Surv. immunol. Res. 3:217-220 (1984) �9 1984 S. Karger AG, Basel

0252-9564/84/0033-021752.75/0

Immunology of the Eye - 19831

Bartly J. Mondino

Department of Ophthalmology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, Calif., USA

The survival of high-risk corneal grafts in a study group receiving transplanted corneas from donors who were selected on the basis of a negative lymphocyte cross-match, ABO antigen blood group compatibility and max- imized HLA-A and HLA-B matching was compared with a retrospective control group who received corneas obtained randomly [1 ]. Graft survival in the control group was 49 versus 83% in the study group (p < 0.001), suggesting that HLA compatibility may be important in graft survival in high-risk cases. Because of the extensive body of immuno- genetic and transplantation data that is avail- able for inbred strains of mice, studies of cor- neal transplantation in mice may be ex- tremely useful. However, othotopic corneal allografts in mice are virtually impossible to perform because of the small size of the mu- fine cornea. New approaches to the study of corneal alloimmunity were developed utiliz- ing heterotopic corneal grafting in which syn- geneic and allogeneic corneas were grafted to the thoracic cage [2] or abdominal subcuta- neous pouch of recipient mice [3]. Syngeneic grafts were not rejected, while fresh allografts

i This work was supported in part by NEI grant EYO4607.

were usually rejected. Murine models such as this may be useful in the study of the factors involved in corneal rejection. Exposing do- nor corneas to hyperbaric oxygen to selec- tively destroy cells bearing Ia antigens (Lan- gerhans' cells and passenger leukocytes) re- duced the rate of allograft rejection [3]. The distribution of the important Langerhans' cell population of the cornea and conjunctiva of mice at various ages was reported [4].

The complement system and the role it plays in ocular immunologic reactions were explored in several publications. Normal hu- man aqueous humor was found to contain hemolytic C1, C4, C2, C3, C5, C6 and C7, but the small ratios of aqueous humor to serum measurements suggested that there was relatively little of these complement components in normal aqueous humor when compared to serum [5, 6]. The mean values of these complement components in aqueous humor and the median ratios of aqueous hu- mor to serum measurements for each com- plement component were substantially higher in inflamed than in normal aqueous humor. A study of the role of complement in murine corneal infection induced by Pseudo- monas aeruginosa showed that C5 plays little or no role in susceptibility or resistance to infection but that depletion of C3 using cobra

218 Mondino

venom factor diminishes the ability of mice to restore a clear cornea following infection [7]. The numbers of complement receptor cells as well as Fc receptor cells in the ocular and lymphoid tissues of rabbits immunized intravitreally with ovalbumin were deter- mined [8].

Measurements of immune complexes by Raji radioimmunoassay in aqueous humor from rabbits with primary immunogenic uveitis or recurrent uveitis showed that im- mune complexes were associated with clini- cally evident inflammation and suggested that they may be important in the pathogen- esis of these experimental ocular inflamma- tory diseases [9]. A study in humans suggest- ed that circulating immune complexes may play a role in the pathogenesis of Mooren's ulcer and other marginal corneal ulcers asso- ciated with collagen vascular disease [10]. The ciliary processes of the rabbit eye, like the choroid plexus and the renal interstitium, were shown to possess intrinsic binding ac- tivity for the Fc fragment of IgG, which may be involved in the local entrapment of im- mune complexes present either in the circula- tion or the aqueous humor [11 ]. Other parts of the eye, including the cornea, iris, choroid, and retina, were negative for such activity.

Sympathetic ophthalmitis is a bilateral granulomatous uveitis in which autoimmu- nity is thought to develop to ocular tissues following a penetrating injury to one eye with a severe reaction developing not only in the injured but also in the noninjured eye. Pro- lapse of uveal tissue and exposure of uveo- retinal antigens to conjunctival lymphatics may be crucial in the development of this disease [12]. Patients with sympathetic oph- thalmia may have an increased prevalence of HLA-A11 suggesting that a genetic factor may play an important role in the pathogene-

sis of sympathetic ophthalmia [ 13]. Patients with sympathetic ophthalmia appear to have increased C3 levels, normal levels of IgG, IgA, IgM, and normal proportions of active and total T lymphocytes and B lymphocytes [141.

Lymphokines may play a role in immu- nogenic uveitis. Intravitreal injection oflym- phokines released in vitro by mitogen- and antigen-activated lymphocytes caused uveitis in the normal rabbit eye which was more severe and more prolonged with the mitogen- activated lymphokines [15]. Lymphokines may attract lymphocytes nonspecifically to the eye and may also excite polyclonal B cell activation and plasma cell formation.

Atopic ocular disease was the subject of several publications. Studies in humans with allergic ocular disease [16] and in rabbits treated with compound 48/80 (a mast cell degranulator) [ 17] showed that the absence of eosinophils from conjunctival scrapings did not preclude the diagnosis of allergic ocular disease because eosinophils may be present in the deep and superficial conjunctival tis- sues and may not be recovered in conjuncti- val scrapings. The tears of patients with ver- nal conjunctivitis were shown to contain ele- vated levels of both IgG- and IrE-specific antibodies to rye grass and ragweed pollen antigens [18]. Cromolyn sodium 4 % ophthal- mic solution (an inhibitor of mast cell de- granulation) may be used to treat ragweed allergic conjunctivitis, and the preseason level of serum IgE antibody to ragweed may be a predictor of drug response [ 19].

Animal models of human ocular diseases were explored. An animal model of chronic cicatrizing trachoma was developed in cyno- molgus monkeys [20]. Inoculation with a sin- gle dose of Chlamydia trachomatis caused an acute self-limited follicular conjunctivitis,

Immunology of the Eye - 1983 219

whereas repeated weekly reinoculat ions were

necessary to produce a chronic progressive disease resembling t r achoma in humans. Phlyctenulae are vascularized, focal, nodular

infiltrates o f the h u m a n conjunct iva or cor- nea that are associated with tuberculosis or

Staphylococcus aureus. Rabbi ts i m m u n i z e d with cell wall antigens o f S. aureus mixed

with complete Freund 's ad juvant developed corneal phlyctenulae following topical chal- lenge with viable S. aureus [21]. Studies o f

the i m m u n e responses o f these rabbits showed that they expressed humora l i m m u - nity to ribitol teichoic acid, a major antigenic determinant o f all strains o f S. aureus, and

that hypersensit ivity to ribitol teichoic acid may be impor tan t in the deve lopment o f phlyctenulae [22].

Studies to determine the specific cell types

involved in certain ocular diseases were re- ported. Helper T cells defined by monoc lona l antibodies vastly predomina ted in benign, polyclonal ocular lymphoid proliferations, and the helper-suppressor T-cell ratio sug-

gested that these lesions represented a T-cell ant igen-dependent response characterized by a proliferation o f helper T cells, which in turn drive B cells to proliferate and to differentiate into a clinical detectable t umor [23]. The helper-suppressor T-cell ratio was lower in monoclona l B cell proliferations, suggesting that the benign T cells in these proliferation's

represented a residual cell populat ion rather than a distinctive subset originating in re-

sponse to the B-cell neoplasm.

References

1 Foulks, G.N.; Sanfilippo, F.: Beneficial effects of histocompatibility in high-risk coneal transplanta- tion. Am. J. ophthal. 94:622-629 (1982).

2 Streilein, J.W.; McCulley, J.; Niederkorn, J.Y.: Heterotopic corneal grafting in mice: a new ap- proach to the study of corneal alloimmunity. In- vestve Ophthal. vis. Sci. 23:489-500 (1982).

3 Chandler, J.W.; Ray-Keil, L.; Gillette, T.E.: Exper- imental corneal allograft rejection: description of murine model and a new hypothesis of immuno- pathogenesis. Curt. Eye Res. 2: 387-397 (1982/1983).

4 Hazlett, LD.; Grevengood, C.; Berk, R.S.: Change with age in limbal conjunctival epithelial Langer- hans' cells. Curr. Eye Res. 2:423--425 (1983).

5 Mondino, B.J.; Rap, H.: Hemolytic complement activity in aqueous humor. Archs Ophthal. 101: 465-468 (1983).

6 Mondino, B.J.; Rap, H.: Complement levels in normal and inflamed aqueous humor. Investve Ophthal. vis. Sci. 24:380-384 (1983).

7 Cleveland, R.P.; Hazlett, L.D.; Leon, M.A.; Berk, R.S.: Role of complement in murine corneal infec- tion caused by Pseudomonas aeruginosa. Investve Ophthal. vis. Sci. 24:237-242 (1983).

8 Hail, J.M.; Pribnow, J.F.: Fc and complement receptor lymphocytes in the ocular tissues of rab- bits immunized intravitreally with ovalbumin. In- vestve Ophthal. vis. Sci. 24:192-195 (1983).

9 Howes, E.L.; Char, D.H.; Christensen, M.: Aqueous immune complexes in immunogenic uveitis. Investve Ophthal. vis. Sci. 23:715-718 (1982).

l0 Berkowitz, P.J.; Arentsen, J.J.; Felberg, N.T.; Laibson, P.R.: Presence of circulating immune complexes in patients with peripheral corneal dis- ease. Archs Ophthal. 101:242-245 (1983).

l l Peress, N.S.; Roxburgh, V.A.; Gelfand, M.C.: Binding sites for immunoglobulin G in rabbit cil- iary processes. Investve Ophthal. vis. Sci. 23: 457- 463 (1982).

12 Rao, N.A.; Robin, J.; Hartmann, D.; Sweeney, J.A.; Marak, G.E.: The role of the penetrating wound in the development of sympathetic oph- thalmia. Archs Ophthal. 101:102-104 (1983).

13 Reynard, M.; Schulman, I.A.; Azen, S.P.; Minck- let, D.S.: Histocompatibility antigens in sympa- thetic ophthalmia. Am. J. Ophthal. 95:216-221 (1983).

14 Hammer, H.: Immunological studies in patients suffering from sympathetic ophthalmitis. Graefes Arch. clin. exp. Ophthal. 219:146-148 (1982).

15 Liu, S.H.; Prendergast, R.A.; Silverstein, A.M.:

220 Mondino

Role of lymphokines in immunogenic uveitis. In- vestve Ophthal. vis. Sci. 24:361-367 (1983).

16 Abelson, M.B.; Madiwale, N.; Weston, J.H.: Con- junctival eosinophils in allergic ocular disease. Archs Ophthal. 101:555-556 (1983).

17 Abelson, M.B.; Udell, I.J.; Weston, J.H.: Conjunc- tival eosinophils in compound 48/80 rabbit mod- el. Archs Ophthal. 101:631-633 (1983).

18 Ballow, M.; Donshik, P.C.; Mendelson, L.; Ra- pacz, P.; Sparks, K.: IgG-specific antibodies to rye grass and ragweed pollen antigens in the tear secre- tions of patients with vernal conjunctivitis. Am. J. Ophthal. 95:161-168 (1983).

19 Friday, G.A.; Biglan, A.W.; Hiles, D.A.; Murphey, S.M.; Miller, D.L.; Rothback, C.; Rand, S.: Treat- ment of ragweed allergic conjunctivitis with cro- molyn sodium 4% ophthalmic solution. Am. J. Ophthal. 95:169-174 (1983).

20 Taylor, H.R.; Johnson, S.L.; Prendergast, R.A.; Schachter, J.; Dawson, C.R.; Silverstein, A.M.: An animal model of trachoma. II. The importance of repeated reinfection. Investve Ophthal. vis. Sci. 23:507-515 (1982).

21 Mondino, B.J.; Kowalski, R.: Phlyctenulae and catarrhal infiltrates. Occurrence in rabbits immu- nized with staphylococcal cell walls. Archs Oph- thai. 100:1968-1971 (1982).

22 Mondino, B.J.; Cruz, T.A.; Kowalski, R.P.: Im- mune responses in rabbits with phlyctenules and catarrhal infiltrates. Archs Ophthal. 101: 1275- 1277 (1983).

23 Knowles, D.M.; Jakobiec, F.A.: Identification ofT lymphocytes in ocular adnexal neoplasms by hy- bridoma monoclonal antibodies. Am. J. Ophthal. 95:233-242 (1983).

Dr. BaVtly J. Mondino, Department of Ophthalmology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90024 (USA)