Differential Effect of Macrophage Depletion on Two Forms of Experimental Uveitis Evoked by Pigment Epithelial Membrane Protein (EAPU), and by Melanin-Protein (EMIU)

Abstract

The purpose of the present study was to clinically and histologically investigate the influence of macrophage depletion on the development of experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU), and experimental melanin-protein induced uveitis (EMIU) in the Lewis rat. EAPU is mainly characterized by pigment epitheliitis. Posterior mononuclear cell accumulations enclose and destroy the retinal pigment epithelium (RPE). In EMIU the inflammation is specifically localized in the uvea.EAPU was induced by immunization with RPE membrane protein, and EMIU was evoked by immunization with purified choroidal melanin. Systemic treatment with dichloromethylene diphosphonate (Cl2MDP)-containing liposomes just before the expected beginning of the clinical signs of EAPU (at day 7 and 9 after immunization) resulted in a considerable delay of the uveitis process. In the treated animals the typical plaque shaped cell accumulations (containing many macrophages) along the RPE were lacking. Two weeks after the treatment, severe rebound EAPU developed. Local treatment by subconjunctival liposome injections did not exert any effect on EAPU. In EMIU, macrophage depletion by systemic treatment did not noticeably influence the clinical and histological development of the inflammation.Systemic treatment at the peak stage of EAPU (at day 12 and 14 after immunization) resulted in the rapid disappearance of the clinical signs of uveitis. Vitreous and anterior chamber cells were virtually absent two days later. This situation remained unchanged until the experiment was terminated two weeks later. Already deposited cell accumulations along the RPE did not regress but stopped their progression.Hematogenous macrophages thus appear to play a crucial role in the development of EAPU but the effect of early macrophage depletion on EAPU appeared to be temporary due to blood repopulation, A possible explanation for the differential influence of macrophage depletion on EAPU and EMIU is discussed, and is based on differences in immunopathogenesis, © 1997 Academic Press Limited Key words: experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU); experimental melanin-protein induced uveitis (EMIU); macrophages; uvea; retinal pigment epithelium; pigment epithelial membrane protein; dichloromethylene diphosphonate (C12MDP). 1* IntroductionThree markedly different types of experimental auto immune uveitis have been described which can. be

Macrophage Depletion Prevents Leukocyte Adhesion and Disease Induction in Experimental Melanin-protein Induced Uveitis

“…The antiin¯ammatory effects of macrophage depletion are associated with a pronounced inhibition of leukocyte±endothelium interaction, leukocyte emigration and tissue in®ltration. These results differ from observations by Broekhuyse et al (1997), who did not ®nd attenuated in¯ammation after macrophage depletion in EMIU. The most probable reason for the con¯icting results are the different treatment regimens used to deplete macrophages.…”

“…We hypothesize that preventing the in®ltration of monocytes alone would not have precluded recognition of antigen by T-cells in the iris and would have caused adhesion and in®ltration of granulocytes and lymphocytes. This may also explain why macrophage depletion at later time points did not affect in¯ammation (Broekhuyse et al, 1997).…”

“…In our study macrophage depletion was started 9 days earlier, 2 days before administration of the antigen. However, Broekhuyse reported that in pilot experiments for his study administration of Cl 2 MDP-liposomes before day 7 also failed to ameliorate in¯ammation (Broekhuyse et al, 1997).…”

“…Spontaneous recurrence has been observed in one quarter of immunized animals (Chan et al, 1994). Interestingly, depletion of macrophages by systemic treatment with Cl 2 MDP-liposomes in early EMIU did not change the time course or severity of the in¯ammatory response while Cl 2 MDP-liposomes did ameliorate in¯ammation in another model of autoimmune uveitis, namely experimental autoimmune pigment epithelial membrane protein-induced uveitis (EAPU) (Broekhuyse et al, 1997). It has therefore been proposed that macrophages are less important for the initiation of EMIU and that the immunopathogenesis of EAPU is macrophage-dependent whereas that in EMIU is not.…”

Ocular and Extraocular Inflammation Induced by Immunization of Tyrosinase Related Protein 1 and 2 in Lewis Rats

“…Later, MAP was also found to induce an occasional mild choroiditis in the posterior part of the eyes of Lewis rats. Although the histological ®ndings on the retina and choroid were not described in detail (Chan et al, 1994;Broekhuyse et al, 1997), the histological changes of the anterior segment in EAAU were well-described. Our ®ndings in the anterior segment were very similar to that induced by MAP.…”