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Corneal Graft Rejection and Graft Failure


inadequate or prolonged corneal preservation, poor graft material, surgical trauma ... hormone and by comtaminated neurosurgical instruments and cortical electrodes. ... – PowerPoint PPT presentation

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Title: Corneal Graft Rejection and Graft Failure

Corneal Graft Rejection andGraft Failure
  • REJECTION Khodadoust line rejection line
    stromal oedema

Rejection of Solid Allografts,
  • Classification
  • 1 Hyperacute- preformed antibody
  • 2 Acute- lt 4 weeks
  • Activation of T cell clones and destruction of
    graft by cytotoxic T cells
  • 3 Chronic -usually progressive arteriolitis
    refractory to immunosupressive therapy
  • Cornea endothelial loss, mainly

Immune Privilege in the Eye
  • Dynamic process, actively maintained. (Kaplan)
  • Eye dependent modification of afferent and
    efferent limbs of the immune system
  • "Afferent block"
  • Blood eye barrier
  • Modified professional APC cells
  • Ocular fluids suppress compliment activation
  • ACAID (Strelein)

  Factors which unfavourably regulate immune
  • Langerhan's APC Cells
  • Neovascularisation

Corneal immunogenicity
  • Corneal immunogenicity is likely controlled by a
    multiplicity of factors, perhaps the most
    important of which is the human leukocyte antigen
    (HLA) system, which is the major
    histocompatibility complex in humans.
  • Four major loci on chromosome 6 code for the
    various tissue antigens. These loci have been
    designated HLA-A, B, and C (class I antigens) and
    HLA-DR (class II antigens). Class I antigens have
    been found on corneal epithelial, stromal, and
    endothelial cells,while Langerhans' cells, which
    are dendritic cells of mesenchymal origin located
    within the corneal epithelium, appear to be the
    primary cell type expressing class II
    antigens.Transient corneal cells of hematopoietic
    origin (primarily B lymphocytes and macrophages)
    may also express class II antigens.

  • Type IV cell-mediated immune reaction.
  • Role of CD-4 cells
  • Foreign MHC class II antigens act as a strong
    stimulus and can be recognized by host CD4 T
    cells. The host Langerhans cells can also
    process foreign class I antigen and present it in
    conjunction with self-class II molecules to host
    CD4 T cells. The result of either mechanism is
    CD4 T-cell activation. Activated CD4 T cells
    release IL-2 and other lymphokines that stimulate
    the proliferation and activation of CD4 T cells,
    cytotoxic T cells, and B lymphocytes.
  • Role of CD-8 cells
  • Host cytotoxic T cells (CD8 ) can recognize
    foreign class I cell-surface antigens on the
    surface of donor cells. They result in lysis of
    the donor cells. NK activity also has a
    cytotoxic role.
  • B Lymphocytes
  • Antibody production by B cells enables
    opsonization, complement binding, and
    facilitation of antibody-dependent cell-mediated
    cytotoxicity (K cell activity).
  • Exaggerated response by induction of donor MHC
    class II
  • CD8 T cells modulate the response by releasing
    cytokines such as interferon IFN-g. This induces
    class II antigen expression on donor cells.
    Increased class II antigen expression creates a
    positive feedback loop on the cell-mediated
    allograft rejection.

Survival Of PK (Coster)
  • 91 at 1 year
  • 75 5
  • 69 7
  • Loss is 35 at 1 year if corneal bed vascularised

The indications for penetrating keratoplasty
  • fall into the following four general categories
  • optical
  • tectonic
  • therapeutic
  • cosmetic

Preparation of Cornea
  • McCarey-Kaufman, Optisol, or Dexsol media. Some
    surgeons prefer to harvest their donor tissue
    from a fresh whole globe, although this is
    becoming unfeasible given the time delay
    necessitated by required serologic testing of the
    donor for hepatitis B and C, human
    immunodeficiency virus infection, and syphilis.

Indications for PK  
  • Keratoconus 30
  • Bullous Keratopathy 25
  • PreviousGraft18

Graft Rejection
  • Decreased visual acuity, tearing, photophobia,
  • elevated epithelial rejection line, stains with
    fluoroscein and Rose Bengal, progresses across
    cornea over days to 3 weeks. Not serious as
    normally the button is resurfaced with host
    epithelial cells
  • 0.2-0.5mm infiltrates beneath Bowman's with
    associated anterior chamber activityOften 10
    months after surgery.

Subepithelial infiltrates
  • Subepithelial infiltrates are small, discrete
    opacities located immediately beneath the
    epithelium that may be seen diffusely scattered
    across the graft They are very similar in
    appearance to the subepithelial lesions present
    in epidemic keratoconjunctivitis. The lesions can
    be subtle and are often missed with a narrow slit
    lamp beam they are best seen with a broad beam
    casting diffuse side illumination. Subepithelial
    infiltrates clear with topical corticosteroids
    but may leave a faint scar. They may be found at
    one time or another in about 15 of transplants
    and, like epithelial rejections, may be a sign of
    a generalized, low-grade, chronic immunologic
    reaction. We treat both epithelial rejection
    lines and subepithelial infiltrates with topical
    prednisolone sodium phosphate or acetate 1 every
    3 hours while awake. The patient should return in
    1 week, and, if improved, the drops are tapered
    by half every 3 days.

  • sudden onset, full thickness haze and
    circumcorneal injection

  • Khodadoust line - a line of keratoprecipitates
    moving centrally across the cornea followed by
    endothelial cell destruction.
  • Mild-moderate anterior chamber activity and
    stromal oedema
  • May be diffuse reaction affecting entire cornea.
  • Severe resulting in later corneal stromal

The signs of an endothelial rejection include-
  • The signs of an endothelial rejection include
    circumcorneal injection, an anterior chamber
    reaction, keratic precipitates present on the
    graft, an endothelial rejection line, and graft
    edema. The anterior chamber reaction is usually
    mild, frequently with no more than 1 cell or
    flare. The keratic precipitates may be diffusely
    scattered or grouped or may form an irregular
    line of precipitates (Khodadoust line) that
    begins at the graft periphery, often near an area
    of vascularization or synechial formation, and
    then progresses over the endothelial surface of
    the donor tissue, leaving in its wake a
    decompensated, edematous graft .
  • Histologically, lymphocytes are seen adherent to
    the endothelial surface, often separating
    destroyed endothelium from normal-appearing
    endothelial cells.

  • Topical steroids sufficient for more anterior
  • Oral prednisolone tapering over 2 weeks if poor
    response to topical treatment or endothelial
  • Cyclophosphamide / azathioprine / cyclosporin A

Other Complications
  • Many other complications can occur in the late
    postoperative period, some of which are peculiar
    to corneal transplant surgery and others of which
    may be seen after any intraocular surgery.
    Chronic progressive nonspecific endothelial
    decompensation manifests as a gradual onset of
    graft edema secondary to endothelial dysfunction
    not associated with prior rejection, uveitis, or
    glaucoma. Recurrence of host disease in the graft
    may be seen in several situations. Herpes simplex
    keratitis can frequently recur in the graft,
    whereas bacterial keratitis is far less common.
    Several of the corneal dystrophies may recur
    after penetrating keratoplasty, with Reis Buckler
    Reis-Bücklers' dystrophy being the most common.
  • Among the stromal dystrophies, lattice dystrophy
    recurs more frequently than either granular or
    macular dystrophy.

HSV- graft survival
  • HSV- graft survival 70 at 3 yearsCover post
    operatively with oral acyclovir / topical
    acyclovir in conjunction with the steroid
    drops.Corneal grafts affected by recurrent Herpes
    simplex have a typical appearance because the
    disease occurs at the graft interface (the cut
    ends of the corneal nerves presumably release
    virus at this location).

  • HSV- graft survival 70 at 3 yearsCover post
    operatively with oral acyclovir / topical
    acyclovir in conjunction with the steroid
    drops.Corneal grafts affected by recurrent Herpes
    simplex have a typical appearance because the
    disease occurs at the graft interface (the cut
    ends of the corneal nerves presumably release
    virus at this location).
  • HZO- poor candidates for grafts as decreased
    sensation, lid abnormalities, vascularisation,
    uveitis, glaucoma
  • Bacterial / fungal- source from donor tissue,
    host tissue and environment
  • Increased risk if loose sutures, steroids, KCS,
  • Acanthamoeba- primary or recurrent infection in
    graft. Suspect if poor response to usual
    antibiotic Rx

  • Irreversible graft oedema occurring in immediate
    post-op period 
  • Due to -
  • inadequate or prolonged corneal preservation,
    poor graft material, surgical trauma
  • effect of IOL
  • semiflexible closed loop A/C IOL or
  • iris supported IOLs have an increased incidence
    of graft failure.

  • May be pre-existing, aphakia, pseudophakia, PAS,
    A/C IOL related,
  • viscoelastic related

Transmission of donor disease
  • Transmission of donor disease to the host may
    occur and can be serious or even life
    threatening. Reports in the literature on
    transplantation of infected donor tissue into
    previously healthy recipients reveal cases of
    bacterial endophthalmitis, fungal
    endophthalmitis,fungal keratitis, and bacterial
    keratitis. Transmission of rabies into four
    patients and Creutzfeldt-Jakob disease in one
    patient have led to the death of each recipient.
  • Corneal tissue from five donors who at the time
    of their death were not known to be infected with
    the human immunodeficiency virus (HIV) has been
    transplanted into 10 healthy recipients. Serial
    antibody testing for HIV has not shown conversion
    from negative to positive in the recipients over
    a period of at least 130 days. One recipient has
    refused HIV testing but has remained healthy and
    symptom-free over a period of several years.
    Long-term follow-up of these individuals will
    determine whether HIV antibody seroconversion or
    development of the full acquired immunodeficiency
    syndrome may occur from transplantation of
    infected donor tissue.

Transmission of donor disease
  • Corneal donors are tested for hepatitis B and C,
    syphilis, and HIV infection. Positive tests
    preclude the use of this donor tissue for

CJD and the Eye
  • Creutzfeld-Jakob Disease (CJD) is a frightening
    but nonetheless intriguing disease. It occurs in
    most populations at approximately 1 case per
    million per year. It is referred to as classical
    or sporadic CJD to disitnguish it from new
    variant CJD (nvCJD) of which there have been to
    date a total of 25 cases and which is thought to
    be the human equivalent of bovine spongiform
    encephalopathy (BSE). Classical CJD is not
    contagious but has been transmitted by
    transplantation of cornea 1 (world total of 3
    cases), dura mater, pituitary growth hormone and
    by comtaminated neurosurgical instruments and
    cortical electrodes. Although there is rapidly
    progressive dementia invariably leading to death
    usually within months of onset, it is a diagnosis
    that is only confirmed postmortem by
    characteristic spongiform change or
    immunochemical identification of the pathological
    isoform of the prion protein in the brain.
    Although it has long been an absolute
    contraindication to corneal donation its
    exclusion can only be achieved by a low threshold
    of suspicion as there is as yet no serological
    screening test.

Eye Banking and Audit
  • All consultant ophthalmic surgeons who undertake
    ocular tissue transplantation should have
    knowledge of the procedure of eye procurement and
    banking, understand the unique risks involved and
    accept that they have ultimate responsibility for
    their patients who should be well informed.
  • All Medical Directors of Eye Banks should ensure
    that all ocular tissue is traceable to its
    destination. This includes tissue that is used in
    research or is discarded as unsuitable or surplus
    to requirement in addition to that used in
    recipient patients.
  • All consultant ophthalmologists and their junior
    staff who undertake transplantation of any kind
    should actively take part in routine long term
    follow-up of clinical outcome. Revised forms for
    transplant, six month and annual follow-up
    thereafter are currently being evaluated.

Action So Far
  • After receiving expert advice from the Spongiform
    Encephalopathy Advisory Group in December 1997,
    all surgeons offered the three patients
    explantation of ocular tissue. Two patients
    accepted the advice and had further surgery by
    January 1998. All three remain well.
  • The Duty Office at UKTSSA now routinely asks if a
    postmortem on a donor is pending. No tissue is
    issued form the CTS Banks in Bristol and
    Manchester until such time as the result is known
    (December 1997).
  • The CTS Eye Bank policy on sclera has been
    changed to ensure that sclera cannot be held in
    stock and that sclera from any single eye is not
    transplanted into more than one individual and
    can always be traced to a named recipient (i.e. a
    policy which is in line with corneal
  • Sir William Stewart chaired an expert group who
    undertook and subsequently published on behalf of
    the governemnt (April 1998) an independent review
    of the incident which contains recommendations.
    Copies can be obtained from Margaret Hallendorff
    at the College.
  • Guidelines for retrieval of donor eyes have now
    been accepted by the College and are available,
    including on this website. All ophthalmic units
    are expected to have read this document.
  • A re-designed ocular tissue donor information
    form and contrainidication list are now issued
    with UKTSSA retrieval boxes (July 1998).

Ocular Tissues Standards and Audit Group (OTSAG)
  • The recommendations of the Stewart report are
    under active consideration principally by the
    Ocular Tissues Standards and Audit Group (OTSAG).
    This Group was established in 1996 and seeks to
    define essential and best practice in the fields
    of ocular and non-ocular tissue transplantation.
    The following proposals are currently under
  • The Royal College of Ophthalmologists should
    develop a portfolio of documents defining
    standards in the transplantation of the cornea,
    sclera and all other ocular and non-ocular
    tissues into the human eye.
  • The portfolio should be compiled and updated by
    OTSAG which is accountable to the Royal College
    of Ophthalmologists and to the Corneal Advisory
    Group at UKTSSA.
  • All units regularly undertaking ocular tissue
    transplantation should contribute to the supply
    of ocular tissue for transplantation and research
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