Ocular Immunology

UNIVERSITÄT BERN

Christine Watté, DVM, Dipl.ECVO BSC 22 June 2016; NCSU Plan of the lecture

1. GENERAL PRINCIPLES OF IMMUNOLOGY 2. DEFENSE MECHANISMS OF TEARS AND OCULAR SURFACE 3. IMMUNE PRIVILEGE OF THE CORNEA 4. OCULAR IMMUNE PRIVILEGE, ACAID, THERAPEUTIC APPLICATIONS 5. IMMUNE MECHANISMS OF SELECTED DISEASES Why study ocular immunology? PART 1: GENERAL PRINCIPLES OF IMMUNOLOGY When is the immune system active? When is the immune system active?

What is Immunology?

• Not just the host response against infectious agents • Study of all mechanisms leading to recognition and response against what is recognized as foreign (non-self) • Purposes: • Fighting pathogens (bacteria, viruses, fungi, parasites) • Tolerance against commensals • Regulating auto-reactivity The immune system sees things differently

See /hear Molecules / Receptors Knowledge Knowledge Learning Learning Innate and adaptive immunity

1st Line defense

2nd Line defense Specificity of innate and adaptive immunity Innate Adaptive Specificity of innate and adaptive immunity Innate Adaptive Specificity of innate and adaptive immunity Innate Adaptive Specificity of innate and adaptive immunity Innate Adaptive Specificity of innate and adaptive immunity Innate Adaptive Innate Immunity Pattern Recognition Receptors Examples: • Toll-like Receptors (TLRs) • Nod-like receptors (NLRs) • RIG-I-like Receptors (RLRs) • Mannose-Binding Lectin (MBL)

Present in all cellular compartments

Can differentiate between broad classes of pathogens PRRs signal the earliest events in inflammation

INFKb: Nuclear factor-Kb; IRFs: Interferon regulatory factor PRR recognize microbes & danger

Molecular structures that are characteristic of microbes Pathogen-Associated Molecular Patterns (PAMPS)

Host molecules released from damaged or dying cells Damage-Associated Molecular Patterns (DAMPS) Innate Immunity Complement Proteins Adaptive Immunity

Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012 by Saunders, an imprint of Elsevier Inc. CD4 Th cells can differentiate in subsets with distinct functions Phases of adaptive immune responses Specificity Memory and Contraction Regional Immunity

Cance Viruses r Fungi

IMMUNE Bacteria SYSTEM Parasites

Toxins Pollution

Specialized Immune Responses in Epithelial and Immune Privileged Tissues Diverse ocular tissues with different challenges

• Microbes at the ocular surface • Preserve optical clarity • Little regenerative capacity Immune responses in the eye are adapted to suit the functional needs of the diverse ocular tissues 1st Line

Protection Vision

Plan of the lecture

1. GENERAL PRINCIPLES OF IMMUNOLOGY 2. DEFENSE MECHANISMS OF TEARS AND OCULAR SURFACE 3. IMMUNE PRIVILEGE OF THE CORNEA 4. OCULAR IMMUNE PRIVILEGE, ACAID, THERAPEUTIC APPLICATIONS 5. IMMUNE MECHANISMS OF UVEITIS LET’S TAKE A BREAK PART 2: DEFENSE MECHANISMS OF TEARS AND OCULAR SURFACE Healthy ocular surface

Lubrication Resist Commensal pathogenic flora microbes Multiple layers of protection

• Anatomic and physical barriers

• Defense mechanisms of tears

• Defense mechanisms of ocular epithelia

• Eye associated lymphoid tissue Eyelids & Eyelashes

Eyelids

• Protect the eyeball

• Wipe the eye clean

• Distribute the tear film

• Shunt tears to the lacimal puncta

• Secrete the lipid layer Eyelashes

• Prevent fine particles from entering the eye

McCurnin; Small Animal Physical Diagnosis and Clinical Procedures (1991) Tears wash and eyelids wipe Tears: more than lubrication

Aqueous tears

Mucins

Antimicrobial proteins and peptides

Complement

Immunoglobulins Mucins: High molecular weight glycoproteins

Dryeyes.com mucin_sigmaaldrich.com. Mucin producing tissues of the eye

Lacrimal gland

Cornea

MUC1 MUC4 MUC16 MUC5AC

Conjunctiva & Goblet cells

Gipson IK, Exp Eye Res 2004 Type and origin of mucins

Source Mucin gene Mucin type Epithelial cells MUC1 MUC4 MUC16 Membrane Associated Goblet cells MUC5AC MUC5B MUC 2 Gel Forming Lacrimal gland MUC1 MUC4 MUC5B MUC7 Small Soluble

Paulsen; Int Rev Cyto (2006) Mucins hold water

Hydrate the epithelium & stabilize the tear film Mucins: front line defenders of the ocular surface • Repulse or trap microorganisms • Reservoir of antimicrobial proteins and peptides • Binding sites for surveiling neutrophils • Maintain a healthy CALT • Wound healing

• During infection: • Increased mucus secretion • Altered glycosilation • Cleavage of transmembrane mucins of the glycocalix • Intracellular signaling to increase cellular resistance to infection

CALT: Conjunctiva Associated Lymphoid Tissue Antimicrobial proteins and peptides (AMP): A chemical barrier against microbes

Source: • Lacrimal glands and epithelium • Serum exudates • Infiltrating cells Target: • Bacteria, fungi and viruses

MS Gregory, Innate immune system and the eye, 2011 AMP: the shortlist

Lactoferrin Complement Lipocalin

α and β Defensins Lysozyme Cathelicidin

Secretory phospholipase A2 Surfactant proteins Secretory IgA …………….. Dog tear film protein analysis

125 different proteins in the tear film of healthy dogs

Dog Tear Film Proteome In-Depth Analysis. Winiarczyk M et al. (2015) PLoS ONE Lactoferrin Complement Lipocalin

α and β Defensins Lysozyme Cathelicidin

Secretory phospholipase A2 Surfactant proteins Redundancy If the immune system falls short of one factor, most of the time it can compensate forSecretory this deficit IgA with other factors ……….. Dynamic regulation of AMP

Lysozyme, lactoferrin, lipocalin, Open eyes sIgA

Increased sIgA, complement, Closed eyes serum derived proteins and PMN

Ocular infection More potent defensins Effect of AMP on Microorganisms

Action Substance

Lysozyme, secretory phospholipase A2, cathelicidin, Disrupt microbial membrane defensin, SLP1, Complement factors

Interfere with microbial growth Lactoferrin, Lipocalin A, SP-D

Interfere with microbial adherence Lactoferrin

Neutralize and/or aggregate toxins sIgA, Defensin and microorganisms

SLP1: secreted leukocyte protease inhibitor-1 Effect of AMP on the Epithelium

Action Substance

Promote proliferation defensins, cathelicidins

Inhibit bacterial adhesion and invasion SP-D, lactoferrin

Amplify apoptosis of infected cells lactoferrin

SP-D: surfactant protein D Effect of AMP on Immune Cells

Action Substance Chemoattract Immune cells SP A-D

Opsonization IgA, complement

Promote pahgocytosis Defensins, complement

Potentiate bactericidal activity of Neutrophils Lactoferrin Reduce inflammation (through neutralization of Cathelicidin, defensins bacterial toxins)

SP A-D: surfactant protein A&D Lysozyme

• Function: • Enzyme: disrupts bacterial cell wall • Quantity:

• Major tear protein in people Tear lysozyme concentration in people estimated by the agar diffusion • Low quantity in dogs tears technique (substrate: Micrococcus lysodeikticus) • present in sheep, goats, llamas, cattle, horses, dogs, and rabbits Positively charged peptides (e.g. Defensins & Cathelicidin)

Positively charged AMP Negatively charged microbial membrane

Pore formation Cell lysis Complement

• Constitutive low-level expression of activated complement proteins in tears (e.g. C3, C4, factor B) • Source: • Ocular epithelia • Serum • PMN • Enable rapid and controlled activation of the complement cascade Complement proteins

Factor B

C4 Immunoglobulins

• Secretory IgA, IgG, IgM • Variable concentrations within healthy canine tears • Age • Time of day • Day to day variations Secretory IgA

• Dimeric antibody

• Junction chain

• Secretory component

• Plasma cells in the conjunctiva and lacrimal glands

• Transported through the epithelium

Koeppe & Stanton: Berne and Levy physiology 6thed; 2008 Secretory IgA: How does it work?

• Form Immune Complexes (IC) Agglutinate and neutralize microbes

Antigen-specificity

non-specific Ag binding (glycans) SEM IgA-mediated agglutination of Salmonella typhimurium

Mantis N.J. Mucosal Immunology 2011 Secretory IgA

• Immune complexes reinforce epithelial barrier function

• Favors commensals close to Epithelium the epithelium

• Inhibit microbial invasion of the epithelium

• IC uptake by M cells

Mantis N.J. Mucosal Immunology 2011 Tear IgG

• Low concentrations

• Produced during re-exposure

• Diffuses passively or actively transcytosed

• Mode of action:

• Activate the complement cascade

• Promote phagocytosis by macrophages

Kill Microbes Tear IgM

• Low concentrations (pentamer, large molecular weight)

• Produced during primary infection

• Mode of action:

• Activate the complement cascade

Kill Microbes

M. R. Ehrenstein & C. A. Notley; Nature Reviews Immunology 2010 Epithelial defense mechanisms

• Tight junctions

• High cell turn-over

• Pattern Recognition Receptors (e.g. TLRs)

Abelson, Rev Ophthalmol; 2009 PRR: Toll-Like Receptors

• Total of 10 TLR in humans • All 10 TLRs are present in the eye • Ocular surface • Iris, ciliary body, choroid and RPE • Key receptors that signal the earliest events in inflammation • Release of inflammatory mediators • Chemotaxis of immune cells • Expression of adhesion molecules Regulation of TLR-signaling

• Spatial regulation of TLR expression

• Basal and wing cells (e.g.TLR5 for flagellin)

• Intracellular compartments (e.g. TLR2&4 for lipopeptide and LPS)

• Modulation of inflammatory signals after TLR5 stimulation by flagellin from pathogenic bacteria versus commensal bacteria

LPS: Lipopolysacharade TLRs on the equine ocular surface

TLR mRNA expression in the corneal, limbal and conjunctival epithelium

K. Gornik et al, Vet Ophthalmol 2011 Eye associated lymphoid tissue

• Functionally linked to the mucosal immune system

• Eye Associated Lymphoid Tissue

• Lacrimal Gland Associated Lymphiod Tissue (LGALT)

• Conjunctiva Associated Lymphiod Tissue (CALT)

• Lacrimal Drainage Associated Lymphiod Tissue (LDALT)

= Atomically and immunologically connected Eye associated lymphoid tissue

CALT LGALT

LDALT

Knop & Knop; Conjunctiva immune surveillance; 2011 Lymphoid follicles of the third eyelid Follicle Associated Epithelium Feline

PAS staining

• Thinner epithelium

Canine • No goblet cells

• M-cells SEM M cell

TEM M cell

E.A Giuliano & K. Finn Vet ophth 2011; E. A Giuliano et al., Graefe’s Arch Clin Exp Ophtalmol, 2002 Conjunctival follicles

• M-cells sample surface antigens • APCs present Antigens to CD4+Th cells • CD4+Th cells help B cells transform into Ab producing plasma cells

FAE

Corthésy, Trends in Biotechnology, 2002 Eye associated lymphoid tissue

Diffuse lymphoid tissue Lymphoid follicles Blood circulation (Immune effector sites) (Immune inductive sites)

Knop & Knop, 2011, Conjunctiva immune surveillance When pathogens evade ocular defense mechanisms • Stimulation of TLR vasodilation inflammatory cytokines • Signal inflammation: chemoattractants adhesion molecules

• Recruitment of Innate Immune cells

• Inflammatory APCs initiate the adaptive immune response

• Generation of antigen-specific T and B cells

• Conventional adaptive immune response Anti- and pro-inflammatory responses

ANTI- INFLAMMATORY INFLAMMATORY

Knop & Knop, 2011, Conjunctiva immune surveillance

DRY EYE AND ASSOCIATED OCULAR SURFACE INFLAMMATION Tear production: Integrated Lacrimal Functional Unit

Lacrimal glands

Eyelids

Ocular surface epithelia

Nerves that connect them Dysfunction of any component: • Destabilize the tear film • Alter volume, composition, or distribution of tears Dry eye in canine patients

Quantitative disorder = Aqueous tear deficiency = Keratoconjunctivitis sicca

Quantity

Quality Immune-mediated KCS: Lacrimal gland inflammation

• Early inciting events??? • Genetic predisposition • Environmental stress • Hormonal imbalances • Lacrimal and/or Immune dysregulation • Effect: • Lymphoplasmacytic infiltrates in the lacrimal glands

• Concurrent systemic abnormalities (40%): T

TCR • Circulating rheumatoid factor antibodies MHC • Hyper-gamma-globulinemia Mature APC

• Dysfunction of other glands (xerostomia, PRR TLR hypothyroidism, diabetes) Dry Eye

Regardless of the inciting cause dry eye is always accompanied by:

• Redness

• Irritation

• Inflammation

= Self-perpetuating cycle of tissue destruction Self-perpetuating cycle of surface inflammation

Altered tear film Dessication Altered tear osmolarity Quantity/Quality/Stability

Disrupts tight junctions Decreased goblet cells Squamous metaplasia Altered ocular surface Decreased mucin production Cell death

Invasion of Immune cells Inflammatory cytokines Inflammatory APC phagocytose necrotic cells Vascular permeability Inflammation Activation of autoreactive B Adhesion molecules and T cells Self-perpetuating cycle of surface inflammation

Ocular surface Inflammatory mediators impede neural transmission at the inflammation ocular surface

Sensory isolation of the Neuronal reflex signaling to the lacrimal gland lacrimal gland is interrupted

Damage to the lacrimal Cellular debris are shed into glands & reduced tear tears secretion

Plan of the lecture

1. GENERAL PRINCIPLES OF IMMUNOLOGY 2. DEFENSE MECHANISMS OF TEARS AND OCULAR SURFACE 3. IMMUNE PRIVILEGE OF THE CORNEA 4. OCULAR IMMUNE PRIVILEGE, ACAID, THERAPEUTIC APPLICATIONS 5. IMMUNE MECHANISMS OF UVEITIS LET’S TAKE A BREAK PART 3: IMMUNE PRIVILEGE OF THE CORNEA Corneal transparency

• Essential for good vision

• Relies on several factors:

• Anatomic

• Physiologic

• Immunologic Immune privilege of the cornea

Cornea possess tissue specific immune regulatory mechanisms that aim to prevent destructive immune responses

• Corneal Angiogenic Privilege

• Corneal Immune Privilege 1. Angiogenic privilege of the cornea

• Absence of blood and lymph vessels from the cornea • Corneal avascularity is an active process: • Balanced production of angiogenic factors • Excess of inhibitors of angiogenesis

Anti- Angiogenic angiogenic Angiogenic and anti-angiogenic factors in the normal cornea sVEGFR VEGFs angiostatin bFGFs endostatin MMPs TSP PEDF

Anti- Angiogenic angiogenic

VEGF: vascular endothelial growth factor; bFGF: basic fibroblastic growth factor; MMP: matrix metalloproteinase; sVEGFR: soluble VEGF receptor; TSP: Thrombospondin; PEDF: pigment epithelium derived factor Angiogenic and anti-angiogenic factors in the normal cornea

VEGFs sVEGFR

Anti- Angiogenic angiogenic

R.J-C. Albuquerque; Blood 2013 Pathologic conditions modify the balance

Epithelial loss Hypoxia Inflammation

Anti- Angiogenic angiogenic Blood and lymphatic vessels co-migrate into the cornea:

Confocal Immunohistochemistry of the cornea

Corneal sutures

Cornea

Limbus

Green: blood vessel Red: lymphatic vessel

C. Cursiefen, et al., J Clin Invest; 2004 Macrophages stimulate corneal vascularization

F. Bock et al., Prog Ret Eye Res (2013) Importance of corneal vascularization in the immune response (e.g. corneal transplantation) 1 Host-graft interface 2 APCs and Ag leave the cornea via lymphatics 3 Antigen presentation in the regional lymph nodes 4 Effector cells return via corneal blood vessels

D. Hos & C Cursiefen, Adv Anat Embryol Cell Biol, 2014 VEGF-VEGFR in animal species

• Corneal avascularity is due to sVEGFR1 • Manatees have vascularized corneas because they are genetically dedicient in sVGFR

IHC soluble VEGFR-1 (red-brown)

Manatee Dugong African elephant Beaked whale

B.K Ambati; Nature 2006; J.Y Harper, Vet Ophthalmol; 2005 VEGFR 1-2 expression in the dog

• VEGFR1 in corneal epithelium and endothelium • VEGFR1-2 expression increases in vascularized corneas (soluble and membrane bound forms)

D.R. Binder, Vet. Ophthalmol, 2012 VEGF expression in the horse

Equine deep stromal abscesses: • Fungal hyphae • Delayed vascularization • Low VEGF-A expression (IHC)

R. Stoppini

M de Linde Henriksen, Vet. Ophthalmol, 2013 2. Immune privilege of the cornea

• Low antigenicity of the corneal tissue • Few and immature APCs • Local immune suppression • Direct contact with aqueous humor Low antigenicity of the corneal tissue

• Low Cellularity • Little antigenicity • Low MHC I, MHC II virtually absent • Epithelium > endothelium • Endothelium • Increased protective mechanisms

J Hori, J Leuk Biol (2008); M. Fernandez, MEA J Ophthalmol (2010) Few and immature APCs in the cornea

Resident population of APC

Central cornea Peripheral cornea Few APCs More APCs Immature (no MHC II) Some MHC II, connect via dendrites

MHC II: Major Histocompatibility Complex class II molecules; serve for antigen presentation Hamrah, Antigen presenting cells in the eye and ocular surface; 2011 Corneal suppressive factors

Factor Effect FasL Apoptosis T cells, activation of PMNs Inhibit of T cell proliferation PDL-1 Inhibit cytokine secretion T cell apoptosis Non-classical class Ib Inhibit NK cell activity Protect from complement-mediated cellular Complement regulatory proteins lysis Multiple Factors that modulate adaptive and Contact with Aqueous humor innate immunity Survival of corneal grafts relies in part on Anterior Chamber Associated Immune Deviation (ACAID)

PDL-1: Programmed death ligand 1

CORNEAL TRANSPLANTATION Corneal transplantation

• Landmarks: • >1900: keratoplasty trials and errors • 1905: successful Penetrating Keratoplasty in a human patient

Dr E. Zirm, 1905, Czech Republic Corneal transplantation

• 1905-1995: penetrating keratoplasties • 1995-now: partial thickness grafts GOAL: Replace only the diseased corneal layers Improve graft acceptance PK

DMEK

- Pentrating Keratoplasty - Endothelial Keratoplasty

Eye bank association of America – statistical report 2014 Cornea.org Corneal transplantation

• 1905-1995: penetrating keratoplasties • 1995-now: partial thickness grafts GOAL: Replace only the diseased corneal layers 1 week post PK Improve graft acceptance

1 week post DMEK

- Pentrating Keratoplasty - Endothelial Keratoplasty

Eye bank association of America – statistical report 2014 Cornea.org Corneal transplantation

• >100.000 corneal grafts /year worldwide • No HLA matching (human equivalent of MHC) • Limited immunosuppression • High success • Compared to other tissue transplants = tissue characteristics and ocular immune privilege • Low risk corneas • Replace only diseased tissue • Reduce sutures • Successrate year 1 DMEK 99% PK 86% What modifies graft survival?

Decrease survival Increase survival Corneal inflammation Deplete macrophages

Corneal vascularization Inhibit vascularization (Lymphatic > blood vessels) Interfere with ACAID Induce ACAID prior to transplantation

ACAID: Anterior Chamber Associated Immune Deviation Effect of inflammation and vascularization on graft survival

Acceptance Rejection

Normal risk Avascular High risk Alymphatic High risk High risk (no blood/lymph vessels) (no vessels but inflamed) (only blood vessels) (blood/lymph vessels)

Modified from: T. Dietrich, J. of Immunol, 2010 New therapies that target vascularization

Block VEGF production  Insuline receptor substrate inhibitor-1 (Aganirsen) Block VEGF-VEGFR binding  Blocking Ab (Avastin) or Ab fragments (Lucentis)  VEGF-trap fusion protein (Aflibercept)

Block intracellular signaling  Tyrosine kinase inhibitors  mTor inhibitor Corneal transplantation in veterinary patients • Great species variations • Better tolerated in feline patients • Rejection in canine and equine patients • Individual / breed variations: • Make up of the immune system • Tendency to develop corneal vascularization: Boxer • Indications: • Optical • Cosmetic • Therapeutic = High risk corneas • Tectonic/reconstructive Corneal transplantation in veterinary patients

Pictures gift from R. Stoppini, Italy

LET’S TAKE A BREAK NON-ULCERATIVE IMMUNE-MEDIATED KERATOPATHIES Immune mediated keratopathy

• Corneal pathology that results from abnormal activity of the immune system (exaggerated activity or autoimmunity) • Equine IMMK • Canine CSK • Feline stromal keratitis Canine chronic superficial keratitis (CSK)

• Clinical appearance: • Bilateral fibrovascular infiltration and inflammation of the cornea • Infiltrating cells: • Predominantly CD4+ T cells • Macrophages • Plasma cells • Neutrophils • Increased expression of: • IFNγ • MHC II • Systemic: • Increased serum levels of VEGF CSK – Risk factors

• Immunogenetic predisposion • GSD /Greyhounds • Leukocytes of affected dogs react to corneal antigens • MHC II genes • DLA-DRB1*01501/DQA1*00601/DQB1*00301 • Risk for disease development : • 2.7x heterozygotes • 8x homozygotes • SNP in the regulatory region that controls MHC transcription • Affects level/pattern of MHC expression • Environmental factors • UV exposure /Altitude • Hormonal imbalance • female

Borer CSK - Treatment

Reduce stimulation Immune response • Sun protection • Topical steroids • CsA / Tacrolimus • Adjunct therapy • Radiation (Sr90/soft-X rays)

Target both avenues for maximum therapeutic effect Feline stromal keratitis

Progressive inflammation, edema and vascularization of the cornea Trigger • FHV-1 AHT Effector • Immune response

Virus-induced immunopathology Develops with repeated viral reactivation

Borer UCD Borer Spectrum of FHV-1 related ocular surface disease • Ophthalmia neonatorum • Conjunctivitis • Symblepharon • Dendritic ulcers • Geographic ulcers • Sequestrum • KCS • Eosinophilic keratitis • Stromal keratitis Spectrum of FHV-1 related ocular surface disease

Borer Borer

Borer FHV-1 life cycle Latency Reactivation

Primary Recurrent Infection Disease

URT URT✗ Conjunctiva Cornea (Cornea)

• Initial transient viremia • Viral DNA recovered from multiple ganglia: trigeminal, ciliary, vestibular • FHV-1 may cause local ocular disease but viral infection is not necessarily limited to the eye

Mod. Lachman, Exp Rev Mol Med (2003) Immuno-pathogenesis experimental cats

Experimental cat model (Nasisse 1989 - 1995) • Subconjunctival CCS + FHV-1 = Stromal keratitis • Suppression of the local immune response • Increased viral load, increased cellular damage, delayed clearance • Viral particles in the stroma • Cellular infiltrates: neutrophils /leukocytes • Continued disease process after viral clearance Immuno-pathogenesis experimental rodents

Rodent model • Phase 1: Innate immunity • Cytokines/VEGF • Phase 2: CD4Th cells • Cytokines • Orchestrate stromal keratitis • Virus-specific CD4+T • Bystander activated CD4+T • (Auto-reactive T cells) • Phase 3: • Exacerbation of disease

Knickelbein; Future Virology 2010 Treatment

• Trigger • Immune response • FHV-1 • Topical steroids? • CsA / Tacrolimus?

Target both avenues for maximum therapeutic effect? Targeting the immune response

• Topical steroids • + Reduced cellular infiltration, scarring, vascularization • - Exacerbate active viral infection, opportunistic infection • Cyclosporine • + T cell specific suppression, reduces vascularization • - Suppressing T cells may interfere with viral control. No direct effect on bystander activated T cells

Weigh the benefits against the risk Comparative comments: Herpes Simplex Keratitis in people

• Topical or oral antivirals

• Topical corticosteroids (fluo -)

• Topical cyclosporine

• Long-term oral antiviral therapy Ch. Tappeiner / the cornea

Plan of the lecture

1. GENERAL PRINCIPLES OF IMMUNOLOGY 2. DEFENSE MECHANISMS OF TEARS AND OCULAR SURFACE 3. IMMUNE PRIVILEGE OF THE CORNEA 4. OCULAR IMMUNE PRIVILEGE, ACAID, THERAPEUTIC APPLICATIONS 5. IMMUNE MECHANISMS OF UVEITIS LET’S TAKE A BREAK Spend some time doing other things. Come back later. PART 4: OCULAR IMMUNE PRIVILEGE & ACAID THERAPEUTIC APPLICATIONS Overview

1. History and meaning of immune privilege 2. Multiple aspects of immune privilege 3. Anterior Chamber Associated Immune Deviation 4. Clinical applications • Corneal transplantation • Cell therapy Ocular Immune Privilege - landmarks