Transcript antigen specific cytotoxic T cells

Immunology
of
Uveitis
(Autoimmune Uveitis)
Dr S.H. Zarkesh
Department Of Immunology, Medical School, Isfahan University
Of Medical Sciences, Isfahan,
I.R.IRAN
 email: [email protected]
 Website: www.shef.ac.uk/hamid
Autoimmune Disease
Definition
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Ehrlich referred to this phenomenon as horror
autotoxicus
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Specific adaptive immune response directed
against self antigen(s) with loss of tolerance,
usually peripheral, not central
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Trigger(s) is usually unknown.
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Immune response involves both environmental
and genetic factors
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female predominance
Autoimmune Disease
Characteristics
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remissions and exacerbations
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organ specific or organ non-specific
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persistence of antigen due to lack of clearance
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tissue damage is produced by:
 antigen specific cytotoxic T cells (CD8+)
 antigen-non-specific NK cells and
macrophages
 immune complexes
 autoantibodies , and/or
 granulocytes
Possible Pathogenic Defects
Human Autoimmunity
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Multiple genes are involved in human autoimmune disease e.g.
IDDM (type I), especially involving the MHC
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Defects in several of these genes may:
– disrupt multiple tolerance pathways and
– contribute in an additive or synergistic way to these polygenic
diseases
Important individual roles for:
 Fas-FasL
 IL-2/IL-2R (AICD)
 B7-CTLA-4 interaction
This suggests that each role may be involved in different pathways
of tolerance, perhaps for distinct types of self antigens
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Human Autoimmune Diseases
Organ Non-Specific Diseases
• SLE (systemic lupus erythematosus)
• RA (rheumatoid arthritis)
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Autoimmune uveitis
can be
• part of a systemic autoimmune syndrome involving
multiple tissues, such as Behc¸et’s disease, systemic
sarcoidosis.
• In other diseases the eye may be the only target,
such as in idiopathic uveitis, birdshot
retinochoroidopathy, and sympathetic ophthalmia
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Uveitic diseases are believed to have an
• autoimmune component supported by:
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1) lack of a known infectious trigger
• 2) and by frequent presence of immunological
responses to retinal proteins.
• 3) Many uveitic diseases show strong
• associations with particular human leukocyte
antigen (HLA) haplotypes.
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The model of experimental autoimmune
uveitis/uveoretinitis
• (EAU)
•
In rodents is used as an animal model for
• human uveitis.
• The classical model of EAU is induced by
• active immunization with a retinal antigen (Ag) emulsified in
• complete Freund’s adjuvant (CFA), a mineral oil
supplemented
• with heat-killed mycobacteria.
• In all but the most
• susceptible mouse and rat strains, an injection of pertussis
• toxin must be given as an additional inflammatory stimulus
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uveitogenic stimulus that is thought to trigger uveitis in
humans, which is believed to involve
• 1) an exposure to a retinal or cross reactive Ag, combined
with an infectious event that
• provides innate inflammatory danger signals.
• 2) Uveitogenic retinal proteins include
• retinal arrestin (soluble Ag),
• interphotoreceptor
• retinoid-binding protein (IRBP),
• rhodopsin,
• recoverin,
• phosducin,
• and retinal pigment epitheliumderived RPE-65.
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Of the available models,
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the mouse model of EAU induced with retinoid-binding protein
(IRBP) is the best characterized and the most widely used.
The typical histological appearance of EAU resembles that of
human uveitis, with inflammatory infiltrates in the vitreous,
retina,
and choroid and damage to the photoreceptor cell layer. You can
see the details of this phenomenon in next slide.
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Adaptive/effector T cells from EAUinduced animals can pass the disease to
naı¨ve, genetically compatible recipient
animals by adoptive transfer.
The donor T cells are activated with the
immunizing Ag in vitro and are infused into
recipient animals.
The recipients develop a destructive disease
rapidly, usually within a week.
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Recently, an alternative model to IRBP/CFAinduced uveitis have been developed .
Dendritic cells (DC) are professional
Ag-presenting cells capable of stimulating naı¨ve T
cells, and are likely to be the main Ag-presenting
cells in the early stages of EAU induction.
A model of EAU was developed
by injection of matured splenic DC loaded with the
major uveitogenic peptide of IRBP into naı¨ve wildtype mice.
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Compared with the classical EAU model induced by active
immunization with IRBP or its peptide in CFA,
1) duration of the disease is shorter, the pathology
appears to be less severe,
2) and the inflammatory infiltrate has a predominantly
granulocytic rather than mononuclear cell composition.
Importantly,
3) EAU elicited with Ag-pulsed DC is not only clinically
distinct from CFA induced EAU, but also is driven by unique
effector mechanisms
. This model may offer new insights into the heterogenous
nature of human uveitis.
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Cytokines play an important role in maintaining lymphocyte
homeostasis under conditions of health and disease.
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Intraocular expression of cytokines has been studied in patients
with uveitis, with reports of increased levels of inflammatory
cytokines and decreased levels of regulatory
Cytokines.
The roles of various cytokines and how they affect the
critical checkpoints of uveitis, as studied in animal models
and to a lesser extent in patients, are shown in Table 1 and
discussed in the following slides.
Th1 Cells and Cytokines in
Uveitis
(IFN-gamma and IL-12)
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IL-12, composed of 2 heterodimeric subunits, p35 and p40
is produced by DC and macrophages, is a key Th1-inducing
cytokine.
The roles of IL-12 and of IFN-g, the main signature
cytokine of the Th1 lineage, have been intensively studied in
EAU models in the 1990s.
At that time, the Th17 subset
(discussed ahead) had not yet been described, and the Th1
subset was thought to be the major pathogenic effector T cell
subset in uveitis.
An IRBP-specific uveitogenic T cell line
polarized to the Th1 phenotype in the presence of IL-12 and
producing massive amounts of IFN-g was highly uveitogenic
in naı¨ve recipient animals.
Emerging Treatments of Clinical Uveitis
Targeting Cytokines and Their Receptors
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Established therapies for uveitis are based
largely on
nonspecific immunosuppression
(corticosteroids, antimetabolites,and alkylating
agents).
However, because of the severe side effects of
these treatments, it is important to develop new
approaches based on increased understanding
of basic disease mechanisms, so as to intervene
more specifically in the pathogenic processes
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Although involvement
 of many cytokines has been demonstrated in
experimental
 Uveitis as shown in the next slide.
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One of the hazards involves the pleiotropic
nature of some cytokines and the possibility to elicit
unexpected reactions. As an example, a clinical trial to
treat
multiple sclerosis that was undertaken on the basis of
early
data in mice showing that IFN-g can have protective
effects
in EAE (similarly to EAU) resulted in exacerbation of
the
disease and had to be stopped
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CsA was first shown to have a therapeutic
effect in the rat EAU model before going to
clinical trials.
 The macrolides FK-506 (tacrolimus) and
rapamycin (sirolimus) also target the IL-2
signaling pathway and are effective for
some types of uveitis
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More recent studies have examined IL-2
receptor-directed therapy with monoclonal
antibodies (daclizumab) as an approach
 to target activated T cells.
 This therapy has shown efficacy in
advanced clinical trials.

Interestingly,the possibility that such
treatment might actually aggravate
 T cell-mediated autoimmunity because IL-2
is necessary for the maintenance and
activity of Treg cells (at least in mice)
 was not fulfilled.
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The mechanism behind the therapeutic
effects
 of daclizumab is complex and incompletely
understood,
 but includes an enhancement in CD56bright NK cells with inhibitory function
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Since the eye is a small and relatively closed
organ, local therapies in the eye are an
attractive approach that can obviate systemic
side effects.
Intravitreal injections or implants are already
in use for such local therapies, and biological
products can also be delivered into the eye.
Locally produced IL-10 has been shown to be
beneficial in animal models
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This
opens the possibility for intraocular injection
of other antiinflammatory
• molecules, such as IL-27 and IL-35, or even
• in vitro generated Treg cells. For this purpose,
it will be important
• to develop minimally invasive and highly
efficient
• local drug delivery approaches
Approach to Treatment

Anterior Uveitis
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Posterior Uveitis
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Topical:
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Local:
 Steroid drops
 Periocular steroid
injections
 Cycloplegics
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Systemic:
 Corticosteroids
 Steroid sparing agents
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Systemic:
 Corticosteroids
 Steroid sparing agents
Treatment of Refractory Uveitis:
Conventional Therapies
Drug
Dosage and
route
Monitoring
Methotrexate
10-25 mg/week Monitor as in RA
Oral or parenera
Cyclosporine
5 mg/kg/day, oral
Monitor creatinine,
Mg++ and lytes
Azathioprine
1-1.5 mg/kg/day,
oral
Montor CBC and
LFTs
Cyclophosphamide
1-1.5 mg/kg/day,
oral
Monitor CBC and
Urinalysis