Corneal Allograft Rejection

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BY SURASARIT KHAWLAOR CORNEAL ALLOGRAFT REJECTION 1

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Transcript of Corneal Allograft Rejection

Page 1: Corneal Allograft Rejection

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BY

SURASARIT KHAWLAOR

CORNEAL ALLOGRAFT

REJECTION

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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

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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

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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

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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.

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Mechanism of immunosuppressive

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