09-20 2021-03-25 Niios-Usa Inc. Superposition provenant d'un donneur pour le traitement ou le soulagement de troubles cornéens antérieurs
WO2021094780A1 (fr) * 2019-11-13 2021-05-20 The University Of Nottingham Tissu cornéen

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AU2001236740A1 (en) 2001-08-14
WO2001056379A9 (fr) 2002-10-17

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