Indian Journal of Ophthalmology

EDITORIAL
Year
: 2001  |  Volume : 49  |  Issue : 2  |  Page : 77--78

Will the cytokine be the future therapy of uveitis?


Jyotirmay Biswas 
 Medical and Vision Research Foundation, 18 College Road, Chennai - 600 006, India

Correspondence Address:
Jyotirmay Biswas
Medical and Vision Research Foundation, 18 College Road, Chennai - 600 006, India




How to cite this article:
Biswas J. Will the cytokine be the future therapy of uveitis?.Indian J Ophthalmol 2001;49:77-78


How to cite this URL:
Biswas J. Will the cytokine be the future therapy of uveitis?. Indian J Ophthalmol [serial online] 2001 [cited 2020 Mar 29 ];49:77-78
Available from: http://www.ijo.in/text.asp?2001/49/2/77/22652


Full Text

The lead article "Role of cytokines in experimental and clinical uveitis" by Singh and coworkers[1] in IJO could surprise some ophthalmologists. Is this article relevant to Indian ophthalmologists? Yes, it is. Laboratory research in the past has led to new directions in understanding several ophthalmic diseases and introduced new therapeutic modalities. Recently Andrew Dick[2] in his editorial "The continuing need to publish laboratory science in clinical journals" commented, "There is an unarguable necessity to understand the molecular and cellular biology and pathology to improve what are mostly unsatisfactory therapy. By increased knowledge of underlying biological and pathological processes of visual disorders we will undoubtedly improve our patient care further." More recently Time magazine had a cover page article "Drugs of the future".[3] The drugs of future will not be by trial and error, but by design. The new generation drug will be formulated from genetic, molecular biologic and immunological research.

In this new millennium it is likely that there will be a paradigm shift in our understanding and management of various ophthalmic diseases including uveitis.[4] Since the description by Gordon in 1964, systemic corticosteroid has remained the mainstay in the management of noninfectious intraocular inflammation. In the 1970s, immunosuppressive drugs were introduced for vision-threatening and recalcitrant uveitis. Today, at least three new approaches are emerging in management of non infectious uveitis[5] - monoclonal antibodies (tumor necrosis factor antibody); antigen specific tolerazing therapy (oral S-antigen therapy); and gene therapy.[6] A randomized masked trial investigating the efficacy of oral tolerance by feeding retinal S-antigen is underway.[7] Nussenblatt and co-workers have also reported use of antibody directed against T-cell activated (TAC) portion of interleukin - 2 receptor.[7]

It is now quite evident that T lymphocytes and cytokines play a major role in the pathogenesis of uveitis. In the last 20 years at least 68 articles have appeared in peer-reviewed journals on cytokines and uveitis. Coincidentally, Ocular Inflammaton Today, a newsletter from the International Ocular Inflammation Society (IOIS) has published a similar article, "Cytokines in experimental and clinical uveitis" in October 2000. The article by Singh and coworkers in this issue is therefore quite timely and appropriate.

In a very simplistic way cytokines can be termed as a type of low molecular weight protein which communicates between cells. They, in fact, dictate which kind of cells or antibody will be involved in the defence mechanism of the host. There are at least 21 cytokines identified till date. Cytokines are produced by T cells, B cells, macrophages, endothelial cells and mast cells. T helper (Th) cells are now classified based on the type of cytokines they produce. Interleukin 2 (IL-2), interferon gamma (IFN γ.) and tumour necrosis factor α (TNF α) are produced by Th1 cells. These cytokines are involved in the cell mediated immune reaction like delayed hypersensitivity reaction (e.g. sympathetic ophthalmia). On the other hand, interleukin 4, 5,9,10 and 13 are liberated by Th2 type of cells. These cytokines play important role in humoral immune response generated by B-lymphocytes. Cytokines work by autocrine or paracrine stimulation and thus differ from endocrinal hormones. Cytokines can be pro-or anti-inflammatory and they can have both pro-and anti-inflammatory properties. Most cytokines are pro-inflammatory in nature, such as, IL-1,2,3,6,8 and TNF. IL-10 and transforming growth factor - beta (TGF-β) are recognized as anti-inflammatory cytokines. Few, such as IL-4 and IFN γ possess both pro- and anti-inflammatory properties; the exhibition of any one of them depends on the local immunological milieu. Cytokines can act in synergy or they can act antagonistically. As far as the ocular immune system is concerned, IL-2, IL-6 and IFN γ appear to be the most important cytokines. However, many studies have demonstrated an intraocular expression of other cytokines in uveitis as well. These include TNF, IL-1, and IL-8. The precise contribution of these mediators to uveitis remains to be determined. A recent study has demonstrated elevated aqueous and serum IFN -γ and IL-2 in uveitis, are associated with serious loss of vision.[8] In another study, high levels of IL-12 were found in the aqueous humour and vitreous of uveitis patients indicating that a Th1 -lymphocyte - mediated immune response occurs in uveitis and that IL-12 plays an important role in initiation and maintenance of intraocular inflammation.[9]

Can cytokines be used in the management of uveitis?[4] Nishi and coworkers[10] have shown marked inhibition of aqueous flare and fibrin deposit in IL-1 receptor antagonist treated rabbit eyes following cataract extraction. Anti-TNFα has been tried by Japanese groups (Ohno & Coworkers) in. patients with ocular Behcet's disease refractory to available treatments. Currently anti-tumour necrosis factor antibody is in phase 3 trial in rheumatoid arthritis. (Infliximab and Etanercept.)[11] Cytokines can be used not only in uveitis but also in noninflammatory eye diseases like subretinal neovascularisation (recombinant INF α2a and retinal tumours. Combination of the cytokine IFNγ and ziduvidine in the AIDS related Kaposi's sarcoma has been described.[4] Today these cytokines can be cloned, and monoclonal antibodies against cytokines can be produced. In addition, new cytokines are discovered new functions of previously described cytokines are increasingly recognized this opening new possibilities. Cytokine therapy requires repeated intradermal, intramuscular or parenteral injection. It is quite heartening to know that now such cytokines can be given orally too. Recently, it has been reported that oromucosal administration of IFN-γ can successfully inhibit experimental autoimmune encephalomyclitis in rats.

Although it is quite evident that in the management of intraocular inflammation immunosuppression by steroids and cytotoxic agents may be supplanted by new range of immunomodulators, these new drugs need to be tested in human uveitic conditions. The results from the animal model cannot be applied directly to human diseases.[12] Side-effects of these new molecules need to be weighed against the standard therapy. Last but not the least, the cost of such therapy needs to be evaluated. The initial step is therefore to understand the precise role of cytokines in intraocular inflammation. The article by Singh & coworkers provides insight into the current advancement in cytokine research in uveitis and will prepare us for the new therapy in uveitis.

References

1Singh VK, Geeta R, Agarwal S. Role of cytokines in clinical and experimental uveitis. Indian J Ophthalmol 2001;49:81-90.
2Dick AD. The continuing need to publish laboratory science in clinical journals (editorial). Br J Ophthalmol 2000;84:1213-14.
3Lemonick MD. The future of drugs. Time (January22),2001.pp31-41.
4Okada AA. Cytokine therapy in eye disease. Arch Ophthalmol 1998;116:1514-16.
5Okada AA, Forrester JV. Ocular inflammatory disease in the new millennium. Arch Ophthalmol 2000;118:116-19.
6Nussenblatt RB, Csaky K. Perspectives on gene therapy in the treatment of ocular inflammation. Eye 1997;11:217-21.
7Nussenblatt RB, Whitcup SM, de Smet MD, Caspi RR, Kozhich AT, Wiener HL, et al. Intraocular inflammatory disease (uveitis) and the use of oral tolerance: A status report. Ann N Y Acad Sci 1996;778:325-37.
8Lacomba MS, Martin CM, Chamond C, Galena JMG, Omar M, Esterez C. Aqueous and serum interferon gamma, interluekin (IL-2, IL-4 and IL-10) in patients with uveitis. Arch Ophthalmol 2000;118:768-72.
9E-I Shabrawi Y, Livir-Rollates C, Christan W, Baltatzis S, Foster CS. High levels of interleukin IL-12 in the aqueous humor and vitreous of patients with uveitis. Ophthalmology 1998;105:1659-63.
10Nishi O, Nishi K, Imanishi M. Synthesis of interluekin-1 and prostaglandin E2 by lens epithelial cells of human cataracts. Br J Ophthalmol 1992;76:338-34.
11Camussi G, Lupia E. The future role of anti-tumor necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs 1998;55:613-20.
12Rao NA. Do the experimental models represent human uveitis or retinal autoimmunity. Indian J Ophthalmol 1999;47:62-63.