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   Table of Contents      
Year : 2001  |  Volume : 49  |  Issue : 2  |  Page : 81-90

Role of Cytokines in experimental and clinical uveitis

Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Correspondence Address:
Vijay K Singh
Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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PMID: 15884511

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Uveitis is a major cause of visual impairment. Experimental autoimmune uveitis mimics the clinical conditions of posterior uveitis in many ways. T-cells (particularly CD4[+] helper-T-cells) have been shown to play an important role in pathogenesis of experimental and clinical uveitis. Based on the pattern of cytokine they secrete, CD4[+] helper cells have been divided into Thl and Th2 subsets. Various Thl and Th2 cytokines appear to be involved in the pathogenesis and/or recovery from uveitis. This article discusses in detail the uveitopathogenic and therapeutic potential of Thl and Th2 cytokines in experimental and clinical uveitis.

Keywords: Autoimmunity, experimental autoimmune uveitis, human uveitis, Th1 and Th2 cytokines

How to cite this article:
Singh VK, Rai G, Agarwal SS. Role of Cytokines in experimental and clinical uveitis. Indian J Ophthalmol 2001;49:81-90

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Singh VK, Rai G, Agarwal SS. Role of Cytokines in experimental and clinical uveitis. Indian J Ophthalmol [serial online] 2001 [cited 2024 Mar 1];49:81-90. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?2001/49/2/81/22654

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Indian J Ophthalmol 2001;49:81-90

The immune system has both non-specific and specific components. Non-specific or innate immunity is the basic resistance to disease that an individual is born with. Innate defence mechanisms provide the first line of host defence and the innate system is fully functional before infectious agents enter the body. In contrast, the acquired immune system (specific component) is activated only after a pathogen has entered the-body.[1] A developed immune system is capable of distinguishing between self and non-self, raising an appropriate response to eliminate or neutralize the foreign molecule and tolerate the self. When the immune response is directed against the self, it is known as autoimmunity. Earlier it was believed that all self-reactive lymphocytes are eliminated during development, and failure to eliminate them leads to autoimmune reaction. Later experimental evidence revealed that not all self-reactive lymphocytes are deleted during maturation. Instead, normal healthy individuals have been shown to produce mature self-reactive lymphocytes. Since; the presence of self-reactive lymphocytes does not inevitably result in autoimmune reaction; their activity must be regulated in normal individuals through clonal anergy or clonal suppression. A breakdown in this regulation leads to activation of self-reactive clones of T and B-cells, resulting in cellular or humoral autoimmunity[2]. Autoimmune responses are usually sustained and persistent, leading to long-term tissue damage presumably because the self antigens that drive the response can only be removed from the system by destroying the cells that produce them.

Uveitis is an intraocular inflammation involving primarily the uveal tract, i.e. the iris, ciliary body and choroid. Autoimmunity plays an important role in certain uveitic entities. It is known to cause a variable degree of visual loss depending on the type and severity of uveitis. Morbidity is characterised by an inflammatory attack on the uvea and the neuroretina[3]. Infection, autoimmune disease, trauma, and malignancy can induce uveitis.[4] The disease may be of infectious or autoimmune aetiology. The latter includes sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, Behcet's disease, birdshot retinochoroidopathy, and sarcoiduveitis.[5] The possible role of retinal antigens in the aetiopathogenesis of a subset of human uveitis is supported by the observation that many patients with uveitis show lymphoproliferative response to human and bovine retinal antigens.[6-10]

  Experimental Autoimmune Uveitis as Animal Model for Human Posterior Uveitis Top

Our understanding of the immunopathogenic mechanisms of posterior uveitis has been benefited enormously by the development of an animal model of uveitis, experimental autoimmune uveitis (EAU).[11-13]EAU closely resembles human uveitic conditions of suspected autoimmune aetiology and serves as a model for these sight-threatening diseases. Subsequently it has helped in elucidating the basic mechanisms involved in pathogenesis and in development of new therapeutic approaches.

EAU is predominantly a T-cell mediated intraocular inflammatory disease induced in susceptible species/ strains of animals by active immunization with ocular-specific proteins (or peptides derived from them).[14-18]The two major uveitogenic retinal proteins are S-antigen and interphotoreceptor retinoid-binding protein (IRBP). [11, 12, 18, 19] EAU is induced either by active immunization or by adoptive transfer. In active immunization the retinal antigens or their peptides along with mycobacterium emulsified in complete Freund's adjuvant are injected into the footpad of the animal followed by an intravenous injection of Bordetella pertussis. In adoptive transfer, lymphocytes from an animal with EAU are transferred to a naive recipient. The naive recipient develops EAU in 3 - 4 days after the transfer as compared to 12 to 14 days in case of active immunization in rats [Figure - 1]. The disease can also be transmitted to nave syngeneic animals by injection of Major Histocompatibility Complex (MHC) II-restricted T-cell lines specific to retinal antigens. [20, 21] Several examples of molecular mimicry between retinal S-antigen fragment and microbial proteins or self-protein (human leukocyte antigen) have also been demonstrated.[22-25] Microbial peptide or peptide derived from human leukocyte antigen has been shown to induce EAU in susceptible animals. The experimental animal used in the majority of early studies on EAU is the Lewis rat, an inbred strain that is highly susceptible to EAU induced by all known uveitogenic antigens. [14, 26, 27]Taken together with unique anatomic sequestration of the vertebrate eye, EAU is a useful model of organ-specific autoimmunity mediated by T - lymphocytes, [28, 29]useful for studying many aspects of immunobiology and immunomodulation. [30, 31] Interestingly, Rao[32] raises a question whether the S-antigen induced uveitis model represents human uveitis or retinal autoimmunity. Thus additional studies are required to fully understand the complex workings of the ocular immune system.

  Th1 and Th2 cytokines Top

In 1986, Mosmann and colleagues revolutionized the field of immunology by dividing T-helper (Th) cells into two distinct populations with contrasting and cross-regulating cytokine profiles.[33] Studies on leishmania infection in mice were instrumental in establishing functional relevance of these subsets of Th cells. Th1 cells produce interferon-γ (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factorβ


); promote production of opsonizing and complement-fixing antibodies, macrophage activation, antibody-dependent cell cytotoxicity and delayed type hypersensitivity (DTH) reactions. In contrast, Th2 cells produce several interleukins (IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13); provide help for humoral immune response, particularly of the IgE type and mucosal immunity through facilitation of IgA synthesis.[34] Furthermore, Th1 cells are considered to give rise to phagocyte-dependent and Th2 cells phagocyte-independent host response. The factors responsible for the polarization of the specific immune response into a predominant Th1 and Th2 profile have been extensively investigated. Strong evidence suggests that Th1 and Th2 cells develop from the same Th-cell precursor under the influence of environmental and genetic factors acting at their level of antigen presentation (Figure 2).

From mice, the concept of Th1 and Th2 response has extended to rats[35] and humans,[36] and has been applied to infectious diseases, cancer, transplantation, neonatal tolerance, immunodeficiency, autoimmunity, allergy, virology and more. Sufficient evidence has now accumulated to demonstrate the role of Th1 and Th2 cytokines in induction and control of several experimental as well as human autoimmune diseases.[36]Evidence has accumulated from animal models to indicate that Th1-type lymphokines are involved in the genesis of various organ-specific autoimmune diseases, such as uveitis, autoimmune thyroiditis, allergic encephalomyelitis, multiple sclerosis, arthritis or insulin-dependent diabetes mellitus.[37] Studies in humans also favour a Th1-type of lymphokine profile in target organs of patients with organ-specific autoimmunity. In contrast, Th2-cell predominance was found in skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus and allergic diseases. The concept of Th1 and Th2 cells not only allows one to explain different types of protective immune responses but also provides a basis for pathogenesis of several immunological diseases.

  Anterior Chamber Associated Immune Deviation (ACAID) and Cytokines Top

Injection of antigen into the anterior chamber of the eye induces suppression of antigen-specific DTH called ACAID. It has been shown that two types of splenic regulatory cells impair the induction and expression phase of DTH, and are involved in ACAID.[38] These cells mediate the effect through a cytokine. D'Orazio and Niederkorn[39] have shown that ACAID evokes antigen-specific, systemic down regulation of Th1 responses to antigen inoculated into the anterior chamber of the eye. IFN-γ production is suppressed in ACAID[38]. It has been reported that IFN-γ when injected intracamerally robbed the eye of immune privilege and prevented ACAID induction. [40, 41]

IL-12 production is also suppressed in-ACAID.[42]TNF has been associated with prevention of ACAID induction when injected intracamerally. The cytokine profile of the infiltrating T-cells in the eye with ACAID induction showed higher expression of IL-4 and-IL-10.[42]Kosiewicz et al[38] has shown that spleen and lymph node cells of mice produced significant amounts of IL-4 when ACAID was induced in their eyes. A high level of IL-10 secretion is associated with ACAID induction. The role of IL-10 in ACAID was confirmed in IL-10 knockout mice. Anterior chamber injection of ovalbumin into IL-10 knockout mice elicited normal DTH responses and not ACAID.[43] CD4[+] spleen cells from hosts primed in the anterior chamber with ACAID-inducing antigens developed normal DTH responses. This is suggestive of the proposition that immune privilege in the activation of the Th2 population is due to the selective activation of Th2 population. In ACAID, the immune response is directed away from Th1 pathway towards a Th2-like pathway in which DTH is suppressed.

  Th1 and Th2 Cytokines in EAU Top

The pathogenesis of EAU is mediated through the Th1 response. The susceptibility to EAU is characterised by conversion of early Th0 (CD4[+] T cells expressing cytokines of both types) or Th2-like response to Th1-type, whereas resistance is associated with Th2-type response.[44] Various Th1 and Th2 cytokines have been implicated in pathogenesis/recovery/resistance of EAU (Table 1). There is also a suggestion that regulatory influences other than skewing the response toward the Th2 pathway may be equally effective in conferring genetic resistance to EAU.[45]

  Th1 Cytokines Top

Th1 cells induce several cytotoxic cells and inflammatory reactions mediated by IL-2, IFN-γ, TNF-β

and IL-12; and are responsible for cell-mediated inflammatory reactions, DTH and tissue injury in autoimmune diseases. Th1-dominant immune responses are associated with inflammation and tissue injury. Th1 responses predominate in organ-specific autoimmune diseases. Cytokines have also been shown to play important role in aetiopathogenesis of EAU and human uveitis.

  IFN-γ Top

IFN-γ plays a central role in host defence, in both innate and acquired immunity. Aberrant expression of MHC class II proteins in ocular tissues has also been observed in uveitis. As the autoreactive T-cells that mediate autoimmune pathology are predominantly Th1 lymphocytes and produce copious amounts of IFN-γ, it was proposed that expression of MHC class II molecules on target cells by IFN-γ may be a risk factor for developing organ-specific autoimmune diseases.[46] In EAU as well as in uveitis patients, IFN-γ mRNA and protein have been detected in the inflammed eye. The expression of IFN- γ mRNA is temporally correlated with the onset of uveitis suggesting involvement of IFN-γ in induction and pathogenesis of uveitis.[47-50] Egwuagu and colleagues[51] recently generated transgenic rats (rats produced by injection of foreign cloned DNA in a fertilized egg where it integrates into the chromosomal DNA for birth of transgenic pups) with targeted expression of IFN-γ in the eye and examined whether constitutive ocular expression of IFN-γ would influence the course of EAU. They found that onset of EAU in rats is markedly accelerated and exacerbated by IFN-γ.

In the mouse model, depletion of systemic IFN-γ has been shown to result in exacerbation of EAU.[52]Mouse strains that are resistant to EAU induction, were converted to susceptible phenotype by peripheral administration of anti-IFN-γ antibody showing that endogenously produced IFN-γ at systemic levels acts to downregulate EAU in mice.[53] Jones et al[54] have demonstrated, using IFN-γ knockout mice (mice having a disrupted gene with loss of function in place of normal gene), that IFN-γ is not required for priming of pathogenic T-cells or for effecting retinal damage and photoreceptor loss typical of EAU, and a grossly similar disease is caused in the knockout mice by a deviant effector response (elevated IL-5, IL-6, IL-10, lymphotoxin but not IL-4). These results therefore suggest a protective effect of IFN-γ in EAU and imply potential benefits of IFN-γ therapy in the treatment of uveitis. Thus it is obvious that IFN-γ plays an important role in pathogenesis of EAU. The different effect of IFN- γ in mice and rat models is due to systemic and local effects, respectively.[55] Systemic effects are exerted on the components of the immune system, and are different from local effects that are exerted on the target tissues.

  IL-2 Top

IL-2 is produced by helper Thl cells. Major targets of IL-2 action are T-cells, B-cells and NK cells. The primary function of IL-2 is to cause proliferation and activation of T-and B-cells. It has been suggested that development, severity and subsidence of EAU are dependent on the level of IL-2. [49, 56, 57] Anti-IL-2 receptor antibody has been found effective in controlling EAU. The phenomenon of oral tolerance has been established in a number of experimental models of autoimmune disease. Two major mechanisms that have been proposed to mediate oral tolerance are anergy and active suppression. Rizzo et al[58]have shown that IL-2 can dramatically enhance oral tolerance from disease induced by IRBP in BIO A mice.

  IL-12 Top

IL-12 is the central cytokine in development and progression of tissue specific autoimmunity. It is produced by professional antigen presenting cells such as dendritic cells, skin Langerhans cells and B-cells. The dependence of Th-driven autoimmune disease models on IL-12 is explained by the role of this cytokine in driving differentiation of naive T-cells to Thl pathway.[59]Yokoi et al[60] demonstrated that anti-IL-12 treatment at the time of priming with IRBP not only prevented development of EAU and of pathogenic Thl cells, but also induced suppressive Th2 cells that protected animals from further challenge by the same antigen. Anti IL-12 treatment did not impair in vivo splenocyte proliferation significantly, but production of IL-2 and IFN-γ was greatly reduced while IL-4 and IL-5 was increased. Tarrant et al[61] have shown that IL-12 deficient mice were unable to develop EAU after immunization with a maximal disease inducing regimen, and their antigen specific responses to the uveitogenic antigen were Th2 like. However, they were able to develop EAU when infused with their own primed cells that had been incubated with antigen in the presence of IL-12. It is therefore concluded that the resistance of IL-12 knockout mice to EAU involves an inability to develop a pathogenic Thl response to the uveitogen and that endogenous IL-12 is required for pathogenesis of EAU. Furthermore, Tarrant et al[62] demonstrated that administration of IL-12 aborts development of EAU in IRBP-immunized mice by curtailing development of uveitogenic effector T cells.



The TNF family consists of three members, i.e., TNF-α

, TNF-β

(also known as lymphotoxin a; LT-α

and LT-β

). The major source of TNF-α

is activated monocytes/ macrophages. Ex-vivo analysis of cytokines produced in response to the immunising antigen showed an enhancement in the level of TNF-α

following IL-4 treatment. Dick et al[63] have shown that inhibiting TNF a activity prevents tissue destruction without inhibiting retinal T-cell infiltration in EAU. Neutralizing TNF a activity has been shown to suppress Thl effector mechanisms protecting against target organ damage.

IL-18 and TNF-β

have not been investigated in EAU or human uveitis.

  Th2 Cytokines Top

Th2 cytokines include IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, and are associated with help to B-cell antibody production.[64] The activation of Th2 cells generally protects the organism from a Thl-dependent autoimmune disease. A brief account of the involvement of Th2 cytokines, in EAU is given below.

  IL-4 Top

IL-4 is a small soluble glycoprotein secreted by activated T-lymphocytes, basophils and mast cells. In the case of EAU, IL-4 has been shown to play an important role and enhance the level of IFN-γ production. Uveitopathogenic effector T-cells of mice have a Thl-like phenotype. Antigen-specific uveitogenic cells do not produce IL-4 but addition of IL-4 enhances production of IFN-γ. Furthermore, Kezuka et al[65] have shown that priming of mice with IRBP peptide 518-529 causes a shift from Thl to Th2 (IL-4 and IL-10) dominated immune response, thereby playing a pivotal role in prevention of IRBP-mediated EAU. Rizzo et al[66] have also suggested that administration of IL-4 is required to shift response towards a non-pathogenic Th2 pathway.

A higher level of IL-4 has been reported in eyes with EAU.[49] An elevated level of IL-4 has also been reported in orally or orchidically (intratesticular) tolerized mice with retinal antigen.[67] Caspi et al[48] have suggested that susceptibility to EAU is connected with a Thl-dominant response, but resistance can involve either a "null" response (Thl-low/Th2-low) or a Th2-dominant response.

  IL-6 Top

IL-6 has a wide variety of activities on immune cell function, replication and differentiation. It is produced mainly by monocytes, T-lymphocytes and fibroblasts. It induces B-cell differentiation, activates T-cells and induces myelomonocytic differentiation as well. IL-6 produces uveitis if administered intraocularly.[68]Elevated levels of IL-6 producing cells have been reported in uveitic eyes of mice.[54] In addition, primed lymph node cells produced higher levels of IL-6 in response to IRBP. It has also been suggested that at onset of EAU, the ocular microenvironment loses its immunosuppressive properties due to local production of IL-6.[69]

  IL-10 Top

IL-10 was originally characterized as a cytokine-synthesis inhibitory factor because of its capacity to inhibit cytokine production by mouse Thl cells, monocytes, macrophages and B-cells. It is currently regarded as a potential therapeutic agent for inflammatory diseases involving Thl-type response because of its ability to downregulate Thl cells and macrophages.[70] IL-10 is an important cytokine for aetiopathogenesis of EAU. The disease is negatively regulated by IL-10. Increase in IL-10 mRNA expression during late phase of EAU may reflect a role in disease resolution.[71] Endogenous IL-10 limits expression of EAU and may play a role in natural resolution of disease.[49]The data suggests that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. IL-10 along with IL-4 is required to induce oral tolerance against-EAU.[67]

The antidepressant and phosphodiesterase inhibitor, rolipram, enhances IL-10 production by monocytes/ macrophage but its protective effect against EAU is independent of IL-10.[72]

  IL-13 Top

IL-13 is a cytokine that is produced by a subset of T-cells and dendritic cells. IL-13 inhibits production of proinflammatory cytokines by activated monocytes, induces B-cell proliferation, IgE production and expression of certain adhesion molecules on endothelial cells.[73] Roberge et al[74] has shown that uveitis induced in monkeys by immunisation with human retinal S-antigen can be treated by IL-13. They have shown that IL-13 inhibited intraocular inflammation and produced an increase in circulating polymorphonuclear neutrophils and a decrease in lymphocytes. Thus administration of IL-13 appears to be a promising modality of treatment of severe uveitis.

IL-5 and IL-9 have not been investigated in EAU or human uveitis.

  Th1 and Th2 Cytokines and Human Uveitis Top

Various Th1 and Th2 cytokines have been investigated in ocular fluids (vitreous and aqueous humour), serum samples and supernatant of stimulated peripheral blood mononuclear cells (PBMC) of different categories of uveitis patients. Number of cytokine-producing cells in ocular tissues of uveitis patients have also been enumerated and compared with healthy controls. Chan and Li[75] have reported T-cell infiltration in other non-infectious inflammatory diseases like ligneous conjunctivitis, pars planitis, sarcoid uveitis, sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. T-cell infiltration has been documented mainly in Behcet's disease and scleritis. Numerous CD4[+] T cells and Thl cytokine mRNAs have been detected in eyes with active sympathetic ophthalmia and Behcet's disease. This demonstrates that the infiltrating T-lymphocytes have Thl function and promote cellular immune response in the eye. Behcet's disease is the most studied of the various types of uveitis, in relation to cytokines.

Excessively elevated IL-2 levels may enhance the development and recurrence of human uveitis. IL-2 has been detected in ocular fluid of uveitis patients. [50, 76] The number of IL-2 producing cells in PBMC of Behcet's disease patients with active uveitis was significantly higher than inactive cases and controls.[77] Elevated levels of soluble IL-2R has been reported in the serum of patients with juvenile chronic arthritis associated with uveitis.[78] High levels of soluble IL-2R have been reported in the serum of patients with active Behcet's disease.[78] This suggests that the disease activates the immune system. IFN-γ has also been reported in the ocular tissues of uveitis patients. [50, 68]

el-Shabrawai et al[79] found statistically significant differences in IL-12 levels in vitreous/aqueous humor of patients with uveitis (active > inactive > control). This further supports the general hypothesis that uveitis is a Thl-mediated disease where IL-12 plays a pivotal role in the initiation and maintenance of intraocular inflammation. High levels of IL-12 in vitreous and /or aqueous humor of patients with uveitis also suggest that susceptibility to ocular autoimmunity may be related to genetic predisposition to an elevated Thl response.

Ongkosuwito et al[50] failed to detect IL-4 in ocular fluid samples from patients with uveitis. Raziuddin et al[80] have reported enhanced level of IL-4 in the culture supernatant of stimulated PBMC of uveitis patients. Furthermore, Sugi et al[81] did not find any difference in the number of IL-4 producing cells in PBMC of active and inactive uveitis patients. Elevated levels of IL-6 have been reported in aqueous humor [76, 82, 83] and vitreous [76, 84] of patients with uveitis. Investigators have failed to establish a correlation between IL-6 level in ocular fluids and clinical severity or aetiology of the disease. Human retinal pigment epithelium (RPE) has also been shown to produce IL-6. Unstimulated RPE produced small amounts of IL-6, but on stimulation with IL-1, IL-6 production was markedly upregulated. Thus RPE may be the source of this cytokine in ocular inflammatory states.[85] Furthermore, in comparison to controls, elevated levels of IL-6 were found in aqueous humour as compared to serum of patients with uveitis.[86]The soluble IL-6 receptor levels in aqueous humour were 2-10 times higher than IL-6 levels. In serum samples, soluble IL-6 receptor levels were 1000 times higher than the corresponding IL-6 values. These results confirm the role of IL-6 in intraocular inflammation and give new information regarding the presence of its soluble receptor in inflamed eyes. Low levels of soluble IL-6R in aqueous humour compared to the levels in serum suggest the presence of active regulatory mechanisms that require further investigation.

Elevated levels of IL-10 have been reported in ocular fluids (aqueous and vitreous) of uveitis patients [50, 79, 80]. Raziuddin et al[80] have shown high levels of IL-13 in the PBMC of patients with Behcet's disease.

  Future Directions Top

A coherent view of the role of Th1 and Th2 cytokines in uveitis is emerging as a result of studies both in human and experimental animals. Cytokines have been demonstrated in various ocular fluids and tissues obtained from uveitis patients, and have been shown to induce disease in experimental animals upon intraocular injections. Several unique features of the immunology of the eye, such as immunosuppression associated with ACAID, may also be due to various cytokines.

The balance between Th1 and Th2 types of immune responses plays a crucial role in determining the outcome of a uveitopathogenic challenge. [45, 61, 87, 88] While susceptible strains of mice and rats consistently exhibit a dominant Th1 response to the uveitopathogenic antigen at the time of disease expression, resistant strains exhibit a low Th1, or an overt Th2 response at the same time. Although there have been significant advances in our understanding of the process leading to development of polarised Th1 and Th2 effectors at the single cell level[89], the evolution of a Th1 or Th2 responses in vivo remains poorly documented. Several Th1/Th2 cytokines have been shown to be involved in the pathogenesis of uveitis, among which IFN-γ and IL-12 are of particular importance. Usually activation of Th2 cells is a protection against Th1-dependent autoimmune diseases. The anti-inflammatory Th2 cytokines IL-4 and IL-10 seem to be promising candidates for therapy in human uveitis.

Oral tolerance in EAU may occur by anergy/depletion or by suppression, depending on the feeding regimen. Tolerance involving putative regulatory cells appears to require production of both IL-4 and IL-10 cytokines.[90] It would be worthwhile to explore therapeutic feeding regimens involving administration of IL-4 and IL-10. In brief, an understanding of the role of cytokines in inflammatory eye diseases can help us develop therapies to abrogate the effects of important mediators of inflammatory responses. An antibody directed against the T-cell activated (Tac) portion of the IL-2 receptor is under clinical trial for treatment of uveitis.

  Acknowledgements Top

Financial assistance from Indian Council of Medical Research towards research on the subject is gratefully acknowledged. GR is a PhD student of SGPGI. The laboratory infrastructure was provided by a JICA grant-in-aid to the SGPGI project.[94]

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