Cornea and External Eye Disease - Corneal Allotransplantation, Allergic Disease and Trachoma

Foreword

Preface

Contents

Contributors

Chapter 1

Immune Privilege of Corneal Allografts

1.1 History of Corneal Transplantation and Immune Privilege

1.2 How Successful Is Corneal Transplantation?

1.3 Immune Rejection of Corneal Allografts

1.3.1 Role of CD4+ T Lymphocytes in Corneal Allograft Rejection

1.3.2 Role of CD8+ T Lymphocytes in Corneal Allograft Rejection

1.3.3 Role of Antibodies in Corneal Allograft Rejection

1.3.4 Role of Macrophages and NK Cells in Corneal Allograft Rejection

1.3.5 What are the Eff ectors of Corneal Allograft Rejection?

1.4 Role of Atopic Diseases in Corneal Allograft Rejection

1.5 Immune Privilege of Corneal Allografts Is a Tripartite Phenomenon

1.5.1 Aff erent Blockade of the Immune Response to Corneal Allografts

1.5.2 Immune Deviation in the Central Processing Component of the Immune Reflex Arc

1.5.3 Eff erent Blockade of the Immune Response to Corneal Allografts

References

Chapter 2

Mechanisms of Corneal Allograft Rejection and the Development of New Therapies

2.1 Status of Corneal Transplantation

2.2 Success Rate of Corneal Transplantation

2.3 Maintenance and Erosion of Corneal Privilege

2.4 The Corneal Allograft Response

2.5 Antigen Uptake in the Eye

2.6 Antigen Processing

2.7 Antigen Presentation

2.8 T Cell Activation, Proliferation, and Clonal Expansion

2.9 Eff ector Arm of the Allograft Response

2.10 Current Management of Corneal Transplants

2.11 Prevention of Allograft Rejection

2.12 Stratifi cation of Risk

2.13 Protecting Immune Privilege

2.14 Minimizing Antigenic Diff erences Between Donor and Recipient

2.15 Systemic Immunosuppression

2.16 Surgical Techniques and Postoperative Management

2.17 Management of Acute Rejection Episodes

2.18 New Therapies with Novel Mechanisms

2.19 Antibody-based Immunosuppressive Agents in Transplantation

2.20 Engineered Antibodies for Eye Disease

2.21 Gene Therapy of the Donor Cornea

2.22 Vectors for Gene Therapy of the Cornea

2.23 Transgenes for Prolonging Corneal Graft Survival

2.24 Future Prospects

References

Chapter 3

New Developments in Topical and Systemic Immunomodulation Following Penetrating Keratoplasty

3.1 Introduction

3.2 Immunology

3.2.1 Acute Rejection

3.2.2 Major Histocompatibility Complex (MHC)

3.2.2.1 Direct Pathway of Allorecognition

3.2.2.2 Indirect Pathway of Allorecognition

3.2.3 Chronic Rejection

3.3 Normal-risk vs. High-risk Transplantation

3.3.1 Normal-risk Transplantation

3.3.2 High-risk Transplantation

3.3.3 Rationale for Systemic Immunosuppression

3.3.4 Why Is Immunomodulation with Topical Steroids Not Suffi cient to Prevent Immunologic Graft Rejection in High-Risk Patients?

3.3.5 Rationale for Topical Immunomodulation

3.4 Immunosuppressive Agents

3.4.1 History

3.4.2 Corticosteroids

3.4.3 Cyclosporine A

3.4.3.1 CSA in Corneal Transplantation

3.4.4 Tacrolimus (fk506)

3.4.4.1 Tacrolimus in Corneal Transplantation

3.4.5 Mycophenolate Mofetil (MMF)

MMF in Corneal Transplantation

3.4.6 Rapamycin (Sirolimus)

3.4.7 RAD (Everolimus)

3.4.8 FTY 720

3.4.9 FK788

3.5 Pimecrolimus

3.5.1 Pimecrolimus in Corneal Transplantation

3.5.2 Biologic Agents

3.5.2.1 Basiliximab and Daclizumab

3.6 Guidelines for Practitioners

3.6.1 Systemic Immunosuppression with Drugs with Proven Effi cacy in Corneal Transplantation

3.6.1.1 Preoperative Evaluation

3.6.1.2 How to Use Cyclosporine in High-risk Corneal Transplantation

3.6.1.3 How to Use MMF in High-risk CornealTransplantation

3.6.2 Topical Immunosuppression

3.7 Conclusion

References

Chapter 4

Cytokine Analysis of the Aqueous Humor in the Context of Penetrating Keratoplasty

4.1 Immune Privilege of the Anterior Ocular Segment

4.1.1 Anterior Chamber-Associated Immune Deviation (ACAID)

4.1.2 The Th1/Th2 Paradigm

4. 2 Pitfalls in the Determination of Cytokine Levels from Aqueous Humor

4.3 Relevance of Individual Cytokines in Corneal Transplantation

4.3.1 Interleukin 1b

4.3.1.1 General Functions from In Vitro Experiments

4.3.1.2 Eff ects in Animal Models of Corneal Transplantation

4.3.1.3 Interleukin 1b Levels in Human Aqueous Humor

4.3.2 Interleukin 2

4.3.2.1 General Functions from In Vitro Experiments

4.3.2.2 Eff ects in Animal Models of Corneal Transplantation

4.3.2.3 Interleukin 2 Levels in Human Aqueous Humor

4. 3.3 Interleukin 6

4.3.3.1 General Functions from In Vitro Experiments

4.3.3.2 Eff ects in Animal Models of Corneal Transplantatoin

4.3.3.3 Interleukin 6 Levels in Human Aqueous Humor

4.3.4 Interleukin 10

4.3.4.1 General Functions from In Vitro Experiments

4.3.4.2 Eff ects in Animal Models of Corneal Transplantation

4.3.4.3 Interleukin10 Levels in Human Aqueous Humor

4.3.5 Interferon Gamma (IFN- gamma )

4.3.5.1 General Functions from In Vitro Experiments

4.3.5.2 Eff ects in Animal Models of Corneal Transplantation

4.3.5.3 INF- gamma Levels in Human Aqueous Humor

4.3.6 Tumor Necrosis Factor Alpha (TNF- alpha )

4.3.6.1 General Functions from In Vitro Experiments

4.3.6.2 Eff ects in Animal Models of Corneal Transplantation

4.3.6.3 TNF- a Levels in Human Aqueous Humor

4.3.7 Transforming Growth Factor Beta (TGF- beta)

4.3.7.1 General Functions from In Vitro Experiment

4.3.7.2 Eff ects in Animal Models of Corneal Transplantation

4.3.7.3 TGF- b 2 Levels in Human Aqueous Humor

4.3.8 Fas, Fas Ligand and Soluble Fas Ligand

4.3.8.1 General Functions from In Vitro Experiments

4.3.8.2 Eff ects in Animal Models of Corneal Transplantation

4.3.8.3 sFasL Levels in Human Aqueous Humor

4.3.9 Further Cytokines and Immunomodulative Factors

4.3.9.1 Interleukin 1 Receptor Antagonist

4. 3.9.2 Interleukin 4

4.3.9.3 Interleukin 5

4.3.9.4 Interleukin 8

4.3.9.5 Interleukin 12

4. 3.9.6 Alpha-Melanocyte-Stimulating Hormone/ Calcitonin Gene-Realted Peptide/ Thrombospondin/Somatostatin

4. 4 Cytokine Profi les in the Context of Corneal Transplantation

4.4.1 Cytokine Profi les in Animal Models

4.4.2 Cytokine Profi les in Humans

4.4.2.1 Cytokines in the Serum of Patients Following PK

4.4.2.2 Cytokines in Human Corneas

4. 4.2.3 Cytokines in Human Aqueous Humor

References

Chapter 5

Limbal Stem Cell Transplantation: Surgical Techniques and Results

5.1 Introduction

5.1.1 The Corneal Epithelium

5.1.2 The Limbus and Corneal Epithelial Homeostasis

5.2 Corneal LESC Defi ciency

5.2.1 Diagnosis and Classifi cation of Corneal LESC Defi ciency

5.3 Management of Patients with Limbal Stem Cell Defi ciency

5.3.1 Conservative Options

5.3.2 Surgical Options for Partial Limbal Stem Cell Defi ciency

5.3.3 Surgical Options for Total Limbal Stem Cell Defi ciency

Correct any dry eye disease and lid abnormality that is contributing to ocular surface failure

Remove the conjunctival epithelium from the cornea and restore a normal stromal environment

Transplant corneal LESCs to reestablish an intact and transparent epithelium

5.4 Surgical Techniques for Transplanting Corneal Limbal Stem Cells

5.4.1 Conjunctival Limbal Autograft (CLAU)

5.4.2 Living-Related Conjunctival Limbal Allograft Transplant (lr-CLAL)

5.4.2.1 Clinical Outcomes of CLAU and lr-CLAL

5.4.3 Keratolimbal Allograft Transplant

5.4.4 Ex Vivo Expansion and Transplantation of Cultured Limbal Stem Cells

5.4.5 Regulations Governing the Clinical Use of Ex vivo Cultured Tissue

5.4.6 Evidence of the Presence of Stem Cells in Ex vivo Cultures and Grafts

5.4.7 Assessing Outcomes Following LESC Transplantation

5.4.8 Evidence for Donor Cell Survival Following Ex Vivo Cultured LESC Transplantation

5.4.9 Role of Tissue Matching in Transplantation of Allogeneic Tissue or Cells

5.4.10 Alternative Sources of Autologous Stem Cells

5.4.11 Issues Surrounding Ex Vivo Cultured LESC Transplantation that Require Further Investigation

5.5 Conclusion

References

Chapter 6

Cell Cycle Control and Replication in Corneal Endothelium

6.1 Relationship of Endothelial Barrier Function to Corneal Transparency

6.2 Corneal Endothelial Cell Loss and Repair Mechanisms

6.2.1 Causes of Cell Loss

6.2.2 Repair of the Endothelial Monolayer

6.3 Are Human Corneal Endothelial Cells Able to Divide?

6.3.1 Proliferative Status In Vivo

6.3.2 Evidence that HCEC Retain Proliferative Capacity

6.4 The Cell Cycle

6.4.1 Positive Regulation of the Cell Cycle

6.4.2 Negative Regulation of G1-Phase of the Cell Cycle

6.5 Potential Causes for Inhibition of HCEC Proliferation In Vivo

6.5.1 Cell–Cell Contacts Inhibit Division

6.5.2 Endothelium In Vivo Lacks Effective Paracrine or Autocrine Growth Factor Stimulation

6.5.3 TGF-Beta2 Has a Suppressive Effect on S-phase Entry

6.6 Proliferative Capacity of HCEC Differs with Donor Age

6.6.1 Analysis of pRb Hyperphosphorylation

6.6.2 Analysis of Replication Competence

6.6.3 Analysis of CKI Protein Expression

6.7 Efforts to Stimulate Corneal Endothelial Proliferation by Interfering with G1-phase Inhibition

6.7.1 Overcoming G1-phase Inhibition

6.7.2 Bypassing G1-phase Inhibition

6.8 Endothelial Topography Affects the Proliferative Capacity of HCEC

6.8.1 Differences in Proliferative Capacity

6.8.2 Differences in Senescence Characteristics

6.9 Identification of Mechanisms Responsible for Decreased Proliferative Capacity

6.9.1 Are Critically Short Telomeres Responsible for Decreased Proliferative Capacity?

6.9.2 Is Sub-lethal Oxidative DNA Damage Responsible for Decreased Proliferative Capacity?

6.10 Future Directions

References

Chapter 7

Current State of the Art of Fitting Gas-Permeable (GP) Contact Lenses

7.1 Corneal Topography and Automatic Fitting Programs

7.2 Fitting CLs

7.3 The Keratoconus

7.3.1 KC Peculiarities in Conjunction with CL

7.3.1.1 Corneal Sensitivity and Maximum Resilience

7.3.1.2 Corneal Contour-KC Stage-KC Type

7.3.2 Forms of Correction

7.3.2.1 Soft Lenses

7.3.2.2 GP Contact Lenses

7.3.2.3 Piggyback

7.3.2.4 Hybrid Lenses

7.3.3 Fitting Techniques

7.3.3.1 The Reshape and Splint Method

7.3.3.2 The Three-Point Touch Method

7.3.3.3 The Apical Clearance Method

7.3.3.4 Scleral Fitting Method

7.3.4 GP Fitting Following Cross Linking

7.4 CL Fitting Following Penetrating Keratoplasty

7.4.1 Indications for CLs Following PK

7.4.2 Indications for CLs Following PK in Comparison with Newer Surgical Techniques

7.4.3 PK Peculiarities in Conjunction with CLs

7.4.3.1 Corneal Sensitivity, Fitting Quality, and Frequent Follow-Ups

7.4.3.2 The Endothelium and Choice of GP Materials

7.4.3.3 Immune Reactions

7.4.4 When to Fit?

7.4.5 Fitting Techniques

7.4.5.1 PK with One or Two Sutures

7.4.5.2 CL Fitting Following Suture Removal

Abbreviations

References

Chapter 8

Allergic Disease of the Conjunctiva and Cornea

8.1 Introduction and Classification

8.2 Clinical Forms

8.2.1 Seasonal and Perennial Allergic Conjunctivitis

8.2.2 Vernal Keratoconjunctivitis

8.2.3 Atopic Keratoconjunctivitis

8.2.4 Giant Papillary Conjunctivitis

8.2.5 Contact Blepharoconjunctivitis

8.2.6 Drug-Induced Conjunctivitis or Keratoconjunctivitis

8.2.7 Urban Eye Allergy Syndrome

8.3 Diff erential Diagnosis

8.4 Diagnostic Tests in Ocular Allergy

8.5 Ocular Immunity and the Allergic Reaction

8.5.1 Innate Immunity and Ocular Allergy

8.5.2 The Allergic Process

8.5.3 Allergic Infl ammation

8.6 The Cornea in Allergic Diseases

8.6.1 Corneal Immunology

8.6.2 Allergic Infl ammation and Corneal Damage

8.6.3 Tear Instability and Corneal Involvement

8.6.4 Corneal Clinical Manifestations in Ocular Allergy

8.6.5 Confocal Microscopy and Allergic Keratoconjunctivitis

8.6.6 Keratoconus and Allergic Conjunctivitis

8.6.7 Keratoglobus

8.6.8 Allergic Keratoconjunctivitis and Corneal Infection

8.6.9 Allergy and Corneal Transplant

8.6.9.1 Immunology

8.6.9.2 Clinical Outcomes

8.7 Treatment of Ocular Allergy

8.7.1 Nonpharmacological Management

8.7.2 Treatment of Allergic Conjunctivitis

8.7.2.1 Topical Ocular Pharmacological Treatment

8.7.2.2 Topical Nonocular Pharmacological Treatment

8.7.2.3 Systemic Pharmacological Treatment

8.7.2.4 Specifi c Immunotherapy

8.7.3 Treatment of GPC

8.7.4 Treatment of Vernal Keratoconjunctivitis

8.7.4.1 Corticosteroids

8.7.4.2 Cyclosporine and Other Immunosuppressive Treatments

8.7.5 Treatment of AKC

8.7.5.1 Cyclosporine and Other Immunosuppressive Treatments

8.7.6 Surgical Treatment of Keratoconjunctivitis

References

Chapter 9

Trachoma

9.1 Introduction

9.1.1 Overview

9.1.2 History

9.2 Clinical Features

9.2.1 Symptoms and Signs

9.2.2 Trachoma Grading Systems

9.2.3 Diff erential Diagnosis

9.3 Chlamydia Trachomatis

9.4 Laboratory Diagnosis

9.5 Clinical Signs and Infection

9.6 Epidemiology

9.6.1 Prevalence and Distribution

9.6.2 Age and Gender

9.6.3 Risk Factors for Active Trachoma and C. Trachomatis Infection

9.7 Pathophysiology of Trachoma

9.7.1 The Stimulus for Infl ammation and Scarring in Trachoma

9.7.2 Histopathology

9.7.3 The Immune Response in Trachoma

9.7.4 Immunopathogenesis of Conjunctival Scarring

9.8 Trachoma Control

9.8.1 The SAFE Strategy

9.8.2 Surgery for Trichiasis

9.8.3 Antibiotics

9.8.4 Face Washing

9.8.5 Environmental Improvements

9.10 Conclusion

References

Chapter 10

Keratoprosthesis

10.1 Introduction

10.2 Prognostic Hierarchy

10.3 Defi ning Patient Subtypes

10.3.1 Patient Subtype A: The Noninfl amed Eye

10.3.2 Patient Subtype B: The Infl amed Eye

10.4 Experience with Kpro in Patient Subtype A

10.4.1 Boston Type 1 Kpro

10.4.1.1 Pediatric Application of Boston Type 1 Kpro

10.4.2 AlphaCor Kpro

10.5 Experience with Kpro in Patient Subtype B

10.5.1 Osteo-Odonto Keratoprosthesis (OOKP)

10.5.2 Boston Type 2 Kpro

10.6 Other Kpro Designs

10.6.1 Pintucci Kpro

10.6.2 Seoul-Type Kpro

10.6.3 Worst-Singh Kpro

10.6.4 Russian/Ukrainian Experience

10.7 New Directions in Kpro Research

10.7.1 Hydroxyapatite Biologic Haptics

10.7.2 Biologic Coatings

10.7.3 Biologic Scaff olds and Enhanced Hydrogels

10.8 Conclusion

References

Chapter 11

Posterior Lamellar Keratoplasty in Perspective

11.1 Introduction

11.2 Choosing Endothelial Keratoplasty Procedures

11.2.1 Indications

11.2.2 Preoperative Considerations

11.2.2.1 Confi rming the Extent of Endothelial Dysfunction

11.2.2.2 Corneal Scarring

11.2.2.3 Cataract and Intraocular Lens Status

11.2.2.4 Lens/Iris Diaphragm Status

11.2.2.5 Intraocular Pressure

11.2.2.6 Retinal Function

11.3 PLK Surgical Technique

11.3.1 Donor Preparation

11.3.2 Host Dissection for DSEK/DSAEK

11.3.3 Donor Insertion

11.3.4 Techniques for Graft Centration

11.3.5 Techniques for Promoting Donor Adhesion

11.3.6 Post-operative Care

11.3.7 Surgery for Complex Cases

11.3.7.1 Failed Grafts

11.3.7.2 Aniridics, Vitrectomised and Aphakic Eyes

11.3.7.3 Anterior Chamber Lens

11.4 Clinical Results and Complications

11.4.1 Visual Acuity

11.4.2 Astigmatism

11.4.3 Spherical Equivalent

11.4.4 Endothelial Cell Loss

11.4.5 Corneal Donor Dislocation

11.4.6 Pupillary Block

11.4.7 Primary Graft Failure

11.4.8 Rejection

11.4.9 Other Complications

11.5 Conclusion

References

Index