Ординатура / Офтальмология / Английские материалы / Practical Manual of Intraocular Inflammation_Dick, Okada, Forrester_2008
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Tregs can be induced by tolerizing DC and indeed this is the main mechanism thought to underlie mucosal tolerance. In this process, antigen administered via the nasal or gut mucosa is picked up by DC in the lining mucosal tissues and transported to the draining lymph nodes where they induce Tregs. This type of induced “mucosal tolerance” has been shown to prevent induction of many experimental autoimmune diseases including experimental autoimmune uveoretinitis and has been tested in clinical trails of multiple sclerosis and uveitis, with a small clinical benefit. The main problem with this approach has been the lack of strength of the overall tolerance response.
Other strategies have therefore been investigated: one of these is to attempt to induce a high concentration of antigen-specific Tregs by administering “tolerizing DC” loaded with specific antigen. The key to this is to generate sufficient numbers of tolerizing DC, itself a difficult cell to define, since DC demonstrate considerable plasticity and there is a fine line between inducing tolerance or immunity. Indeed DC vaccination is mostly being studied from the standpoint of stimulating immune responses, e.g., to tumors as in cancer immunotherapy or infectious disease. Tolerizing DC can be generated in vitro from bone marrow or circulating DC precursors if the conditions are correct. Thus, antigen-loaded DC have been shown to prevent many experimental autoimmune diseases and most recently to prevent ongoing autoimmune diabetes in a transgenic mouse model. Tolerizing DC have also been shown to prevent experimental autoimmune uveoretinitis (17,18) and this they do via expanding the population of antigen-specific Tregs in the draining lymph node.
The exciting prospect is therefore presented in which it would be possible to regulate a patient’s STOI by culturing autologous DC from the blood in the presence of antigen and to induce large numbers of Tregs, which can then be transfused back to the patient. The question of antigen specificity here may be less important than previously thought; i.e., it may be possible to expand the Tregs using one or more than one retinal or even nonretinal antigen, since Tregs once induced act in a nonantigen-specific manner. In addition, the notion of bystander tolerance described above suggests that Tregs to one antigen may expand to associated antigens if presented in the right context and vicinity. The availability of spontaneous models of uveoretinitis allows these concepts to be tested with direct relevance to the clinical situation of ongoing disease.
BEDSIDE TO BENCH TO BENCH TO BEDSIDE
There is a current trend for “translational medicine,” which encompasses the concept of converting results from experimental studies to clinically relevant treatments for actual diseases, i.e., shifting research from the intellectual pursuit of
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fundamental mechanisms to practically useful research outcomes. In fact, those working in the field of applied experimental medicine will consider that part of their remit has always been to develop translational medicine. Good examples of these approaches are shown in the early translation of results using cyclosporine A, tacrolimus, anti-TNF-a therapy, and the emergence of interferon-a (IFN-a) for the treatment of retinal vasculitis. The history of IFN-a is unusual. IFN-a was the first cytokine to be isolated and has been in clinical use for many years for the treatment of various conditions, including hepatitis C and certain tumors. At one time it was proposed as an antiangiogenic therapy for age-related macular degeneration, but the clinical evidence was not strong. Its role as an immunostimulant and promoter of systemic autoimmunity is well recognized, but in autoimmune uveoretinitis, it was reported to have an inhibitory effect (19). Accordingly, it was trialed in a very large case series of patients with severe STOI due to Behc¸et’s disease with remarkable effect (20). A second large series confirmed these initial results and since then further reports of its effectiveness in non-Behc¸et’s disease have been reported (21). These clinical results have generated a series of bench investigations to determine how IFN-a has this clinical effect. IFN-a is known to modulate the function of other groups of circulating T cells in several conditions and has similar effects in T cells from patients with uveitis (5).
In this regard, the work on DC in uveitis has opened a reverberating loop of bench to bedside research. IFN-a is known to be produced by many cells in response to viral infection but constitutively only by a rare subset of DC, known as plasmacytoid DC (pDC). It followed therefore that if IFN-a is effective in certain forms of severe uveitis, it may be acting as a replacement therapy and thus perhaps there is an intrinsic defect in IFN-a production by pDC, particularly in pDC from patients with uveitis. This turned out to be the case: patients with uveitis have a reduced number of pDC, which collectively have a significantly reduced ability to secrete IFN-a in response to stimulation by toll receptor ligation (TLR9) (5). Thus, the clinical problem and the experience is leading back toward a more complete understanding of the pathogenesis of the disease which may in turn lead to a better understanding to the role of Tregs under the control of DC and eventually better treatments.
CONCLUSION
This Chapter has described a few of the many research questions which are raised by the clinical problem of sight-threatening uveitis and ocular inflammation. We hope it also highlights the importance of such research questions in helping us understand the basis of immune tolerance and how it breaks down in autoimmune disease. The value of animal models discussed and the particular value and
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insights which can be gained from the ocular models for immunological studies has in the past led to the current immunotherapies which we use and will in the future deliver hopefully more promising therapies.
REFERENCES
1.Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140(3):509–516.
2.Kilmartin DJ, Fletcher ZJ, Almeida JA, et al. CD69 expression on peripheral CD4þ T cells parallels disease activity and is reduced by mycophenolate mofetil therapy in uveitis. Invest Ophthalmol Vis Sci 2001; 42(6):1285–1292.
3.Curnow SJ, Falciani F, Durrani OM, et al. Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Invest Ophthalmol Vis Sci 2005; 46(11):4251–4259.
4.Murphy CC, Duncan L, Forrester JV, et al. Systemic CD4(þ) T cell phenotype and activation status in intermediate uveitis. Br J Ophthalmol 2004; 88(3):412–426.
5.Plskova J, Greiner K, Muckersie E, et al. Interferon-alpha: a key factor in autoimmune disease? Invest Ophthalmol Vis Sci 2006; 47(9):3946–3950.
6.Nussenblatt RB, Palestine AG, Rook AH, et al. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983; 2(8344):235–238.
7.Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19(3):281–286 (review).
8.Wacker WB, Lipton MM. Experimental allergic uveitis: homologous retina as uveitogenic antigen. Nature 1965; 206 (981):253–254.
9.Forrester JV, Liversidge J, Dua HS, et al. Comparison of clinical and experimental uveitis. Curr Eye Res 1990; 9(suppl):75–84 (review).
10.Gocho K, Kondo I, Yamaki K. Identification of autoreactive T cells in Vogt- Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 2001; 42(9):2004–2009.
11.Lambe T, Leung JC, Ferry H, et al. Limited peripheral T cell anergy predisposes to retinal autoimmunity. J Immunol 2007; 178(7):4276–4283.
12.Lim WK, Chee SP, Sng I, et al. Immunopathology of progressive subretinal fibrosis: a variant of sympathetic ophthalmia. Am J Ophthalmol 2004; 138(3):475–477.
13.DeVoss J, Hou Y, Johannes K, et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med 2006; 203(12):2727–2735.
14.Broderick CA, Smith AJ, Balaggan KS, et al. Local administration of an adenoassociated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther 2005; 12(2):369–373.
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15.Bloquel C, Bejjani R, Bigey P, et al. Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF-alpha soluble receptor in uveitis. FASEB J 2006; 20(2):389–391.
16.Gocke AR, Cravens PD, Ben LH, et al. T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. J Immunol 2007; 178(3):1341–1348.
17.Jiang HR, Muckersie E, Robertson M, et al. Antigen-specific inhibition of experimental autoimmune uveoretinitis by bone marrow-derived immature dendritic cells. Invest Ophthalmol Vis Sci 2003; 44(4):1598–1607.
18.Siepmann K, Biester S, Plskova´ J, et al. CD4þCD25þ T regulatory cells induced by LPS-activated bone marrow dendritic cells suppress experimental autoimmune uveoretinitis in vivo. Graefes Arch Clin Exp Ophthalmol 2007; 245(2):221–229.
19.Mizuguchi J, Takeuchi M, Usui M. Type I interferons as immunoregulatory molecules; implications for therapy in experimental autoimmune uveoretinitis. Arch Immunol Ther Exp (Warsz) 2002; 50(4):243–254.
20.Kotter I, Eckstein AK, Stu¨biger N, et al. Treatment of ocular symptoms of Behc¸et’s disease with interferon alpha 2a: a pilot study. Br J Ophthalmol 1998; 82(5):488–494.
21. Plskova J, Greiner K, Forrester JV. Interferon-alpha as an effective treatment for noninfectious posterior uveitis and panuveitis. Am J Ophthalmol 2007; 144(1): 55–61.
22.Bizheva K, Pflug R, Hermann B, et al. Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography. Proc Natl Acad Sci U S A 2006; 103(13):5066–5071.
Index
Abatacept, 165–166 Acquired Immunodeficiency
Syndrome (AIDS) 71–72
Acute annular outer retinopathy (AAOR), 106 Acute anterior uveitis, 3, 13
Acute idiopathic blind spot enlargement (AIBSE), 105–106
Acute macular neuroretinopathy (AMN), 106 Acute posterior multifocal placoid pigment
epitheliopathy (APMPPE), 59, 60, 107–108
Acute retinal necrosis (ARN), 58–60, 65–67, 127, 149
Acute zonal occult outer retinopathy (AZOOR), 106
Adalimumab, 165
AIDS. see Acquired immunodeficiency syndrome (AIDS)
associated ocular conditions, 73
and cytomegalovirus (CMV) retinitis, 68–70 AIRE gene. see Autoimmune regulator
(AIRE) gene Amebiasis, 91
American College of Rheumatology, 146 American Uveitis Society
criteria for diagnosis of ARN syndrome, 66–67 Anakinra, 165
Angiography, 39–40 Angiotensin-converting enzyme (ACE), 94 Animal models
for uveitis-uveoretinitis, 185–188 Anterior segment inflammation, 18 Anterior segment STOI
infectious, 130–131
[Anterior segment STOI] noninfectious, 136–137 treatment of, 125–126
Antigen-presenting cells (APC), 9, 13 Anti-inflammatory therapy
intraoperative, 172–173 postoperative, 174 preoperative, 171–172
ARN. see Acute retinal necrosis (ARN) Arteritis, 26, 48
Autoimmune regulator (AIRE) gene, 187 Autoinflammatory response, 8–10
activation of, 12 ocular disorders, 8 systemic disease, 8
evidence for, 10–14 Azathioprine, 144, 155–156
Bacillus Calmette-Guerin (BCG) vaccination, 77–78
Bacterial endophthalmitis, 75–77 Bacterial infections, 75–83
Bartonella henselae infection, 82–83 Baylisascaris procyonis, 90
Behc¸et’s disease, 5–6, 58, 59, 92–94, 159 international criteria for classification, 6
Bench to bedside research, 190–191 Binocular indirect ophthalmoscopic
grading of vitreal haze, 20–21 Biologic agents, 150, 162–166 Birdshot chorioretinopathy, 109–110 Birdshot choroidopathy
fluorescein angiography in, 41
195
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Index |
Blau syndrome, 95
Bone mineral density, 145–146
Borrelia burgdorferi, 81
Brucella species, 83
Campath-1H, 165
Candidemia, 84
Cat scratch disease, 82–83 Caucasian populations
birdshot chorioretinopathy, 109 pars planitis in, 114
Cellcept. see Mycophenolate mofetil Central retinal vasculitis, 20, 25–26, 34 Childhood arthritis
classifications of, 7 Choriocapillaris occlusive, 27 Chorioretinitis, 27
clinical signs of, 28–30 fundus color photographs, 29 symptoms, 27–28
Choroidal neovascular membrane (CNV), 131 Choroidal vasculopathy, 26–30
Choroiditis, 59–60
Chronic infantile neurologic cutaneous articular (CINCA) syndrome, 165
CINCA. see Chronic infantile neurologic cutaneous articular (CINCA) syndrome
Clinical diseases and animal models, 187 CME. see Cystoid macular edema (CME) CNV. see Choroidal neovascular membrane (CNV) Color vision, 140
Combination therapy
for noninfectious anterior segment STOI, 137 for noninfectious PSII, 135
Congenital rubella, 74 Conjunctiva, 167, 172 Contraindications
azathioprine, 156 cyclophosphamide, 159 cyclosporin A, 160 IFN-a, 163
infliximab, 164 methotrexate, 157 mycophenolate mofetil, 158 tacrolimus, 161
Corneal melt, 130 Corticosteroids, 152–153
adverse effects of, 154
for initial stages of STOI, 126
[Corticosteroids] local, 166–171
fluocinolone acetonide intravitreal implant, 169–171
intravitreal injections of, 166–169 noninfectious anterior segment STOI, 137 noninfectious PSII, 136
periocular injections of, 166–169 for mild and moderate PSII, 124–125 prescription for STOI, 133
relative contraindications of, 155 Corticosteroid therapy
for noninfectious PSII, 35 for ocular inflammation, 81
Cotton wool spots, 56–57 Crohn’s disease, 150 Cyclophosphamide, 158–160 Cyclosporin, 134, 144 Cyclosporin A, 160–161
versus tacrolimus, 161 Cyclosporine, 100 Cysticercosis, 91
Cysticercus cellulosae, 91 Cystoid macular edema (CME),
167, 172
documenting resolution of, 47 Cytomegalovirus (CMV) retinitis,
68–70, 170
Daclizumab, 165
Danger theory of immune response, 9 DC. see Dendritic cells (DC) Dendritic cells (DC)
vaccination, 189–190 Dengue fever virus, 75
DHFR. see Dihydrofolate reductase (DHFR) Differential diagnosis
based on the predominant PSII feature, 52–64
Diffuse subretinal fibrosis (DSF) syndrome, 112–113
Diffuse unilateral subacute neuroretinitis, 90 Dihydrofolate reductase (DHFR), 157 Disease burden, 3
Dosage azathioprine, 156
cyclophosphamide, 159 cyclosporin A, 160 IFN-a, 163
Index
[Dosage] infliximab, 164 methotrexate, 157
mycophenolate mofetil, 158 tacrolimus, 161
Early treatment diabetic retinopathy study (ETDRS), 140
Echinococcosis, 91 Electrophysiology, 142 Endophthalmitis
bacterial, 75–77 fungal, 84–85
ETDRS. see Early treatment diabetic retinopathy study (ETDRS)
Familial juvenile systemic granulomatosus, 94–95
Fluocinolone acetonide intravitreal implant, 169–171
Fluorescein angiography (FA). see Fundus fluorescein angiography
Fluorescein treponemal antibody absorption (FTA-ABS) test, 80
Folic acid, 157
Frosted branch angiitis, 57, 103–104
Fundus fluorescein angiography, 39, 40–42, 141 of PSII, 132
Fundus photography, 141
of inflammatory choroidal neovascular membrane, 132
Fungal endophthalmitis, 84–85 Fungal infections, 83–86
Gene knockdown, 189 Gene therapy, 188–189
Geographic choroiditis. see Serpiginous choroidopathy
German measles, 74 Glaucoma
intravitreal injections and, 168 and Retisert implant, 170, 171
Hepatotoxicity, 157 Herpetic retinopathy
color fundal photographs, 62
197
Histoplasma capsulatum, 85 Histoplasmosis-like disease, 85–86
HIV. see Human Immunodeficiency Virus (HIV) retinopathy, 71–73
HLA associations with noninfectious ocular inflammation, 13
Human Immunodeficiency Virus (HIV) 37 Human T lymphocyte virus type 1 (HTLV-1)
uveitis, 73–74 Hypothalamic-pituitary-adrenal axis, 152
IFN-a. see Interferon-a (IFN-a) Immune recovery uveitis, 70–71 Immunity, trigger by noninfectious
PSII, 8–10 Immunomodulatory therapy (IMT),
150–152
Immunosuppressive agents, 153–162. see also Corticosteroids
for noninfectious anterior segment STOI, 137
for noninfectious PSII, 134–135
IMT. see Immunomodulatory therapy (IMT) Indocyanine green angiography (ICGA),
39–40, 43–47, 142 Infliximab, 163–165
Interferon-a (IFN-a), 162–163, 191 Intermediate uveitis, 53
International Committee on Nomenclature revised diagnostic criteria for
VKH Disease, 97–98
International Study Group Criteria diagnosis of Behc¸et’s disease, 93
Intraocular B-cell lymphoma fundus color photographs of, 32
Intraocular lymphoma, 115–116 Intraocular pressure (IOP), 130, 168 IOP. see Intraocular pressure (IOP)
Ixodes, 81
Juvenile chronic arthritis (JCA), 7 Juvenile idiopathic arthritis (JIA), 7 Juvenile rheumatoid arthritis (JRA), 7
Keratitis, 130. see also Sight-threatening ocular inflammation (STOI)
198
Lumbar puncture, 37
Lyme disease, 81
Mantoux test, 37 Mechanism of action
azathioprine, 156 corticosteroid, 152 cyclophosphamide, 159 cyclosporine A, 160 IFN-a, 162–163 infliximab, 164 methotrexate, 157 mycophenolate mofetil, 158 tacrolimus, 161
Methotrexate, 156–158 Methylprednisolone, intravenous, 126
MEWDS. see Multifocal evanescent white dot syndrome (MEWDS)
Microhemagglutination – T. pallidum (MHA-TP) test, 80
Miliary tuberculosis, 129
Multicenter Uveitis Steroid Treatment (MUST) trials, 170–171
Multifocal choroiditis with panuveitis, 110–112 Multifocal evanescent white dot syndrome
(MEWDS), 104–105
related outer retinopathies, 105–106 Multiple sclerosis, 102–103
MUST trial. see Multicenter Uveitis Steroid Treatment (MUST) trials
Mycobacterium chelonae, 168
Mycobacterium tuberculosis, 77 Mycophenolate mofetil, 134, 144, 158 Myelosuppression, 156, 157, 159
Neoplastic disease, 115–116 Neuroretinitis, 82
diffuse unilateral subacute, 90
Nocardia asteroides, 83
Occlusive choriocapillaris, 27
OCT. see Optical coherence tomography (OCT)
OCT machines. see Ocular coherence tomography (OCT) machines
Index
Ocular coherence tomography (OCT) machines, 183
Ocular fluid sampling, 37 Ocular histoplasmosis, 85–86 Ocular imaging
in management of noninfectious of PSII, 39–40
Oligoclonal bands, 38 Onchocerciasis, 90–91 Ongoing binary signaling, 9 Ophthalmia, sympathetic,
100–101 Ophthalmomyiasis, 91 Optical coherence tomography
(OCT), 46–47, 142 Osteoporosis, 145–146
Panencephalitis, sclerosing, 74 Panuveitis, 63–64
Papillitis
conditions causing a predominant, 56 differential diagnosis of PSII by, 54
Parasitic infections, 86–90 Pars planitis, 113–115
Pattern recognition theory of immune response, 9
PDC. see Plasmacytoid DC (pDC) Perioperative medical treatment,
171–174
Peripheral retinal vasculitis, 25 Periphlebitis, causes of, 26 Perivascular cuff, 22, 23
PIC syndrome, 112–113 Plasmacytoid DC (pDC), 191 Pleocytosis, 38 Pneumocystis, 86
Posterior retinal vasculitis, 25
Posterior segment intraocular inflammation (PSII), 1. see also Uveitis
active disease, 18–26
and associated diseases, 129
clinical color fundal photographs of different forms of, 3
clinical evaluation of, 18–32 signs of associated structural
changes, 30–32 clinical features in, 52
Index
[Posterior segment intraocular inflammation (PSII)]
coexisting systemic disease assessment in, 34–39
corticosteroid therapy for noninfectious, 35 determination of infectious vs. noninfectious,
32–33
generic algorithm for treatment of, 33 immunopathology of, 7–14 infectious, 127–129
noninfectious, 131–136
ocular imaging in the management of noninfectious, 39–40
sight-threatening complication of noninfectious, 42
sight-threatening nature of, 34 treatment of, 124–125
visual function tests in the management of noninfectious, 47–49
Prednisolone, 133, 135. see also Corticosteroids
Presumed autoinflammatory diseases with systemic manifestations, 91–104
without systemic manifestations, 104–115 Primary intraocular lymphoma, 115 Progressive outer retinal necrosis (PORN),
67–68
PSII. see Posterior segment intraocular inflammation (PSII)
Quantiferon1 TB Gold assay, 78
Rapid plasma reagin (RPR) test, 80 Recrudescences, 135
Regulatory T cells, classes of, 11 Retinal infiltrates, 57–59
Retinal vasculitis, 22–26
arterial vs. venous involvement, 26 associated choroidal vasculopathy, 26–30 causes and associations of, 24 conditions causing a predominant, 58 differential diagnosis of PSII by, 54–57 fluorescein angiography in, 40, 41 fundus color photograph of, 25
features of, 57 symptoms, 24–26
199
Retinitis, 28
fundus color photographs, 30 Retisert implant, 169–171
Rickettsia rickettsii, 83 Rift Valley fever virus, 75 Rituximab, 166
“River blindness,” 90–91
Sarcoidosis, 5, 38, 53, 54, 94–96 Sclerosing panencephalitis, 74 Serous retinal detachment, 60–63 Serpiginous choroidopathy, 108–109
color fundal photographs, 62 Sheathing, 57
Sight-threatening disease, determination of, 34 Sight-threatening ocular inflammation (STOI).
see also Uveitis
animal models for pathogenesis of, 185–188 anterior segment
infectious, 130–131 noninfectious, 136–137 treatment of, 125–126
clinical problems in, 181–185 diagnosis of, 181–182
investigative tools for diagnosis of, 182–184 investigation before treatment of, 137–139 monitoring
response to treatment, 139–143 side effects of treatment, 143–146
posterior segment infectious, 127–129 noninfectious, 131–136 treatment of, 124–125
treatment problems in, 184–185
SiRNA. see Small inhibitory RNA (siRNA) Small inhibitory RNA (siRNA), 189 Snowbanking, 22
Standardised Uveitis Nomenclature (SUN), 2, 18
guidelines, 164 Steroid therapy
for noninfectious anterior segment STOI, 136 for noninfectious PSII, 131–133
STOI. see Sight-threatening ocular inflammation (STOI)
SUN. see Standardised Uveitis Nomenclature (SUN)