5. 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
6. 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
Hongmei Fu.Transplantation Reviews 2008;105-115
7. 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
8. 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%)
9. IMMUNE PRIVILEGE OF CORNEA
Jerry Y. Niederkorn. Ocular Immunology & Inflammation 2010; 18(3); 162–171
10. 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
12. 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
13. IMMUNE PRIVILEGE OF CORNEA
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
J.Wayne Streilein. NATURE REVIEWS IMMUNOLOGY 2003 :879-880
15. IMMUNE PRIVILEGE OF CORNEA
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
16. 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
18. 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
19. CORNEAL ALLOGRAFT REJECTION
Common indications to perform keratoplasty
therapeutic(e.g. keratoconus, corneal ulcer)
cosmetic (e.g. removing an unsightly opacity)
20. CORNEAL ALLOGRAFT REJECTION
RISK FACTORS
Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113
21. CORNEAL ALLOGRAFT REJECTION
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
22. CORNEAL ALLOGRAFT REJECTION
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
23. CORNEAL ALLOGRAFT REJECTION
CLINICAL FEATURES
Tham and Abbott. International Ophthalmology Clinic 2002;42(1):105-113
26. CORNEAL ALLOGRAFT REJECTION
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
27. CORNEAL ALLOGRAFT REJECTION
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
DJ Coster et al. Eye 2009; 23: 1894-1897
28. CORNEAL ALLOGRAFT 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
DJ Coster et al. Eye 2009; 23: 1894-1897
Hongmei Fu et al. Transplantation Review 2008; 22: 105-115
29. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
conclusion
Jerry Y. Niederkorn. Current Eye Research 2007; 32: 1005-1016
32. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
33. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
34. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
peripheral During
Blood rejection
rejection Aq. Humor
peripheral
control
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
35. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
cytometric bead array of inflammatory cytokines & chemokines
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
36. CORNEAL ALLOGRAFT REJECTION
IMMUNE MECHANISM
Conclusion
Few absolute principles
T cell-dependent
Heavily depent upon CD4+ T cells
Dependent upon intact repertoire of resident
APC (macrophage, monocyte)
T.H. Flynn et al. American Journal of Transplantation 2008; 8: 1537-1543
37. 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
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
39. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
Dj Coster and KA Williams. Eye 2003; 17: 996-1002
40. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
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
41. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
42. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
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
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
43. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
44. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
45. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
Price MO and Price FW Jr. Ophthalmology 2006; 113(10): 1785-1790
46. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
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
47. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
Alexander Poon FRANZCO et al. Clinical and Experimental Ophthalmology 2008; 36: 415-421
48. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
Alexander Poon FRANZCO et al. Clinical and Experimental Ophthalmology 2008; 36: 415-421
49. PREVENTION OF CORNEAL ALLOGRAFT REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
50. 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
52. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
J. Bradley Randleman and R. Doyle Stulting. Cornea 2006; 25(3): 286-290
53. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
T Hudde et al. British Journal of Ophthalmology 1999; 83: 1348-1352
54. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
T Hudde et al. British Journal of Ophthalmology 1999; 83: 1348-1352
55. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
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
Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113
56. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
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)
Vivien M.-B. Tham and Richard L. Abbott. International Ophthalmology Clinics 2002; 42(1): 105-113
57. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
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
58. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
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
59. TREATMENT OF CORNEAL ALLOGRAFT REJECTION
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