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   Table of Contents      
ORIGINAL ARTICLE
Year : 2006  |  Volume : 54  |  Issue : 4  |  Page : 241-245

The effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous cytokine levels in experimental autoimmune uveitis


1 Firat University School of Medicine, Department of Ophthalmology, Elazig, Turkey
2 Firat University School of Medicine, Department of Immunology, Elazig, Turkey

Correspondence Address:
Peykan Türkçüoglu
Firat University School of Medicine, Department of Ophthalmology, Elazig
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0301-4738.27948

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  Abstract 

Background: To identify the effect of infliximab, cyclosporine A and recombinant IL-10 in experimental autoimmune uveitis.
Materials and Methods: Sixty male rats were assigned to five groups of 12 each. All the groups (except the control group) were administered 30 µg retinal-S antigen intraperitoneally. On the 14th day, after confirmation of uveitis with histopathological study, daily cyclosporine A injection was given in cyclosporine A treatment group and physiological serum in the uveitis-induced placebo treatment and control groups. In the infliximab treatment group, infliximab was administered on the 14th, 15th, 17th, 19th and 21st days. In the recombinant IL-10 treatment group, three doses of recombinant IL-10 were given four hours and a half hours before and eight hours after retinal-S antigen administration. On the 21st day of the study, all rats were sacrificed and vitreous cytokine levels (IL-1, IL-6, IL-8 and TNF-a) were studied with ELISA.
Results: In the treatment groups, cytokine levels (IL-1, IL-6 and TNF-a) were significantly lower than the uveitis-induced placebo treatment group. Compared with the control group, there was no significant difference with respect to TNF-a and IL-8 in the infliximab treatment group; IL-8 in the cyclosporine A treatment group; IL-6 and IL-8 in the recombinant IL-10 treatment group. The drugs used did not significantly differ in respect to their effects on vitreous IL-6, IL-8 and TNF-a levels.
Conclusion: Cyclosporine A, infliximab and recombinant IL-10 reduce the vitreous cytokines levels. Among these drugs, recombinant IL-10, which is still in its experimental phase, might be considered as a new therapeutic agent.

Keywords: Cyclosporine A, experimental autoimmune uveitis, infliximab, recombinant IL-10


How to cite this article:
Demir T, Gödekmerdan A, Balbaba M, Türkçüoglu P, Ilhan F, Demir N. The effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous cytokine levels in experimental autoimmune uveitis. Indian J Ophthalmol 2006;54:241-5

How to cite this URL:
Demir T, Gödekmerdan A, Balbaba M, Türkçüoglu P, Ilhan F, Demir N. The effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous cytokine levels in experimental autoimmune uveitis. Indian J Ophthalmol [serial online] 2006 [cited 2020 Dec 1];54:241-5. Available from: https://www.ijo.in/text.asp?2006/54/4/241/27948

Cytokines are low molecular weight proteins involved in communication between cells during inflammatory processes. Various studies on the pathogenesis of uveitis have reported the activity of many cytokines throughout the process. The presence of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) has been shown in aqueous and vitreous aspirates of the patients with chronic eye inflammation.[1] Interleukin-8 (IL-8) also participates in the inflammatory processes in uveitis by attracting and degranulating neutrophils.[2]

A definitive or effective treatment modality for uveitis has not yet been introduced. The development of an ideal immunosuppressive therapy aiming to suppress inflammation and reduce recurrence in patients with uveitis of undefined etiology remains an important research goal. The aim of the study was to identify the effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous IL-1, IL-6, IL-8 and TNF-a levels in experimental autoimmune uveitis (EAU) in rats.


  Materials and Methods Top


The study was performed at the experimental research center of the university with the consent of the ethics committee. All procedures were performed with strict adherence to guidelines for animal care and experimentation prepared by the Association for Research in Vision and Ophthalmology and by the local animal care committee.

Sixty male Lewis rats, weighing 200-225 g each, were obtained from the university animal laboratory center. The rats were anesthetized with intramuscular administration of 50 mg/kg of ketamin hydrochloride and 5 mg/kg of xsilazin hydrochloride combination. The rats were sacrificed through intracardiac thiopental sodium at a dose of 50 mg/kg.

Five groups of rats were formed with 12 rats in each group. In all the groups (except the control group) immunization was achieved by intraperitoneal administration of 0.1 ml (30 µg) retinal-S antigen (emulsified 1:1 with freund's adjuvant containing Mycobacterium tuberculosis H37 Ra at a concentration of 2.0 mg/ml). On the 14th day after retinal-S antigen administration, enucleation was done on randomly selected two rats from each group. Enucleated eyes were fixed in 4% paraformaldehyde solution, embedded in paraffin. Immunization was confirmed by examining 5-µm tissue sections under light microscope with Hematoxylin and Eosine (H and E) staining.

Infliximab treatment group: After histopathological confirmation of immunization on the 14th day, the rats received infliximab (each dose: 0.5 mg/100 ml) intraperitoneally on the 14th, 15th, 17th, 19th, 21st days.

Cyclosporine A treatment group: After histopathological confirmation of immunization on the 14th day, the rats received cyclosporine A at a dose of 2 mg/kg/day intraperitoneally and it was continued until the end of the study.

Recombinant IL-10 treatment group: The rats received three doses of recombinant IL-10 (each dose: 1000U) intraperitoneally 4 hours and 0.5 hour before retinal-S antigen administration and eight hours after retinal-S antigen administration on day one.

Uveitis-induced placebo treatment group: After histopathological confirmation of immunization on the 14th day, the rats received intraperitoneal physiological serum (each dose: 2 ml/kg/day) and it was continued until the end of the study.

Control group: On the 14th day, when the immunization was confirmed in the other groups, the rats received intraperitoneal physiological serum (each dose: 2 ml/kg/day) and it was continued until the end of the study.

On the 21st day of the study, all the remaining rats were sacrificed and vitreous samples were obtained using a 33-gauge needle for immunological study. Vitreous samples of the right eyes were used for determination of IL-1, IL-6 levels and left eyes for determination of IL-8, TNF-a levels. Immunology laboratory staff did not have the information about which group the eyes belonged to.

In the determination of vitreous cytokine levels, IL-1, IL-6, IL-8, TNF-a, (Biosource International Immunoassay kit, Camarillo, California, USA) ELISA kits were used and the measurements were performed with ELISA automatic optical reader with optical absorbance value of 450 nm (model ELX 800: Bio Tek Instruments, Inc. USA).

Statistical analyses were carried out employing the Statistical Package for Social Sciences software 12.0 for Windows package software (SPSS, Inc, Chicago, IL). The results of all the groups were statistically compared with Kruskal-Wallis test. The intergroup differences were evaluated with Mann Whitney-U test. A P value less than 0.05 was considered as statistically significant.


  Results Top


On the 14th day of the experimental period, immunization was confirmed with the detection of severe cell infiltration, vacuolization and edema in the ganglion cell layer; edema in the inner nuclear layer; irregularity in the outer nuclear layer and damage in the photoreceptor cells in the H and E stained tissue sections.

The mean values and standard deviations of TNF-a, IL-1, IL-6 and IL-8 levels in the control group were 7.93 ± 4.19, 8.29 ± 5.00, 23.62 ± 3.19, 21.50 ± 6.29; in the uveitis-induced placebo treatment group were 35.60 ±12.58, 27.87 ± 6.34, 42.41 ± 19.39, 50.23 ± 31.73; in the infliximab treatment group were 11.80 ± 7.76, 14.66 ± 5.25, 28.18 ± 3.55, 27.88 ± 11.99; in the cyclosporine A treatment group were 15.15 ± 4.52, 17.59 ± 2.64, 28.82 ± 3.45, 28.86 ± 14.17; and in the recombinant IL-10 treatment group were 14.83 ± 5.61, 20.96 ± 4.61, 25.38 ± 4.48, 26.97 ± 7.11, respectively.

IL-1 levels [Figure - 1] were higher in the uveitis-induced placebo treatment group than in the control group ( P <0.001). However, IL-1 levels in the infliximab ( P <0.001), cyclosporine A ( P <0.001) and recombinant IL-10 ( P :0.017) treatment groups were significantly lower than the uveitis-induced placebo treatment group. The infliximab ( P :0.009), cyclosporine A ( P :0.001), recombinant IL-10 ( P <0.001) treatment groups had higher levels of IL-1 than those of the control group. Intergroup comparisons of IL-1 levels between the cyclosporine A and recombinant IL-10 treatment group ( P :0.063); cyclosporine A and infliximab treatment group ( P :0.247) showed no significant differences. But the infliximab treatment group IL-1 levels were significantly lower than the recombinant IL-10 treatment group IL-1 levels ( P :0.023).

TNF-a levels [Figure - 2] in the uveitis-induced placebo treatment group were significantly higher than those of the control group ( P <0.001). However, TNF-a levels in the infliximab ( P <0.001), cyclosporine A ( P <0.001) and recombinant IL-10 ( P <0.001) treatment groups were significantly lower than those of the uveitis-induced placebo treatment group. There was no significant difference in TNF-a levels between the infliximab treatment group and the control group ( P :0.353). The group that received cyclosporine A ( P :0.03) and recombinant IL-10 ( P :0.011) treatment had higher levels of TNF-a than those of the control group. There was no significant difference in TNF-a levels between the infliximab, cyclosporine A, recombinant IL-10 treatment groups ( P :0.133).

IL-6 levels [Figure - 3] were higher in the uveitis-induced placebo treatment group than in the control group ( P <0.001). However, IL-6 levels of the cyclosporine A ( P <0.001), infliximab ( P <0.001) and recombinant IL-10 ( P <0.001) treatment groups were significantly lower than the uveitis-induced placebo treatment group. There was no significant difference in IL-6 levels between the recombinant IL-10 treatment group and the control group ( P :0393). However, the infliximab ( P :0.011) and cyclosporine A ( P :0.04) treatment groups had higher levels of IL-6 levels than the control group. There was no significant difference in IL-6 levels between the infliximab, cyclosporine A and recombinant IL-10 treatment groups ( P :0.189).

IL-8 levels [Figure - 4] were higher in the uveitis-induced placebo treatment group than in the control group ( P :0.003). There was no significant difference in IL-8 levels between the infliximab, cyclosporine A, recombinant IL-10 treatment groups and the control group ( P :0.216). IL-8 levels of the infliximab treatment group were significantly lower than the uveitis-induced placebo treatment group ( P :0.043). However, IL-8 levels of the cyclosporine A ( P :0.053) and recombinant IL-10 ( P :0.065) treatment groups revealed no significant difference compared with the uveitis-induced placebo treatment group.


  Discussion Top


Various studies have been conducted till date to study the etiopathogenesis of human uveitis. However, the development and refinement of the EAU animal models with retinal-S antigen,[3] rhodopsin,[4] recoverin[5] and interphotoreceptor binding protein[6] increased the pace of these studies. Among these antigens, we used retinal-S antigen to induce EAU in our study.

Inflammatory count and measurement of protein concentration in the anterior chamber,[7] histopathological scoring[8] are the methods of detection and grading EAU. In our study, uveitis formation was detected through histopathological evaluation of tissue samples with light microscope. Severe cell infiltration, vacuolization and edema in the ganglion cell layer, edema in the inner nuclear layer, irregularity in the outer nuclear layer and damage in the photoreceptor cells were noted in the rats that received retinal-S antigen. None of these histopathological changes were observed in the control group.

Various cytokines have been detected in the vitreous samples of patients with intraocular inflammation.[1] But biological activities of IL-1, IL-6 and TNF-a suggest that each could be the primary regulators in the development of uveitis.[9] Every nucleated cell can synthesize IL-1 but the most significant source is monocytes or macrophages. IL-1 stimulates T-lymphocyte differentiation, proliferation and production of IL-2. Also, the ability of T cells to respond to antigen presentation is dependent on IL-1.

TNF-a exerts multiple stimulatory effects on T cells by binding to specific receptors and increases the expression of high affinity IL-2 receptors.[10] Furthermore, TNF-a induces the production of IL-1 and promotes the synthesis of prostaglandins.[11],[12] Intravitreal injection of human TNF-a or IL-1 in rabbit eyes induced leukocyte infiltration and protein leakage.[12],[13] When receptors for TNF-a or IL-1 were deleted, the severity of immune complex-induced uveitis was profoundly reduced.[14]

IL-6 is a multifunctional cytokine that regulates the immune response, acute phase reactions and hematopoiesis. Deregulated IL-6 gene expression has been implicated as being involved in the pathogenesis of autoimmune diseases.[15] IL-8, one of the main chemoattractant for neutrophils and T lymphocytes, can also activate neutrophils.[16] IL-8 is produced by leucocytes such as monocytes and macrophages. Raised IL-8 levels were also reported in vitreous samples obtained from patients with various uveitis entities.[17]

Infliximab, a humanized mouse monoclonal antibody to TNF-a, is a novel immunomodulatory agent that is used in a number of autoimmune diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. [18],[19],[20] Infliximab is also effective in the treatment of ocular Behηet disease, anterior uveitis resistant to standard immunomodulatory treatment and sight-threatening refractory posterior uveitis. [21],[22],[23] With our study we showed that infliximab effectively suppressed TNF-a and IL-8 synthesis so that there was no significant difference from the control group. Cyclosporine A and recombinant IL-10 also suppressed the TNF-a synthesis but TNF-a was still high enough to induce inflammation in these treatment groups.

Cyclosporine A, an undecapeptide obtained from several fungal extracts, is an effective immunosuppressant with highly specific anti-T-cell effects.[24] Cyclosporine A binds to intracellular cyclophilin and this complex inhibits calcineurin which plays a critical role in IL-2 gene transcription.[25] Its therapeutic effectiveness in transplantation immunity has been well documented.[24] Cyclosporine A has been shown to be effective in the treatment of immune-mediated ocular diseases.[26],[27] Cyclosporine A prevented disease process in the retinal S-Ag induced EAU model.[28] In our study, cyclosporine A effectively suppressed IL-8 synthesis so that there was no significant difference from the control group.

IL-10 is secreted by activated TH2 lymphocytes, macrophages.[29] IL-10 is an anti-inflammatory cytokine that was shown to suppress Th1 cytokines (IL-2, IFN-gamma and TNF-a) as well as IL-6, that was probably synthesized by other cells as a result of Th1 activation.[30] A major aspect of these effects suggested that IL-10 might prevent the noxious effects of endotoxin if given early enough.[31] Previous studies have shown that IL-10 has a protective role in EAU and reduces cellular infiltration in intraocular inflammation produced by endotoxin.[7],[32] In our study, recombinant IL-10 suppressed the IL-6 and IL-8 so efficiently that there was no significant difference from the control group.

In a uveitis model we showed that infliximab, cyclosporine A and recombinant IL-10 suppressed the synthesis of IL-1, IL-6, IL-8 and TNF-a. However IL-8 synthesis was efficiently suppressed to the level of control group by all three drugs; TNF-a to the level of control group only by infliximab; IL-6 to the level of control group only by recombinant IL-10. None of the medicines suppressed the IL-1 to the level of control group.

In summary, our data show that infliximab, cyclosporine A, recombinant IL-10 can modulate expression of EAU. Recombinant IL-10 may have therapeutic potential in inflammatory and autoimmune eye disease; however, further study is needed to evaluate its safety and efficacy in humans.



 
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    Figures

  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]


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