Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

poorly understood (Raulet and Vance, 2006).

Dendritic cells can also present antigen to T-cells. The T-cell recognizes peptides associated with MHC molecules on the dendritic cell. The nature of the antigen, the cytokine environment, and other molecules on the dendritic cell surface influence the T-cell response. A better understanding of the biology of T-cell responses offers the prospect of more effective therapeutic interventions (Chinen et al., 2006).

b. Adaptive immunity (B-cells, T-cells, APCs) – Adaptive immunity is the immune

response to a specific environmental antigen (Figure 12.2). The main players in this immunity are lymphocytes (T-cells and B- cells) and antigen presenting cells (APC).

Adaptive immunity takes longer than innate immunity to develop, occurring after the primary exposure to a pathogen or vaccine. However, adaptive immune responses are characterized by the ability to respond to a wide range of different types of antigens (i.e. diversity) and the ability to develop long-lasting immunologic memory, which is the result of the expression of rearranged antigen receptors on lymphocytes. This results in a pool of memory lymphocytes

TH2

Activation of

Antigen

Specific B cells

TH1

Activation of

Antigen

Specific Effector

T cells

Cytotoxic Killing

of Cells Infected

with Virus

Memory

B Cells

Ab Secretion from Activated Plasma Cell

Innate Response:

Macrophage Engulfs the Invading Microbe Releases Cytokines which Recruit Inflammatory Cells

Adaptive Response: Memory B Cells

(IgG, E,A) and T Cells are Rapidly

Expanded and Eliminate Microbe

(both T- and B-lymphocytes) that can be rapidly mobilized, expanded and differentiated into peripheral effector cells to mediate a protective immune response against an invasive microbe.

It is noteworthy that innate and adaptive immunity are highly interactive and play critical roles in initiating inflammation, amplifying an immune response, shaping the nature of the immune response, eliminating the pathogen, and terminating the immune effector mechanisms at an appropriate time. Both adaptive and innate immunity share common effector molecules, particularly cytokines and chemokines. These mediators are critical for cell–cell interactions, activation and migration of effector cells, and the generation of an effective immune response.

Induction of a primary immune response begins when an antigen penetrates epithelial surfaces. It will eventually come into contact with macrophages or other antigen presenting cells (APCs), such as B-cells, monocytes, dendritic cells, Langerhans’ cells and endothelial cells. Antigens, such as bacterial cells, are internalized by endocytosis and “processed” by the APC, then “presented” to immunocompetent lymphocytes to initiate the early steps of the immunologic response. Processing by a macrophage results in attaching antigenic fragments associated with MHC II molecules on the cell membrane surface. The antigenclass II MHC complex is presented to a T- helper (TH2) cell which is able to recognize processed antigen associated with a class II MHC molecule on the membrane of the macrophage. This interaction, together with stimulation by interleukin 1 (IL-1), produced by the macrophage, will activate the TH2 cell. Activation of the TH2 cell causes that cell to begin to produce interleukin 2 (IL-2), and to express a membrane receptor for IL-2. The secreted IL-2 autostimulates proliferation of the TH2 cells. Stimulated TH2 cells produce a variety of lymphokines including IL-2, IL-4, IL-6, and gamma interferon that mediate various aspects of the

immune response. For example, IL-2 binds to IL-2 receptors on other T-cells (which have bound the Ag) and stimulates their proliferation, while IL-4 causes B-cells to proliferate and differentiate into antibodysecreting plasma cells and memory B-cells. IL-4 activates only B-cells in the vicinity which themselves have bound the antigen, and not others, so as to sustain the specificity of the immune response.

B-cells develop in the bone marrow and liver (in the fetus). During B-cell activation the cells become enlarged, and with subsequent cell division result in the expansion of specific clonal lineages. Antibodyproducing plasma cells have a very large rough endoplasmic reticulum and Golgi apparatus, which are necessary for the production and secretion of immunoglobulins. The expression of Ig mRNAs increases 6–12-fold while the expression of surface Igs decreases, since plasma cells produce only soluble antibodies.

The rearrangement of immunoglobulin genes takes place during development. In each cell a unique receptor is formed. Cells are eliminated if they express selfrecognizing receptors or fail to express a functional receptor. The lymphocytes recirculate from blood to tissues and back during their life span. The contact between APC and B/T cells occurs in secondary lymphoid organs such as the spleen, lymph nodes and mucosa-associated lymphoid tissues (MALT). Antigen binding is required for the final stages of development. Following antigen recognition, B-cells become activated either by themselves or with T-cell help. Once activated, B-cells proliferate; moreover, following selection, some of the cells differentiate into antibody-secreting plasma cells and later into memory cells. Two types of genetic changes occur during differentiation. First, somatic mutations change the antigen binding properties so that B-cells can bind antigens more avidly. Second, class switching, which results from a change in the heavy chain constant region within the Ig, alters the way that immunoglobulins on

B-cells are recognized by effector cells (e.g. cells from innate immunity).

T-cells are essential components of the adaptive immune system, and respond to immune challenges by interacting with APC of the innate immune system or with B-cells (Santana and Esquivel-Guadarrama, 2006). They can differentiate into two major populations of effector cells – type one (Th1) or helper cells and type two (Th2) or cytotoxic cells. T-cells become tolerant to self antigens during development by mechanisms similar to B-cells. In addition, subsets of T-cells have regulatory functions to control the immune response and prevent innocent bystander destruction of tissue.

2. Mechanisms of cell signaling in immunemediated inflammation (chemokines, cytokines and prostaglandins)

Chemokines are chemotactic mediators controlling cell trafficking under physiological and pathological conditions. Recently, it has been discovered that chemokines are not only important in various inflammatory conditions, but that they also play a role in pain. The complex interplays between cytokines and chemokines are emerging as key communication signals in the shaping of innate and adaptive immune responses against foreign pathogens, including viruses. In particular, the virusinduced expression of cytokine and chemokine profiles drives the recruitment and activation of immune effector cells to sites of tissue infection (Salazar-Mather and Hokeness, 2006).

Chemokines are a group of small (8–10 kDa), secreted proteins that were initially identified by their ability to attract leucocytes. These molecules induce cellular migration along concentration gradients that govern leucocyte accumulation in tissue during inflammation, and modulate interactions with resident cells (Zlotnik and Yoshie, 2000).

Together human and animal studies have identified several chemokines in different forms of uveitis, produced both by resident and infiltrating cells, that strongly

suggests a prominent role for these molecules in its pathogenesis. Importantly, chemokines and their receptors may act as novel therapeutic targets to prevent leucocyte migration, activation, and retention in inflamed ocular tissue.

To date, 47 chemokines and 19 chemokine receptors have been identified and characterized. In recent years, investigations into the role of chemokines and their receptors in ocular disease have generated an increasing number of publications. In the eye, the best understood action of these molecules has arisen from the study of their ability to control the infiltration of leucocytes in uveitis (Wallace et al., 2004).

Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis. They must be produced de novo in response to an immune stimulus. They generally (although not always) act over short distances, short time spans and at very low concentration. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior (gene expression). Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules. Cytokines are made by many cell populations, but the predominant producers are helper T-cells (Th) and macrophages. The largest group of cytokines stimulates immune cell proliferation and differentiation. This group includes interleukin 1 (IL-1), which activates T-cells; IL-2, which stimulates proliferation of antigenactivated T- and B-cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B-cells; interferon gamma (IFNg), which activates macrophages; IL-3, IL-7 and granulocyte monocyte colony-stimulating factor (GM-CSF), which stimulate hematopoiesis. IFN-γ is the most abundant cytokine in uveitis (Takase et al., 2006).

It is known that there are multiple cytokines and chemokines present in the

inflamed eye and these can have several different roles. Experimental animal models of ocular autoimmunity have suggested uveitis is Th1 mediated. Th1 and Th2 subsets can be identified on the basis of their cytokine secretion or by the expression of certain chemokine receptors (Th1 associated with CCR5, CXCR3 and Th2 associated with CCR4).

Prostaglandins (PGs) are unsaturated carboxylic acids, consisting of a 20 carbon skeleton that also contains a 5 member ring. They are biochemically synthesized from the fatty acid, arachidonic acid. They produce a variety of physiological effects including activation of the inflammatory response, and production of pain and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result.

Leukotrienes are derived from arachidonic acid, the precursor of prostaglandins. There are two families of leukotrienes. The first group acts primarily in conditions in which inflammation is dependent on neutrophils, such as cystic fibrosis, inflammatory bowel disease, and psoriasis. The second group (cysteinyl-leukotrienes) is concerned primarily with eosinophil and mast cell-induced bronchoconstriction as in asthma. Leukotrienes act principally on a subfamily of G protein coupled receptors. Leukotrienes are very important agents in the inflammatory response. Some, such as LTB4, have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in vasoconstriction, particularly of venules and of bronchoconstriction, they also increase vascular permeability. Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4.

PGs and leukotrienes are mediators of various aspects of inflammation. In the eye, PGs are primarily involved in vasodilation and disruption of the blood–aqueous barrier. Inflammation, whether in the eye or in other tissues, is more complex than

the tissue response to injury. The complement pathway, arachidonate metabolites, cytokines and chemokines are major components in inflammation, but not necessarily in the response of tissues to injury. Topical or intracameral administration of LTB4 causes PMN chemotaxis without affecting the blood–aqueous barrier. Peptidoleukotrienes such as LTC4 and LTD4, on the other hand, are not chemotactic but increase the permeability of the conjunctival microvasculature. Cyclooxygenase and 5-lipoxygenase products have been detected in the anterior chamber during the course of experimen- tally-induced ocular inflammation and in humans with uveitis, but whether their presence is incidental or causal is yet to be established. In spite of numerous investigations, the precise role and the extent of involvement of arachidonic acid metabolites in ocular and non-ocular inflammatory diseases remain controversial.

B. Autoimmunity

1. Immune privilege

The tissues of the eye are considered to be collectively protected by immune privilege (Forrester and Cornall, 2003). The modern era of research on immune privilege of the anterior chamber (AC) of the eye was initiated by Kaplan and Streilein (1977). Theses investigators injected allogeneic lymphoid cells into the AC of one eye of adult rats. Their first observation was that the recipient rats produced circulating antibodies against donor antigens. Their second observation was that rats that received allogeneic lymphoid cells intracamerally were less able to reject orthotopic skin grafts from the same donor than were normal rats. These experiments revealed that active processes, and not solely sequestration of the antigen from the host immune response, were set in motion by antigens placed in the anterior chamber, and that these processes affected both the eye and the systemic immune apparatus. The distinctive systemic immune response to eye-derived antigens, in which humoral immunity is preserved

while aspects of cell-mediated immunity are inhibited, has been termed anterior cham- ber-associated immune deviation (ACAID) (Streilein et al., 2002; Streilein, 1999).

2. Tolerance

The primary responsibility of the immune system is to protect the host from foreign pathogens. Immune tolerance is selective in that the immune system ignores molecules native to the host and responds aggressively to remove pathogenic microbes. Autoimmune diseases are the result of breakdowns in immune tolerance. The development lineages of B-cells and T-cells contain several checkpoints at which autoreactive cells are blocked from maturation. The immune system maintains control over self/non-self discrimination with functional regulation of mature lymphocytes. Autoimmunity directed against antigens in immune privileged sites, which are normally hidden from the immune system by blood–organ barriers, requires already activated T-cells to enter the tissue where the respective autoantigens are sequestered. Autoimmune uveitis of the retina is such an example. To induce disease autoreactive T-cells must have been activated outside the eye, pass the blood–retinal barrier and react with a retinal autoantigen. Environmental peptides mimicking a highly pathogenic epitope from retinal S-antigen have been described (Wildner and edrichs-Mohring, 2004). These findings suggest that multiple environmental or systemic antigens may mimic organ-specific antigens and cause autoimmune disease inadvertently.

3. HLA association

The association between the human major histocompatibility complex (MHC), HLA (human leukocyte antigen)-B27 and its spectrum of HLA-B27-associated inflammatory diseases and acute anterior uveitis was originally described in 1973, and remains one of the strongest HLA-disease associations (Brewerton et al., 1973a,c,b; Schlosstein

et al., 1973). Despite intensive clinical and basic scientific research, the precise molecular and pathogenic mechanisms linking HLA-B27 and its associated inflammatory diseases remain unclear. However, it is apparent from the evidence of epidemiological and experimental studies, including those of HLA-B27 transgenic animals, that both genetic and environmental factors are important in the pathogenesis of HLA-B27- associated diseases.

C. Infection

1. Viruses

a. Herpesviruses – Herpesviruses are a leading cause of human viral disease, second only to influenza and cold viruses. They are capable of causing overt disease, e.g. chicken pox, and remaining silent for many years only to be reactivated, e.g. shingles. The name herpes comes from the Greek word herpein which means to creep. This reflects the creeping or spreading nature of the skin lesions caused by many herpes virus types.

There are 25 families in the Herpetoviridae but only 4 of them are known to infect the human eye: Herpes simplex virus type I (HSV-1), herpes simplex virus type II (HSV-2), Epstein–Barr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV).

Herpes viruses are enveloped viruses. They bud from the inner nuclear membrane which has been modified by the insertion of herpes glycoproteins. The viral membrane is quite fragile and a virus with a damaged envelope is not infectious. Besides drying, the virus is also sensitive to acids, detergents and organic solvents, as might be expected for a virus with a lipid envelope.

The hallmark of herpes infection is the ability to infect epithelial mucosal cells or lymphocytes. The virus then travels up peripheral nerves to a nucleated neurone where it may stay for years followed by reactivation. A reddened skin area may give

rise to a macula which crusts to form a papula. The fluid in this blister is full of virus. As long as the virus is kept moist it can remain infectious.

Both the cellular and humoral arms of the immune response are involved in infections caused by herpesviruses. Interferon is important in limiting the initial infection and NK cells are also involved at this stage. Cytotoxic T-cells and macrophages form the cellular arm of the immune response and kill infected cells. The humoral arm of the response (usually antibodies against surface glycoproteins) leads to neutralization of the virus. The virus can escape the immune system by spreading from one cell to another without entering the extracellular space and coming in contact with humoral antibodies. This means that cell-mediated responses are vital in controlling herpes infections. The cell-mediated and inflammatory responses lead to some of the disease symptoms. Clinically, anterior chamber inflammation occurs in up to 10% of patients with HSV keratitis (Gaynor et al., 2000; Liesegang, 1999) and roughly 50% of immunocompetent patients with herpes zoster ophthalmicus (Liesegang et al., 1989). Although the diagnosis of anterior herpetic uveitis is usually straightforward in the setting of dermatitis or dendritic keratitis, it can be quite challenging in the absence of these lesions. Moreover, patients usually are first seen with the fairly non-specific complaints of blurred vision, redness, pain and photophobia. Often overlooked clues to the diagnosis of herpetic anterior uveitis include the presence of localized corneal scars or edema, decreased corneal sensation, geographically or diffusely distributed keratic precipitates, acutely elevated intraocular pressure and iris atrophy – which is frequently localized and tends to produce both pupillary distortion and a sectoral transillumination defect. In addition, herpetic anterior uveitis is almost always unilateral.

b. HIV and AIDS – Human immunodeficiency virus (HIV) is a retrovirus that is the

cause of AIDS (Acquired Immunodeficiency Syndrome), a syndrome where the immune system begins to fail, leading to many lifethreatening opportunistic infections. HIV primarily infects vital components of the human immune system such as CD4 T-cells (destroying them), macrophages and dendritic cells. As CD4 T-cells are required for an effective immune system, destruction of CD4 T-cells by HIV compromises the immune system, leading to AIDS. HIV also directly attacks organs such as the kidneys, heart, and brain, leading to acute renal failure, cardiomyopathy, dementia and encephalopathy. Many of the problems faced by people infected with HIV result from failure of the immune system to protect the organ from opportunistic infections and the development of cancer.

HIV is a virus that is found in body fluids, especially blood and semen. The virus has molecules on its surface that allow it to attach to CD4 T-cells in the immune system. Once this happens, it enters the cell and effectively hides from the immune response while it reproduces and spreads to infect other lymphocytes. At this stage, an infected person carries the virus but shows no outward signs of AIDS. HIV may not cause any symptoms for several years as it spreads through the immune system. Eventually, the immune system is sufficiently compromised so that infections, e.g.

Pneumocystis carinii, pneumonia, or skin cancer, e.g. Kaposi’s sarcoma, develop.

Symptomatic anterior uveitis is rare in HIV-positive patients. The uveitis associated with cytomegalovirus retinitis, the commonest ocular manifestation in AIDS patients, is rarely symptomatic and patients do not typically present with a red, painful eye with blurred vision. Verma et al. reported 12 cases of symptomatic anterior uveitis in HIV-positive patients. They emphasize that in an HIV-positive patient with symptoms of uveitis, who does not have active CMV retinitis, the ophthalmologist must search for other causes such as tuberculosis or lymphoma, in those with granulomatous

uveitis, or herpes zoster, in those with nongranulomatous uveitis (Verma et al., 1999).

Cidofovir ([S]-1-[3-hydroxy-2-phophonyl- methoxypropyl] cytosine), an acyclic nucleotide analog, is effective in delaying progression of cytomegalovirus (CMV) retinitis (Lalezari et al., 1997). Non-granu- lomatous uveitis has been reported to be a complication in 26–44% of patients receiving intravenous cidofovir (Davis et al., 1997; Rahhal et al., 1996). The cause of this reaction is unknown, but has been associated with protease inhibitor use (Chavez-de la et al., 1997), suggesting that patients with a better immune function are at increased risk, and possibly explaining why recently reported rates of uveitis are higher than those reported during the drug’s development. In patients receiving intravitreal injections of cidofovir, the rate of anterior uveitis appears to be lower with concomitant use of probenecid through unknown mechanisms (Ambati et al., 1999). Ambati et al. studied receiving cidofovir for CMV retinitis to gain additional insight into factors related to the development of drug associated uveitis. They found that patients who developed uveitis had a greater rise in CD4 T-lym- phocyte counts while on cidofovir, and there is evidence linking CD4 T-lymphocytes to the pathogenesis of uveitis. The development of uveitis in these patients is important because uveitis in an immunocompromised patient can trigger potentially morbid diagnostic procedures or systemic treatment. Recognition of cidofovir associated uveitis can save the patient invasive interventions (Rosenbaum et al., 1980).

2. Bacteria

As prokaryotes all bacteria have a relatively simple cell structure lacking a cell nucleus and organelles such as mitochondria and chloroplasts. Most bacteria are relatively small and possess distinctive cell and colony morphologies (shapes) as described below. The most important bacterial structural characteristic is the cell wall. Bacteria

can be divided into two groups (Grampositive and Gram-negative) based on differences in cell wall structure as revealed by Gram staining.

Gram-positive bacteria possess a cell wall containing a thick peptidoglycan layer and teichoic acids while Gram-negative bacteria have an outer lipopolysaccharide (LPS) containing membrane and a thin peptidoglycan layer located in the periplasm. The LPS is also referred to as endotoxin and gives the bacteria its virulence. Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation induced by the administration of LPS (Bhattacherjee et al., 1983; Rosenbaum et al., 1980). LPS enhances the expression of various inflammatory mediators, such as interleukin (IL)-6 (Koizumi et al., 2003; Ohta et al., 2005), tumor necrosis factor (TNF)- α, and C-C chemokine ligand (CCL) 2/monocyte chemotactic protein (MCP)-1 – all of which contribute to the development of EIU, resulting in the breakdown of the blood–ocular barrier and the infiltration of leukocytes (Mo et al., 1999).

Infectious bacterial uveitis is treated by using the appropriate antibiotic to kill the pathogen. Because the body’s response to an invading microbe may be as damaging as the infection itself, anti-inflammatory treatments are frequently appropriate.

IV. CURRENT THERAPY

A. Non-Steroidal Anti-Inflammatory

Drugs

Prostaglandins promote inflammation, pain, and fever; support the function of platelets that are necessary for the clotting of blood; and protect the lining of the stomach from the damaging effects of acid. Prostaglandins are produced within the body’s cells by the enzyme cyclooxygenase (Cox). There actually are two Cox enzymes, Cox-1 and Cox-2. Both enzymes produce prostaglandins which promote inflammation, pain, and fever. However, only Cox-1

produces prostaglandins that support platelets and protect the stomach.

Non-steroidal anti-inflammatory drugs (NSAIDs) block the Cox enzymes and reduce prostaglandins throughout the body. As a consequence, ongoing inflammation, pain, and fever are reduced. Since the prostaglandins that protect the stomach and support the platelets and blood clotting also are reduced, NSAIDs can cause ulcers in the stomach and promote bleeding. NSAIDs differ in how strongly they inhibit Cox-1 and, therefore, in their propensity to cause ulcers and promote bleeding.

Ketorolac tromethamine 0.4% ophthalmic solution may be used for the reduction of ocular pain. As well as reducing pain and ocular inflammation, it is also used to treat cystoid macular oedema and to inhibit miosis (Perry and Donnenfeld, 2006).

A controlled clinical trial comparing the effect of topical NSAIDs versus potent corticosteroid preparations in acute anterior non-granulomatous uveitis concluded that there was no difference between the two groups initially. However, after 7 days of treatment the authors found significantly less inflammation in the corticosteroid treated group; a difference that disappeared on day 14 (Sand and Krogh, 1991).

When adverse reactions to corticosteroid eye drops are suspected, NSAID eye drops may be a useful alternative (Spinelli and Krohn, 1980).

B. Corticosteroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex and are involved in a wide range of physiologic responses – such as the stress response, the immune response, regulation of inflammation, carbohydrate metabolism, protein catabolism, and blood electrolyte levels.

Glucocorticoids, such as cortisol, are antiinflammatory by preventing phospholipid release, reversing increased vascular permeability, effecting the migration of

lymphocytes, and inhibiting eosinophil action, as well as through several other mechanisms.

Most patients with acute anterior uveitis rapidly resolve after treatment with topical corticosteroids. However, many forms of uveitis are chronic in nature and require prolonged treatment.

The aims of treatment are to control inflammation, prevent visual loss, and minimize the long-term complications of chronic inflammation (i.e. macular edema and posterior subcapsular cataract). Macular edema is the most common cause of visual loss in acute anterior uveitis, and thus, the commonest indication for treatment. Therapy is usually indicated if visual acuity has fallen to less than 6/12, or if the patient is experiencing visual difficulties performing their everyday tasks. In patients with longstanding macular edema and poor vision, a trial of immunosuppressive medications may be indicated to determine whether the visual loss is reversible. Many patients with unilateral chronic uveitis can be managed with topical corticosteroids to control inflammation in the anterior segment, with periocular corticosteroids used for the treatment of macular edema. Patients with useful vision in only one eye must be managed aggressively to control inflammation and preserve vision, including the combined use of systemic corticosteroids, immunosuppressive medications and the newer biologic drugs.

1. Topical treatment

Topical corticosteroids are the mainstay of treatment for both acute and chronic anterior uveitis. Mydriatics should be used with moderate or severe active inflammation in the anterior segment to ensure that the pupil remains mobile and to limit the formation of peripheral anterior synechiae and secondary angle closure glaucoma.

2. Periocular corticosteroids

Periocular corticosteroids may be injected via a posterior sub-Tenon’s or orbital floor

approach. They are contraindicated in patients with a history of glaucoma or cor- ticosteroid-induced ocular hypertension. If a beneficial response is achieved, repeated injections can be given when necessary, usually every 1–3 months. Periocular corticosteroids can be used safely in all age groups, but young children may require sedation or general anesthesia. Bilateral periocular injections may be used to avoid systemic corticosteroids in children, during pregnancy, and in patients with diabetes or psychiatric illness.

Treatment failures in patients with unilateral chronic uveitis should be assessed carefully as further treatment frequently necessitates the use of systemic drugs. The risks and benefits of long-term systemic treatment with corticosteroids and other drugs for unilateral ocular disease must be carefully evaluated and discussed with the patient.

3. Systemic corticosteroids

Corticosteroids are the mainstay of systemic treatment for patients with chronic uveitis, and the usual indication for treatment is the presence of macular edema and a visual acuity of less than 6/12 (Hemady et al., 1991; Lightman, 1991). Patients should be treated with an appropriate dose to determine whether the macular edema is reversible. Thus, 1.0mg/kg body weight/day of prednisone should be used for 2 to 3 weeks in divided doses. If there is no response, the addition of a second medication such as cyclosporin (or azathioprine or mycophenolate in older patients) for an additional 4 to 6 weeks should be considered. In children the doses should be adjusted appropriately (McCluskey et al., 2000).

If there is a response to corticosteroids the dose is tapered by 5–10mg a week until the lowest dose that maintains the improved vision is determined. If this dose is 10mg/ day it is not usually necessary to add a second agent, but if frequent relapses occur at the maintenance dose a second drug is usually indicated. All patients receiving

systemic corticosteroids should be regularly assessed for side effects, particularly diabetes, hypertension, and osteoporosis.

C. Immunosuppressive Therapy

Advances in immunology have been accompanied by the emergence of safer, more specific, immunosuppressive drugs, e.g. methotrexate, azathioprine, and cyclosporine A. These drugs have become an important part of the ophthalmologist’s armamentarium against inflammatory and immune-mediated ocular diseases.

Cyclosporin A is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-cells. This complex of cyclosporin and cyclophylin inhibits calcineurin, which is responsible for activating the transcription of IL-2, as well as lymphokine production and interleukin release. It has also an effect on mitochondria, preventing the mitochondrial PT pore from opening, and thus inhibiting the release of cytochrome C, a potent apoptotic factor.

Cyclosporin is often the second drug of choice for patients under 50 years of age (McCluskey et al., 2000). The commonest dose limiting side effects of cyclosporin are hypertension and renal dysfunction, which are usually reversible if the drug is stopped. Several other drugs can be considered in patients who require additional immunosuppressive therapy, with methotrexate being most frequently preferred by uveitis specialists. The decision to start treatment with immunosuppressive drugs is a long-term commitment by both the clinician and patient, as treatment is likely to last for a minimum of 6 months and is often much longer.

V. FUTURE THERAPY –

TARGETING BASIC MECHANISMS

A. Cytokines

The anti-tumour necrosis factor (TNF) monoclonal antibodies are representative