Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

might be beneficial not only for rheumatoid arthritis, but also for systemic lupus erythematosus and other B-lymphocyte-driven diseases. Currently, there is no reported experience of using systemic monoclonal antibodies in management of corneal or limbal allograft rejection. The long-term efficacy and safety of these experimental approaches for ocular surface diseases await further investigation.

Topical application of monoclonal antibodies to manage corneal graft rejection is generally ineffective because of poor antibody penetration across the ocular surface. Subconjunctival injection of antibodies to IL-2 receptor was effective in an animal study [111], and intracameral injection of monoclonal antibodies to CD3 and CD6 were also effective in reversing acute corneal graft rejection clinically [112]. A suitable form of local delivery needs to be developed to facilitate the topical application of monoclonal antibodies for ocular surface diseases and allograft rejection.

Intravenous Immunoglobulin. Intravenous immunoglobulin (IVIG) has proven efficacy in specific immunemediated diseases, such as Guillain-Barre syndrome and idiopathic thrombocytopenic purpura [113]. It has been used in other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, vasculitis, and multiple sclerosis [114–118]. One small study reported that approximately 50% of patients with uveitis refractory to immunosuppressive medication benefited from intravenous immune globulin [119].

IVIG exhibits several immunoregulatory functions mediated by the crystallizable Fc fragment of immunoglobulin G (lgG) and by a spectrum of variable regions contained in the immunoglobulins [120]. Although IgG is the major component of IVIG, other minor constituents such as solubilized lymphocyte surface molecules can also exert regulatory effects on T and B cells. Several mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG, including: (1) functional blockade of Fc receptors on splenic macrophages; (2) inhibition of complement activation by binding C3b and C4b;

(3) modulation of the synthesis and release of cytokines and their antagonists; (4) neutralization of circulating autoantibodies by reacting with idiotypes of natural or disease-related autoantibodies; (5) selection of immune repertoires by selectively suppressing autoantibody producing clones; (6) interaction with surface molecules of T cells, nonpolymorphic determinants of major histocompatibility complex Class 1 molecules, and adhesion molecules of T and B cells; and (7) alteration of the general “architecture” of the immunoregulatory network as assessed by the spontaneous fluctuations of natural antibodies in serum [121].

IVIG has been used successfully in selected cases of recalcitrant mucous membrane pemphigoid [122]. The mechanism by which IVIG produces clinical remission in patients with mucous membrane pemphigoid has not been well delineated. In one representative patient, the titer of the antibody to human β4 integrin was reduced after IVIG and correlated with disease activity. This preliminary finding suggests that IVIG has a direct impact on autoantibody

production. The relative lack of significant side effects makes IVIG a viable therapeutic option for recalcitrant ocular surface inflammation.

Levels of immunoglobulins should be quantified in each patient before therapy. If normal (especially IgA), therapy generally starts at 2–3 g Ig/kg per cycle of treatment divided over 3 days. Premedication orally with 650 mg acetaminophen and 50 mg benadryl to reduce the pain and itching 30 min before infusion is often necessary. A slow, continuous infusion lasting 4–6 h using an infusion pump is given in an ambulatory setting. The infusion cycle is repeated every 2–4 weeks until the ocular surface inflammation has subsided. The frequency of the infusion cycle is spaced to every 4–6 weeks for at least 6 cycles once the beneficial effect is sustained. Administration of IVIG is associated with headaches, malaise, thrombophlebitis, sterile meningitis, and serious vaso-occlu- sive events, such as stroke [119]. IVIG is a pooled blood product that could potentially transmit blood borne infections. It is a very costly therapy.

III.NEW THERAPIES ON THE HORIZON

Our expanding knowledge of other cytokines and molecules in immunoregulation suggests an array of other potential targets, such as monoclonal antibodies to CD4, CD7, CD5, and CD52, which are surface antigens of T cells. The result of blockade at these various sites would be expected to interfere with cellular interactions or cytokine binding of T cells. Oral tolerance has also being investigated, based on the premise that the systemic immune response can be inhibited by oral exposure to an antigen. One small clinical trial on oral feeding with retinal S antigen demonstrated equivocal benefits in patients with uveitis [123].

Severe inflammation in various ocular surface diseases can be difficult to control, and conventional anti-inflammatory or immunosuppressive therapies are often ineffective. Numerous conventional treatments and newer surgical interventions are currently being employed earlier and more aggressively to manage these relentless conditions. For refractory patients, the expanding array of novel agents offers additional options to manage these challenging ocular surface diseases more effectively and to circumvent the untoward side effects of the conventional therapy. Judicious selection of combined medical and surgical modalities should improve the clinical outcome of devastating ocular surface inflammatory diseases.

IV. SUMMARY

1.Corticosteroids are widely used as initial therapy for many autoimmune diseases, ocular surface inflammation, and allograft rejection.

Judicious use of other immunosuppressive drugs, either in combination with corticosteroids for initial therapy, or without corticosteroids when appropriate, can control inflammation with less risk of side effects.

2.Immunosuppressive alkylating agents, such as cyclophosphamide and chlorambucil, cause cross-linking of DNA and RNA in lymphocytes. Bone marrow suppression and carcinogenesis are major side effects.

3.Antimetabolite immunosuppressive agents, such as azathioprine, methotrexate, mycophenolate mofetil, and leflunomide, block synthesis of precursors necesary for DNA replication. Therefore, they tend to target rapidly dividing cells.

4.Immunosuppressive T-cell inhibitors, including cyclosporine and

tacrolimus, inhibit T-lymphocyte activation by indirectly blocking transcription of important lymphokines, such as IL-2, IL-4, and γ- interferon.

5.Biological immunosuppressants include engineered receptors or monoclonal antibodies directed against TNF-α, CD4, CD4, CD20, and receptors for IL-1 and IL-2. Molecules directed against other immunological targets are under investigation. Several have proven useful for treatment of rheumatoid arthritis and graft rejection; however, methods that improve their penetration across the ocular surface would allow topical treatment of ocular surface inflammatory diseases and allograft rejection.

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