Contents

Chapter 1

2.4

The Corneal Allograft Response. . . . . . . . .

15

Immune Privilege of Corneal Allografts

2.5

Antigen Uptake in the Eye . . . . . . . . . . . . . .

15

Jerry Y. Niederkorn

2.6

Antigen Processing. . . . . . . . . . . . . . . . . . . . .

16

1.1

History of Corneal Transplantation

2.7

Antigen Presentation. . . . . . . . . . . . . . . . . . .

16

2.8

T Cell Activation, Proliferation,

and Immune Privilege

1

and Clonal Expansion

17

1.2

How Successful Is Corneal

2.9

E ector Arm of the Allograft

Transplantation?

2

Response

17

1.3

Immune Rejection

2.10

Current Management of Corneal

of Corneal Allografts

3

Transplants

17

1.3.1

Role of CD4+ T Lymphocytes

2.11

Prevention of Allograft Rejection

17

in Corneal Allograft Rejection

3

2.12

Stratification of Risk

18

1.3.2

Role of CD8+ T Lymphocytes

2.13

Protecting Immune Privilege

18

in Corneal Allograft Rejection

3

2.14

Minimizing Antigenic Di erences

1.3.3

Role of Antibodies in Corneal

Between Donor and Recipient

18

Allograft Rejection

4

2.15

Systemic Immunosuppression

18

1.3.4

Role of Macrophages and NK

2.16

Surgical Techniques

Cells in Corneal Allograft Rejection

4

and Postoperative Management

18

1.3.5

What are the E ectors of Corneal

2.17

Management of Acute Rejection

Allograft Rejection?

5

Episodes

19

1.4

Role of Atopic Diseases in Corneal

2.18

New Therapies with Novel

Allograft Rejection

5

Mechanisms

19

1.5

Immune Privilege of Corneal Allografts

2.19

Antibody-based Immunosuppressive

Is a Tripartite Phenomenon

5

Agents in Transplantation

19

1.5.1

A erent Blockade of the Immune

2.20

Engineered Antibodies for Eye Disease

19

Response to Corneal Allografts

6

2.21

Gene Therapy of the Donor Cornea

20

1.5.2

Immune Deviation in the Central

2.22

Vectors for Gene Therapy

Processing Component

of the Cornea

20

of the Immune Reflex Arc

8

2.23

Transgenes for Prolonging Corneal

1.5.3

E erent Blockade of the Immune

Graft Survival

20

Response to Corneal Allografts

9

2.24

Future Prospects

20

References

10

References

22

Chapter 2

Chapter 3

Mechanisms of Corneal Allograft Rejection

New Developments in Topical and Systemic

and the Development of New Therapies

Immunomodulation Following Penetrating

Douglas J. Coster, Claire F. Jessup,

Keratoplasty

and Keryn A. Williams

Alexander Reis and Thomas Reinhard

2.1

Status of Corneal Transplantation . . . . . . .

13

3.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .

25

2.2

Success Rate of Corneal

3.2

Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . .

26

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

13

3.2.1

Acute Rejection . . . . . . . . . . . . . . . . . . . . . . . .

26

2.3

Maintenance and Erosion of Corneal

3.2.2

Major Histocompatibility

Privilege . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

Complex (MHC) . . . . . . . . . . . . . . . . . . . . . . . .

26

3.2.2.1

Direct Pathway of Allorecognition . . . . . .

26

4.1.1

Anterior Chamber-Associated

3.2.2.2

Indirect Pathway of Allorecognition. . . . .

26

Immune Deviation (ACAID) . . . . . . . . . . . . .

38

3.2.3

Chronic Rejection . . . . . . . . . . . . . . . . . . . . . .

26

4.1.2

The Th1/Th2 Paradigm . . . . . . . . . . . . . . . . .

38

3.3

Normal-risk vs. High-risk

4.2

Pitfalls in the Determination

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

27

of Cytokine Levels from Aqueous

3.3.1

Normal-risk Transplantation . . . . . . . . . . . .

27

Humor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38

3.3.2

High-risk Transplantation . . . . . . . . . . . . . . .

27

4.3

Relevance of Individual Cytokines

3.3.3

Rationale for Systemic

in Corneal Transplantation. . . . . . . . . . . . . .

40

Immunosuppression . . . . . . . . . . . . . . . . . . .

27

4.3.1

Interleukin 1b . . . . . . . . . . . . . . . . . . . . . . . . . .

40

3.3.4

Why Is Immunomodulation

4.3.1.1

General Functions from In Vitro

with Topical Steroids Not Su cient to

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

Prevent Immunologic Graft Rejection

4.3.1.2

E ects in Animal Models of Corneal

in High-Risk Patients? . . . . . . . . . . . . . . . . . .

27

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

40

3.3.5

Rationale for Topical

4.3.1.3

Interleukin 1b Levels in Human

Immunomodulation. . . . . . . . . . . . . . . . . . . .

27

Aqueous Humor . . . . . . . . . . . . . . . . . . . . . . .

40

3.4

Immunosuppressive Agents . . . . . . . . . . . .

28

4.3.2

Interleukin 2 . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

3.4.1

History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

4.3.2.1

General Functions from In Vitro

3.4.2

Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . .

28

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

3.4.3

Cyclosporine A . . . . . . . . . . . . . . . . . . . . . . . . .

28

4.3.2.2

E ects in Animal Models of Corneal

3.4.3.1

CSA in Corneal Transplantation . . . . . . . . .

29

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

40

3.4.4

Tacrolimus (fk506). . . . . . . . . . . . . . . . . . . . . .

29

4.3.2.3

Interleukin 2 Levels in Human Aqueous

3.4.4.1

Tacrolimus in Corneal Transplantation . .

29

Humor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

3.4.5

Mycophenolate Mofetil (MMF). . . . . . . . . .

29

4.3.3

Interleukin 6 . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

3.4.6

Rapamycin (Sirolimus). . . . . . . . . . . . . . . . . .

30

4.3.3.1

General Functions from In Vitro

3.4.7

RAD (Everolimus). . . . . . . . . . . . . . . . . . . . . . .

30

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

3.4.8

FTY 720 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31

4.3.3.2

E ects in Animal Models of Corneal

3.4.9

FK788. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31

Transplantatoin . . . . . . . . . . . . . . . . . . . . . . . .

41

3.5

Pimecrolimus . . . . . . . . . . . . . . . . . . . . . . . . . .

31

4.3.3.3

Interleukin 6 Levels in Human Aqueous

3.5.1

Pimecrolimus in Corneal

Humor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

31

4.3.4

Interleukin 10 . . . . . . . . . . . . . . . . . . . . . . . . . .

41

3.5.2

Biologic Agents . . . . . . . . . . . . . . . . . . . . . . . .

31

4.3.4.1

General Functions from In Vitro

3.5.2.1

Basiliximab and Daclizumab . . . . . . . . . . . .

31

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

3.6

Guidelines for Practitioners . . . . . . . . . . . . .

32

4.3.4.2

E ects in Animal Models of Corneal

3.6.1

Systemic Immunosuppression

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

41

with Drugs with Proven E cacy

4.3.4.3

Interleukin10 Levels in Human

in Corneal Transplantation. . . . . . . . . . . . . .

32

Aqueous Humor . . . . . . . . . . . . . . . . . . . . . . .

41

3.6.1.1

Preoperative Evaluation . . . . . . . . . . . . . . . .

32

4.3.5

Interferon Gamma (IFN-g). . . . . . . . . . . . . . .

42

3.6.1.2

How to Use Cyclosporine in High-risk

4.3.5.1

General Functions from In Vitro

Corneal Transplantation . . . . . . . . . . . . . . . .

32

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

3.6.1.3

How to Use MMF in High-risk Corneal

4.3.5.2

E ects in Animal Models of Corneal

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

32

Transplantation . . . . . . . . . . . . . . . . . . . . . . . .

42

3.6.2

Topical Immunosuppression. . . . . . . . . . . .

33

4.3.5.3

INF-g Levels in the Aqueous Humor . . . . .

42

3.7

Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

4.3.6

Tumor Necrosis Factor Alpha (TNF-a) . . .

42

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

4.3.6.1

General Functions from In Vitro

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

Chapter 4

4.3.6.2

E ects in Animal Models of Corneal

Transplantation

42

Cytokines Analysis of the Aqueous Humor in the

Context of Penetrating Keratoplasty

4.3.6.3

TNF-α Levels in Human Aqueous

Philip Maier and Thomas Reinhard

Humor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

4.3.7

Transforming Growth Factor Beta

4.1

Immune Privilege of the Anterior

(TGF-β) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43

Ocular Segment. . . . . . . . . . . . . . . . . . . . . . . .

38

4.3.7.1

General Functions from In Vitro

Chapter 5

6.1

Relationship of Endothelial Barrier

Limbal Stem Cell Transplantation:

Function to Corneal Transparency

70

Surgical Techniques and Results

Alex J. Shortt, Stephen J. Tuft, and Julie T. Daniels

6.2

Corneal Endothelial Cell Loss

and Repair Mechanisms

71

5.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .

53

6.2.1

Causes of Cell Loss . . . . . . . . . . . . . . . . . . . . .

71

5.1.1

The Corneal Epithelium. . . . . . . . . . . . . . . . .

53

6.2.2

Repair of the Endothelial

5.1.2

The Limbus and Corneal Epithelial

Monolayer . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71

Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . .

53

6.3

Are Human Corneal Endothelial

5.2

Corneal LESC Deficiency. . . . . . . . . . . . . . . .

55

Cells Able to Divide?. . . . . . . . . . . . . . . . . . . .

71

5.2.1

Diagnosis and Classification

6.3.1

Proliferative Status In Vivo . . . . . . . . . . . . . .

71

of Corneal LESC Deficiency . . . . . . . . . . . . .

55

6.3.2

Evidence that HCEC Retain

5.3

Management of Patients with Limbal

Proliferative Capacity. . . . . . . . . . . . . . . . . . .

71

Stem Cell Deficiency . . . . . . . . . . . . . . . . . . .

57

6.4

The Cell Cycle . . . . . . . . . . . . . . . . . . . . . . . . . .

72

5.3.1

Conservative Options . . . . . . . . . . . . . . . . . .

57

6.4.1

Positive Regulation of the Cell Cycle . . . .

72

5.3.2

Surgical Options for Partial Limbal

6.4.2

Negative Regulation of G1-Phase

Stem Cell Deficiency . . . . . . . . . . . . . . . . . . .

57

of the Cell Cycle . . . . . . . . . . . . . . . . . . . . . . . .

73

6.5

Potential Causes for Inhibition

7.3.2.4

Hybrid Lenses. . . . . . . . . . . . . . . . . . . . . . . . . .

89

of HCEC Proliferation In Vivo . . . . . . . . . . . .

74

7.3.3

Fitting Techniques. . . . . . . . . . . . . . . . . . . . . .

89

6.5.1

Cell–Cell Contacts Inhibit Division . . . . . .

74

7.3.3.1

The Reshape and Splint Method . . . . . . . .

89

6.5.2

Endothelium In Vivo Lacks E ective

7.3.3.2

The Three-Point Touch Method . . . . . . . . .

89

Paracrine or Autocrine Growth Factor

7.3.3.3

The Apical Clearance Method. . . . . . . . . . .

90

Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

7.3.3.4

Scleral Fitting Method . . . . . . . . . . . . . . . . . .

90

6.5.3

TGF-Beta2 Has a Suppressive E ect

7.3.4

GP Fitting Following Cross Linking . . . . . .

90

on S-phase Entry . . . . . . . . . . . . . . . . . . . . . . .

75

7.4

CL Fitting Following Penetrating

6.6

Proliferative Capacity of HCEC Di ers

Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . .

91

with Donor Age . . . . . . . . . . . . . . . . . . . . . . . .

76

7.4.1

Indications for CLs Following PK . . . . . . . .

91

6.6.1

Analysis of pRb Hyperphosphorylation. .

77

7.4.2

Indications for CLs Following PK in

6.6.2

Analysis of Replication Competence . . . .

77

Comparison with Newer Techniques . . . .

91

6.6.3

Analysis of CKI Protein Expression. . . . . . .

77

7.4.3

PK Peculiarities in Conjunction with CLs. . .

92

6.7

E orts to Stimulate Corneal

7.4.3.1

Corneal Sensitivity, Fitting Quality,

Endothelial Proliferation by

and Frequent Follow-Ups. . . . . . . . . . . . . . .

92

Interfering with G1-phase Inhibition . . . .

78

7.4.3.2

The Endothelium and Choice

6.7.1

Overcoming G1-phase Inhibition . . . . . . .

79

of GP Materials . . . . . . . . . . . . . . . . . . . . . . . . .

92

6.7.2

Bypassing G1-phase Inhibition. . . . . . . . . .

79

7.4.3.3

Immune Reactions . . . . . . . . . . . . . . . . . . . . .

92

6.8

Endothelial Topography A ects the

7.4.4

When to Fit? . . . . . . . . . . . . . . . . . . . . . . . . . . .

92

Proliferative Capacity of HCEC . . . . . . . . . .

79

7.4.5

Fitting Techniques. . . . . . . . . . . . . . . . . . . . . .

93

6.8.1

Di erences in Proliferative Capacity. . . . .

79

7.4.5.1

PK with One or Two Sutures . . . . . . . . . . . .

93

6.8.2

Di erences in Senescence

7.4.5.2

CL Fitting Following Suture Removal. . . .

93

Characteristics . . . . . . . . . . . . . . . . . . . . . . . . .

80

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . .

94

6.9

Identification of Mechanisms

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

Responsible for Decreased

Proliferative Capacity. . . . . . . . . . . . . . . . . . .

80

Chapter 8

6.9.1

Are Critically Short Telomeres

Allergic Disease of the Conjunctiva and Cornea

Responsible for Decreased

Andrea Leonardi

Proliferative Capacity? . . . . . . . . . . . . . . . . . .

81

8.1

Introduction and Classification

97

6.9.2

Is Sub-lethal Oxidative DNA Damage

8.2

Clinical Forms

98

Responsible for Decreased Proliferative

8.2.1

Seasonal and Perennial Allergic

Capacity?

81

Conjunctivitis

98

6.10

Future Directions

82

8.2.2

Vernal Keratoconjunctivitis

98

References

83

8.2.3

Atopic Keratoconjunctivitis

100

Chapter 7

8.2.4

Giant Papillary Conjunctivitis . . . . . . . . . . .

101

8.2.5

Contact Blepharoconjunctivitis

101

Current State of the Art of Fitting

Gas-Permeable (GP) Contact Lenses

8.2.6

Drug-Induced Conjunctivitis or

Silke Lohrengel and Dieter Muckenhirn

Keratoconjunctivitis . . . . . . . . . . . . . . . . . . . .

101

8.2.7

Urban Eye Allergy Syndrome . . . . . . . . . . .

102

7.1

Corneal Topography and Automatic

8.3

Di erential Diagnosis . . . . . . . . . . . . . . . . . .

103

Fitting Programs . . . . . . . . . . . . . . . . . . . . . . .

87

8.4

Diagnostic Tests in Ocular Allergy . . . . . . .

104

7.2

Fitting CLs . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

8.5

Ocular Immunity and the Allergic

7.3

The Keratoconus . . . . . . . . . . . . . . . . . . . . . . .

88

Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

104

7.3.1

KC Peculiarities in Conjunction

8.5.1

Innate Immunity and Ocular Allergy . . . .

104

with CL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

8.5.2

The Allergic Process . . . . . . . . . . . . . . . . . . . .

105

7.3.1.1

Corneal Sensitivity and Maximum

8.5.3

Allergic Inflammation . . . . . . . . . . . . . . . . . .

106

Resilience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

8.6

The Cornea in Allergic Diseases . . . . . . . . .

107

7.3.1.2

Corneal Contour: KC Stage: KC Type. . . . .

89

8.6.1

Corneal Immunology. . . . . . . . . . . . . . . . . . .

107

7.3.2

Forms of Correction . . . . . . . . . . . . . . . . . . . .

89

8.6.2

Allergic Inflammation and Corneal

7.3.2.1

Soft Lenses. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107

7.3.2.2

GP Contact Lenses . . . . . . . . . . . . . . . . . . . . .

89

8.6.3

Tear Instability and Corneal Involvement . .

107

7.3.2.3

Piggyback . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

8.6.4

Corneal Clinical Manifestations

11.2

Choosing Endothelial

11.3.7.3

Anterior Chamber Lens . . . . . . . . . . . . . . . . .

153

Keratoplasty Procedures. . . . . . . . . . . . . . . .

146

11.4

Clinical Results and Complications . . . . . .

153

11.2.1

Indications. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

146

11.4.1

Visual Acuity . . . . . . . . . . . . . . . . . . . . . . . . . . .

153

11.2.2

Preoperative Considerations. . . . . . . . . . . .

146

11.4.2

Astigmatism . . . . . . . . . . . . . . . . . . . . . . . . . . .

153

11.2.2.1

Confirming the Extent

11.4.3

Spherical Equivalent. . . . . . . . . . . . . . . . . . . .

153

of Endothelial Dysfunction . . . . . . . . . . . . .

146

11.4.4

Endothelial Cell Loss . . . . . . . . . . . . . . . . . . .

154

11.2.2.2

Corneal Scarring . . . . . . . . . . . . . . . . . . . . . . .

147

11.4.5

Corneal Donor Dislocation (Fig. 11.4a–c)

155

11.2.2.3

Cataract and Intraocular Lens Status . . . .

147

11.4.6

Pupillary Block . . . . . . . . . . . . . . . . . . . . . . . . .

156

11.2.2.4

Lens/Iris Diaphragm Status . . . . . . . . . . . . .

147

11.4.7

Primary Graft Failure . . . . . . . . . . . . . . . . . . .

156

11.2.2.5

Intraocular Pressure . . . . . . . . . . . . . . . . . . . .

148

11.4.8

Rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

156

11.2.2.6

Retinal Function. . . . . . . . . . . . . . . . . . . . . . . .

148

11.4.9

Other Complications . . . . . . . . . . . . . . . . . . .

156

11.3

PLK Surgical Technique . . . . . . . . . . . . . . . . .

148

11.5

Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

157

11.3.1

Donor Preparation . . . . . . . . . . . . . . . . . . . . .

148

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

157

11.3.2

Host Dissection for DSEK/DSAEK . . . . . . . .

148

11.3.3

Donor Insertion . . . . . . . . . . . . . . . . . . . . . . . .

149

Index

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

161

11.3.4

Techniques for Graft Centration. . . . . . . . .

149