Corneal Allograft Rejection

CORNEAL ALLOGRAFT
REJECTION

BY

SURASARIT KHAWLAOR

OUTLINES

 STRUCTURE OF CORNEA, ENDOTHELIAL FUNCTION
AND IMMUNE PRIVILEGE
 CORNEAL ALLOGRAFT REJECTION

 Keratoplasty

 Risk factor & Types of rejection
 clinical features
 Immune mechanism of corneal allograft rejection
 PREVENTION & TREATMENT OF CORNEAL
ALLOGRAFT REJECTION

STRUCTURE OF CORNEA

 Consist of 3 major layers
 Anterior surface : 6-8 cell-deep epithelial
layer
 Main thickness (stroma) : collagen fiber
supported by scattered keratocytes
 Posterior surface : endothelial monolayer
(maintenance of corneal transparency) &
supported by Descemet’s membrane

Hongmei Fu.Transplantation Reviews 2008;105-115

STRUCTURE OF CORNEA


ENDOTHELIAL FUNCTION

 Endothelial cells
 nonreplicative in humans
 pump water from stroma to anterior
chamber
 If loss of sig. number  decompensation of
pump function  stromal swelling  loss
of transparency & vision


IMMUNE PRIVILEGE OF CORNEA

 Cornea is immune privileged tissue
 Absence of lymphatic & blood vessels in
corneal graft bed
 Expression of Fas ligand on corneal cells

 Low-level expression of MHC class I and II
molecules on corneal cells
 Paucity of indigenous professional antigen-
presenting mФ, Langerhans cells


 Cornea is immune privileged tissue(cont.)
 Phenomenon of anterior chamber-associated
immune deviation (ACAID)
down regulation of systemic DTH from
alloantigens in anterior chamber
 Presence of immunomodulatory cytokines in
aqueous humor in anterior chamber such as
Α-melanocyte-stimulating hormone
Transforming growth factor



rejection rate at the final
observation (8 weeks) in the
FasL- group (89%) was
significantly higher than in
the FasL+ control group
(47%)


Jerry Y. Niederkorn. Ocular Immunology & Inflammation 2010; 18(3); 162–171


 Anterior chamber–associated immune
deviation (ACAID)
 form of eye-derived tolerance which TH1 & TH2-
mediated immunity is suppressed
 characterized by a selective deficiency in delayed
type hypersensitivity (DTH) and Ig isotypes that
fix complement

Koh-Hei Sonoda . J. Exp. Med 1999 ; 190 (9): 1215–1225

ACAID

camero-splenic axis

J.Wayne Streilein. NATURE REVIEWS IMMUNOLOGY 2003 :879-880


 Anterior chamber–associated immune
deviation (ACAID)
 CD4+ Treg known as “afferent Treg” suppress
initial activation & differentiation of naïve T cell
into TH1 effector cells : secondary lymphoid
organs
 CD8+ Treg known as “efferent Treg” inhibit
expression of TH1-mediated immunity, such as
DTH : periphery(eye)



Wilbanks, G. A 1992

Taylor, A. W. 1992

Taylor, A. W. 1994

Taylor, A. W. 1998

Sheibani, N. 2000

Apte, R. S. 1998
Kennedy, M. C. 1995

Sohn, J. H., 2000

Sugita, S. et al. 2000



Junko Hori. Cornea 2009; 28(9): S58-S64


 Conclusion
 Immune privilege consists of 3 majors
mechanism
1) Anatomical, molecular barriers in eye
2) Eye-derived immunological tolerance
known as “ACAID”
3) Immune suppressive intraocular
microenvironment

CORNEAL ALLOGRAFT REJECTION

 Keratoplasty
 plastic surgery of the cornea
 lamellar keratoplasty

a partial thickness graft of the cornea
only epithelium and superficial stroma is
removed
replaced by donor tissue from penetrating or
full-thickness grafting


 Keratoplasty (cont.)
 optic keratoplasty
 transplantation of corneal material to replace scar
tissue that interferes with vision
 penetrating keratoplasty

 a full thickness of the cornea is removed and
replaced with donor tissue, 1st performed in 1906
 tectonic keratoplasty

transplantation of corneal material to replace
tissue that has been lost


 Common indications to perform keratoplasty
 therapeutic(e.g. keratoconus, corneal ulcer)
 cosmetic (e.g. removing an unsightly opacity)

RISK FACTORS

Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113

TYPES OF REJECTION

A. Epithelial rejection
 host epithelium grows inward from remaining host
cornea & limbus to cover the graft
B. Subepithelial rejection
 subepithelial infiltrates with leukocytes
 Both types are
 steroid responsive
 generally self-limited
 tends not to cause visual disturbance
 asymptomatic or only of minimal irritation

TYPES OF REJECTION

C. Endothelial rejection
 Classic rejection presents with endothelial
rejection line (Khodadoust line : consist of
mononuclear white cells) usually begins at
vasculaized portion of peripheral graft-host
junction & progress across endothelial surface
 Damaged endothelium is unable to dehydrate
corneal graft  cloudy & edematous stroma

CLINICAL FEATURES



Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016

IMMUNE MECHANISM

 Inflamed cornea contribute to erosion of
privilege
 With inflammation
 Bone marrow-derived cells are recruited into cornea through
limbal circulation
 Those cells capable of processing & presenting antigens 
when inflammation is resolved  persist for months or years
 The greater number of bone marrow-derived cells in host
cornea at time of surgery the higher the rejection rate
 Chronic inflammation induces generation of blood vessels &
lymphatics in normally avascular cornea

DJ Coster et al. Eye 2009; 23: 1894-1897

IMMUNE MECHANISM

 With inflammation (cont.)
 Induces vessels to leak, facilitating ingress of
cells & proteins into cornea
 Macrophage produce VEGF-C which induce
growth of lymphatics
 Pro-inflammatory cytokines gain access to
cornea & anterior chamber  encourage
rejection


IMMUNE MECHANISM

 Antigen processing can occur at cornea, ocular
environs and draining lymph nodes
 Recipient T cells recognition of donor MHC
alloantigens plays central role in rejection by 2
mechanisms
 Direct pathway : donor APCs are recognized directly by recipient T
cells (important role in acute graft rejection)
 Indirect pathway : recipient APCs process antigen then present it
to recipient T cells (associated with chronic graft rejection)
 Direct pathway weakens with time (donor APCs migrate out of
graft) but indirect be permanently active cause of recipient
APCs traffic through the graft

Hongmei Fu et al. Transplantation Review 2008; 22: 105-115

IMMUNE MECHANISM

conclusion


IMMUNE MECHANISM


IMMUNE MECHANISM

T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543

IMMUNE MECHANISM
peripheral During
Blood rejection
rejection Aq. Humor
peripheral
control


IMMUNE MECHANISM

cytometric bead array of inflammatory cytokines & chemokines


IMMUNE MECHANISM

 Conclusion
 Few absolute principles
T cell-dependent
Heavily depent upon CD4+ T cells
Dependent upon intact repertoire of resident
APC (macrophage, monocyte)


OUTLINES

 STRUCTURE OF CORNEA, ENDOTHELIAL FUNCTION
AND IMMUNE PRIVILEGE
 CORNEAL ALLOGRAFT REJECTION

 Keratoplasty

 Risk factor & clinical features
 Immune mechanism of corneal allograft rejection
 PREVENTION & TREATMENT OF CORNEAL
ALLOGRAFT REJECTION

PREVENTION OF CORNEAL ALLOGRAFT REJECTION

 Incidence of corneal graft rejection from 2.3%-68% in
different studies, at least one episode of rejection may occur
30% of graft
 Polack(1973) report an incidence of homograft rejection in
good prognosis cases to be 9–12%, whereas in retrospective
study over 12 years Smiddy et al.(1986) state incidence to be
approximately 16%
 Overall
 12% of low-risk
 40% of high-risk
 Rejection most common occurs 4-18 Mo following
transplantation (may seen any time after surgery)
53.3% occurr during the 1st year after transplantation
Alireza Baradaran-Rafii et al. Iranian Journal of Ophthalmic Research 2007; 2(1) : 7-14
Sangwan VS et al. Clin Experiment Ophthalmol 2005; 33(6):623-627


Dj Coster and KA Williams. Eye 2003; 17: 996-1002


 Low risk
 Topical corticosteroids (prednisolone) still universally
used for routine postoperative management during 1st 6
Mo, after 6 Mo generally prescribed less frequently
 25% switch to loteprednol, 20% to fluorometholone in
phakic patients (due to their lesser effect on intraocular
pressure )
 In Pseudophakic/Aphakic eyes topical corticosteroids
(prednisolone) used as phakic patients but % usage of
this preparation increased greater than the latter

J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290


 Intermediate-high risk
 Topical corticosteroids (prednisolone) still universally
used for routine postoperative management during 1st
6 Mo, and remained high % usage after that
 Topical cyclosporine is used about 48%, evidences are
controversial
 Sytemic steroids (oral)
 In USA used lesser than before , compared in 1989 and
2004
 In UK used greater than in USA



Price MO and Price FW Jr. Ophthalmology 2006; 113(10): 1785-1790


regimen B had
sig. more
rejection than
regimen A

regimen
C did not
reduce
incidence
of rejection

Price MO and Price FW Jr. Ophthalmology 2006; 113(10): 1785-1790


Alexander Poon FRANZCO et al. Clinical and Experimental Ophthalmology 2008; 36: 415-421

TREATMENT OF CORNEAL ALLOGRAFT REJECTION

 Hill and colleagues (1991) demonstrated in
prospective study that
 IV methylprednisolone 500 mg single dose was more
effective and better tolerated than daily oral
prednisolone 60-80 mg when combined with topical
steroids in graft rejection
 Survival rate of graft 92% versus 55% when pts. were
treated within 8 days of onset of symptoms
(no difference in outcome in who presented later
than day 8)

Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113


T Hudde et al. British Journal of Ophthalmology 1999; 83: 1348-1352


 In case of mild rejection
 Topical prednisolone acetate 1% hourly and
dexamethasone ointment at night was sufficient to
reverse the rejection
 In severe case of rejection
 Topical prednisolone acetate 1% hourly, one dose of
pulsed IV methylprednisolone 500 mg and oral
prednisolone 1 mg/kg/day for 5 days were recommended

The collaborative corneal transplantation studies
Arch Ophthalmol 1992;110:1392–1403



 In severe case of rejection(cont.)
 In 1989 Hill found that graft survival improved if
systemic cyclosporine was used in addition to
systemic & topical steroids (89%) compared to
use of topical steroids alone (10%)
Maximum effect was obtained if cyclosporine
was used for 12 Mo (93% survival rate)
compared with 6 Mo (69% survival rate)



 In severe case of rejection(cont.)
 In1999 Alexander Reis et al. reported a
prospectively randomised clinical trial about
mycophenolate mofetil versus cyclosporn A
Due to wide range of S/E of cyclosporin A
(diabetogenicity, arterial hypertension, HLP,
nephrotoxicity) which could be found about
10% and to need lab. monitoring of drug levels
between 120-150 ng/ml  very costly

Alexander Reis et al. British Journal of Ophthalmology 1999; 83: 1268-1271


MMF is just as effective
as CSA in preventing
acute rejection
following high risk
corneal transplantation

Alexander Reis et al. British Journal of Ophthalmology 1999; 83: 1268-1271


 Recent study from Joseph A and colleagues found that
systemic tacrolimus daily dose 2.5 mg is safe and
effective in reducing rejection & prolonging graft
survival in pts. With high-risk keratoplasty compared
with pts who did not use.

A Joseph et al. British Journal of Ophthalmology 2007; 91: 51-55

Mechanism of immunosuppressive

Corneal Allograft Rejection

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