1
BY
SURASARIT KHAWLAOR
CORNEAL ALLOGRAFT
REJECTION
2
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
3
STRUCTURE OF CORNEA
Consist of 3 major layersAnterior surface : 6-8 cell-deep
epithelial layerMain thickness (stroma) : collagen fiber
supported by scattered keratocytesPosterior surface : endothelial
monolayer (maintenance of corneal transparency) & supported by Descemet’s membrane
Hongmei Fu.Transplantation Reviews 2008;105-115
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STRUCTURE OF CORNEA
Hongmei Fu.Transplantation Reviews 2008;105-115
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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
Hongmei Fu.Transplantation Reviews 2008;105-115
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IMMUNE PRIVILEGE OF CORNEA
Cornea is immune privileged tissue Absence of lymphatic & blood
vessels in corneal graft bedExpression of Fas ligand on corneal
cells Low-level expression of MHC class I
and II molecules on corneal cellsPaucity of indigenous professional
antigen-presenting mФ, Langerhans cells Hongmei Fu.Transplantation Reviews
2008;105-115
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IMMUNE PRIVILEGE OF CORNEA
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
Hongmei Fu.Transplantation Reviews 2008;105-115
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IMMUNE PRIVILEGE OF CORNEA
rejection rate at the final observation (8 weeks) in the FasL- group (89%)
was significantly higher than in the FasL+ control
group (47%)
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IMMUNE PRIVILEGE OF CORNEA
Jerry Y. Niederkorn. Ocular Immunology & Inflammation 2010; 18(3); 162–171
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IMMUNE PRIVILEGE OF CORNEA
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
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ACAID
J.Wayne Streilein. NATURE REVIEWS IMMUNOLOGY 2003 :879-880
camero-splenic axis
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IMMUNE PRIVILEGE OF CORNEA
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)
J.Wayne Streilein. NATURE REVIEWS IMMUNOLOGY 2003 :879-880
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IMMUNE PRIVILEGE OF CORNEA
J.Wayne Streilein. NATURE REVIEWS IMMUNOLOGY 2003 :879-880
Wilbanks, G. A 1992
Taylor, A. W. 1992
Taylor, A. W. 1994
Taylor, A. W.
1998
Sheibani, N.
2000
Sohn, J. H., 2000
Kennedy, M. C. 1995
Apte, R. S. 1998
Sugita, S. et al. 2000
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IMMUNE PRIVILEGE OF CORNEA
Junko Hori. Cornea 2009; 28(9): S58-S64
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IMMUNE PRIVILEGE OF CORNEA
Conclusion Immune privilege consists of 3
majors mechanism1) Anatomical, molecular barriers in
eye2) Eye-derived immunological
tolerance known as “ACAID”3) Immune suppressive intraocular
microenvironment
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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
17
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
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CORNEAL ALLOGRAFT REJECTION
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
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CORNEAL ALLOGRAFT REJECTION
Common indications to perform keratoplasty therapeutic (e.g. keratoconus, corneal ulcer) cosmetic (e.g. removing an unsightly opacity)
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CORNEAL ALLOGRAFT REJECTIONRISK FACTORS
Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113
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CORNEAL ALLOGRAFT REJECTIONTYPES 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
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CORNEAL ALLOGRAFT REJECTIONTYPES 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
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CORNEAL ALLOGRAFT REJECTIONCLINICAL FEATURES
Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113
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CORNEAL ALLOGRAFT REJECTION
Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016
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CORNEAL ALLOGRAFT REJECTION
Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
DJ Coster et al. Eye 2009; 23: 1894-1897
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
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
DJ Coster et al. Eye 2009; 23: 1894-1897
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
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
DJ Coster et al. Eye 2009; 23: 1894-1897Hongmei Fu et al. Transplantation Review 2008; 22:
105-115
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
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016
conclusion
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
peripheral
Blood rejection control
During
rejection Aq. Humor peripheral
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
cytometric bead array of inflammatory cytokines & chemokines
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CORNEAL ALLOGRAFT REJECTION IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
Conclusion Few absolute principles
T cell-dependent Heavily depent upon CD4+ T cells Dependent upon intact repertoire of
resident APC (macrophage, monocyte)
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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
38
PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
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
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 retrospectivestudy over 12 years Smiddy et al.(1986) state incidence to beapproximately 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
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
Dj Coster and KA Williams. Eye 2003; 17: 996-1002
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
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
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
Price MO and Price FW Jr. Ophthalmology 2006; 113(10): 1785-1790
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
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
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
Alexander Poon FRANZCO et al. Clinical and Experimental Ophthalmology 2008; 36: 415-421
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
Alexander Poon FRANZCO et al. Clinical and Experimental Ophthalmology 2008; 36: 415-421
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PREVENTION OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113
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)
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
T Hudde et al. British Journal of Ophthalmology 1999; 83: 1348-1352
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
T Hudde et al. British Journal of Ophthalmology 1999; 83: 1348-1352
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113
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
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113
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)
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
Alexander Reis et al. British Journal of Ophthalmology 1999; 83: 1268-1271
In severe case of rejection(cont.) In 1999 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
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
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
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TREATMENT OF CORNEAL ALLOGRAFT
REJECTION
A Joseph et al. British Journal of Ophthalmology 2007; 91: 51-55
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.
Mechanism of immunosuppressive
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