Transcript Corneal Graft Rejection

Corneal Graft Rejection and
Graft Failure
CORNEAL GRAFT FAILURE
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PRIMARY GRAFT FAILURE
REJECTION ´Khodadoust´ line rejection line:
stromal oedema:
INFECTION
RAISED IOP
DISEASE RECURRENCE
DELAYED ENDOTHELIAL FAILURE
WOUND DEHISCENCE (TRAUMA)
Rejection of Solid Allografts,
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Classification
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1 Hyperacute- preformed antibody
2 Acute- < 4 weeks
Activation of T cell clones and destruction of graft by cytotoxic T cells
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3 Chronic -usually progressive
immunosupressive therapy
Cornea =endothelial loss, mainly
arteriolitis
refractory
to
Immune Privilege in the Eye
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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
privilege
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Langerhan's APC Cells
Neovascularisation
Corneal immunogenicity
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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.
MECHANISM OF CORNEAL GRAFT
FAILURE
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Type IV cell-mediated immune reaction.
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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.
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Survival Of PK (Coster)
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91% at 1 year
75% 5
69% 7
Loss is 35% at 1 year if corneal bed
vascularised
The indications for penetrating
keratoplasty
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fall into the following four general
categories:
optical
tectonic
therapeutic
cosmetic
Preparation of Cornea
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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
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Keratoconus 30%
Bullous Keratopathy 25%
 PreviousGraft18%
Graft Rejection
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CLINICAL FEATURES
Decreased visual acuity, tearing, photophobia,
EPITHELIAL REJECTION
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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
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SUBEPITHELIAL REJECTION
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0.2-0.5mm infiltrates beneath Bowman's with associated anterior
chamber activityOften 10 months after surgery.
Subepithelial infiltrates
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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.
STROMAL REJECTION
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sudden onset, full thickness
haze
and
circumcorneal
injection
ENDOTHELIAL REJECTION
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´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.
The signs of an endothelial rejection
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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 normalappearing endothelial cells.
IMMUNE PRINCIPLES OF GRAFT
REJECTION
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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
Other Complications
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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
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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).
GRAFT INFECTIONS
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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
PRIMARY DONOR FAILURE
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Irreversible graft oedema occurring in immediate post-op period
Due to :-
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inadequate or prolonged corneal preservation, poor graft material,
surgical trauma
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effect of IOL
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semiflexible closed loop A/C IOL or
iris supported IOLs have an increased incidence of graft failure.
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GLAUCOMA
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May be pre-existing, aphakia,
pseudophakia, PAS, A/C IOL related,
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viscoelastic related
Transmission of donor disease
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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.
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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
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Corneal donors are tested for
hepatitis B and C, syphilis, and
HIV infection. Positive tests
preclude the use of this donor
tissue for transplantation
CJD and the Eye
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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
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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
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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).
Ocular Tissues Standards and Audit Group
(OTSAG)
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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 nonocular 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.