Corneal Graft Rejection and Graft Failure

1
Corneal Graft Rejection andGraft Failure
2
CORNEAL GRAFT FAILURE

• PRIMARY GRAFT FAILURE
• REJECTION Khodadoust line rejection line
  stromal oedema
• INFECTION
• RAISED IOP
• DISEASE RECURRENCE
• DELAYED ENDOTHELIAL FAILURE
• WOUND DEHISCENCE (TRAUMA)

3
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

4
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)

5
  Factors which unfavourably regulate immune
privilege

• Langerhan's APC Cells
• Neovascularisation

6
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.

7
MECHANISM OF CORNEAL GRAFT FAILURE

• 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.

8
Survival Of PK (Coster)

• 91 at 1 year
• 75 5
• 69 7
• Loss is 35 at 1 year if corneal bed vascularised

9
The indications for penetrating keratoplasty

• fall into the following four general categories
• optical
• tectonic
• therapeutic
• cosmetic

10
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.

11
Indications for PK  

• Keratoconus 30
• Bullous Keratopathy 25
• PreviousGraft18

12
Graft Rejection

• CLINICAL FEATURES
• Decreased visual acuity, tearing, photophobia,
• EPITHELIAL REJECTION
•  
• 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
•  
• SUBEPITHELIAL REJECTION
•  
• 0.2-0.5mm infiltrates beneath Bowman's with
  associated anterior chamber activityOften 10
  months after surgery.

13
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.

14
STROMAL REJECTION

•  
• sudden onset, full thickness haze and
  circumcorneal injection

15
ENDOTHELIAL REJECTION

• 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
  neovascularisation.

16
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.

17
IMMUNE PRINCIPLES OF GRAFT REJECTION

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

18
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.

19
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).

20
GRAFT INFECTIONS

•  
• 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,
  HSV
• Acanthamoeba- primary or recurrent infection in
  graft. Suspect if poor response to usual
  antibiotic Rx

21
PRIMARY DONOR FAILURE

• 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.

22
GLAUCOMA

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

23
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.

24
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
  transplantation

25
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.

26
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.

27
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
  transplantation)
• 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).

28
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
  consideration
• 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
  nationwide.