Corneal Allograft Rejection Following Immunization Thomas L. S t e i n e m a n n , M . D . , Bruce H. Koffler, M . D . , and C. Darrell Jennings, M . D . Five patients developed corneal allograft rejection after immunization. One patient, a 33year-old woman, received a tetanus toxoid booster nine months after a corneal transplant for keratoconus. Within four days she developed a graft rejection that required a penetrating keratoplasty two years later. Six months later, after hepatitis B immunization, the patient reported decreased vision and the graft was cloudy, but visual acuity was 20/20. The other four patients developed graft rejection after influenza immunization. Two of these four graft rejection episodes were successfully treated with high-dose corticosteroid therapy; all episodes occurred within several weeks of influenza immunization. Patients should be prudently counseled regarding the possible risks of immunization to corneal allograft survival. THE CORNEA is one of the most successfully transplanted human tissues as a result of its immunologie privilege. This privilege is rela tive, and is contingent upon host avascularity. However, rejection rates from 2% to 35% have been documented even in avascular recipi ents. 1,2 Despite the widespread clinical success of corneal transplantation, allograft rejection is the most important cause of delayed corneal graft failure.2 · 3 Nevertheless, the cornea re mains one of the least studied experimental transplantation systems.
Case Reports Casel In January 1983 a 33-year-old woman with keratoconus received a corneal transplant in
Accepted for publication Aug. 17, 1988. From the Department of Ophthalmology, University of Kentucky (Drs. Steinemann and Koffler) and the Department of Pathology, University of Kentucky, Vet erans Administration Hospitals (Dr. Jennings), Lexing ton, Kentucky. Reprint requests to Thomas L. Steinemann, M.D., Department of Ophthalmology, University of Kentucky, 800 Rose St., Lexington, KY 40536-0084.
her left eye. The epithelium was removed ac cording to the protocol suggested by Tuberville, Foster, and Wood. 4 There were no postoperative complications and nine months later best-corrected visual acuity was 20/30 and the graft was clear. In October 1983 she re ceived a tetanus toxoid booster injection. With in four days she experienced fever, chills, and myalgia. About two days later she noted cloudy vision in her left eye. One week later visual acuity was 20/60 and classical signs of graft rejection were noted: inferior graft edema, endothelial keratic precipitates, and a mild ante rior chamber reaction. The host bed blood ves sels were quiet. Intensive topical corticosteroid therapy was begun and a short course of oral corticosteroids was instituted. The symptoms resolved three weeks later. In November 1985 the patient underwent a second penetrating keratoplasty in her left eye for irregular astigmatism. The postoperative course was uneventful. Six months later her best-corrected visual acuity was 20/25 and the graft was clear. In May 1986 she received part 1 of a hepatitis B immunization and within 24 hours she noted cloudy vision in the grafted eye accompanied by generalized achiness. Rec ognizing the symptoms of her previous rejec tion episode, she treated herself with hourly topical corticosteroids (the patient was a physi cian). One week later her best-corrected visual acuity was 20/25 and the graft was clear. One month later she received part 2 of the hepatitis B immunization and again noted visual cloud ing in her grafted eye within two weeks. She treated herself with hourly topical corticoste roids until she could be examined by an oph thalmologist. Two months later, in October 1986, the graft was cloudy and scattered keratic precipitates were noted on the inferior endothelium. Despite a visual acuity of 20/20, the patient still complained of visual clouding in the morning, but no pain or photophobia. The corneal edema and inflammatory reaction re sponded to intensive topical corticosteroid therapy and her graft has remained clear. Case 2 An 84-year-old woman with pseudophakic corneal edema had undergone a penetrating
©AMERICAN JOURNAL OF OPHTHALMOLOGY 106:575-578, NOVEMBER, 1988
AMERICAN JOURNAL OF OPHTHALMOLOGY
keratoplasty in her right eye 14 months previ ously. On examination signs of graft rejection including keratic precipitates, diffuse microcystic edema, and bullae were noted. The pa tient recalled receiving an influenza immuniza tion five weeks previously and had noted deterioration of her vision sometime thereafter. Two weeks before the rejection episode, her visual acuity was 20/50 and the graft was clear. During the rejection episode, visual acuity was 20/400 and the graft was clearly failing. The episode of rejection was alleviated with a regi men of high-dose topical corticosteroids. Case 3 A 73-year-old woman had undergone a pene trating keratoplasty in her right eye three months previously for pseudophakic corneal edema. At her last examination before the re jection episode, visual acuity was 20/200, the graft was clear, and the anterior chamber was quiet. Three weeks later she received an influ enza immunization. One month after the injec tion, her visual acuity had deteriorated to hand motions. Slit-lamp examination showed a dif fusely swollen and edematous graft. A regimen of intensive corticosteroid therapy was institut ed but the graft never recovered. Case 4 A 69-year-old woman had a corneal graft with removal of an intraocular lens in July 1986. She was doing well until four months later when she received an influenza immunization. Eight weeks later she noticed blurring of her vision, but the graft appeared to be clear and the sutures intact; visual acuity was 20/40. She was instilling a topical corticosteroid preparation once a day. About three weeks later (late Janu ary 1987) visual blurriness again developed, accompanied by photophobia and tearing. The slit-lamp examination showed a diffusely thick ened graft (0.74 mm, increased from 0.50 mm) with keratic precipitates but no rejection line; her visual acuity was counting fingers. The graft remained cloudy despite treatment with topical and oral corticosteroids for several weeks. A regraft was performed in March 1987, and this graft has remained clear. Case 5 In March 1986 a 72-year-old woman under went a combined corneal graft and cataract extraction with intraocular lens insertion. She was doing well on a regimen of topical cortico steroids with a "crystal clear" graft and a visual
acuity of 20/40 until six months later when she received a "flu shot." Three weeks after the injection she developed blurred vision. Her visual acuity was stable at 20/40. Slit-lamp ex amination showed keratic precipitates on the corneal endothelium and a small patch of ves sels at the 6 to 7 o'clock graft/host junction. The graft thickness had increased from 0.47 to 0.54 mm. She was treated with intensive topical and oral corticosteroids, and the graft cleared.
Discussion These five patients had clinical evidence of graft rejection in close temporal association with three types of immunization. We hypothe size that immunization may induce expression and subsequent recognition of antigens of the major histocompatibility complex in the cor nea. There is strong evidence in the transplan tation literature that a variety of grafted organ systems do show marked enhancement of major histocompatibility complex antigenic ex pression after rejection. Consequently, donor parenchymal cells with little or no initial major histocompatibility complex antigen expression (thus poorly immunogenic) become vulnerable targets in a sequence of enhanced antigenic expression, host immune cell recognition, and immunologie destruction. 5 Class I major histocompatibility complex an tigens have been demonstrated in the corneal epithelium and stroma. 6 Recent evidence indi cates that their expression on the corneal endo thelium can be induced in vivo via the stimula tion of interferon. 7 Class II major histocompatibility complex antigen molecules may be induced in all three layers of the cornea after exposure to activated T cell products, specifically the lymphokine gamma interferon_6,8,9 (2i a s s n expression on the corneal endo thelium has also been demonstrated in vivo after primary uveitis. 10 The expression of class II antigens on dendritic or Langerhans cells of the corneal epithelium and stroma is also well described. 1112 Class II antigens are stronger transplantation antigens than class I13"15 and have been demonstrated in renal allograft re jection to elicit strong responses. 16 Donor/host compatibility of the class II antigens has been shown to be of greater importance than class I antigens in renal allograft survival. 17 The following models are plausible mecha nisms for immunization-induced graft rejec-
Vol. 106, No. 5
Graft Rejection After Immunization
tion. The first presumes that a local inflamma tory response may be initiated via soluble immune complex deposition in the uvea, iris, and perilimbal vasculature. Local inflammation with increased vascular permeability, nonspe cific destruction, and subsequent microneovascularization may ensue, thus enabling inflam matory products to reach the donor tissue. These inflammatory products include interfer ons, interleukins, and other lymphokines capa ble of enhancing major histocompatibility com plex expression. Our first patient had symptoms preceding the rejection episode which were highly suggestive of serum sick ness, a classic immune complex-mediated dis order. Clinical uveitis appearing in association with serum sickness was described by Theo dore and Lewson 18 in a patient who had re ceived horse antipneumococcal serum. Further experimental evidence was provided by Wong, Anderson, and McMaster 19 who suggested that this type of uveitis is an immune complex disease manifested histologically by uveal and glomerular vascular damage. The temporal as sociation between viral syndromes and renal allograft rejection is well described in the trans plantation literature. 2023 Theoretically, a similar stimulus for rejection could be provided by immunization via a generalized activation of T cells. At least one such case has been described in the renal transplant literature occurring one month after an influenza immunization. 24 Two other mechanisms are possible. Systemically released gamma interferon may reach the corneal graft along with activated T cells fol lowing immunization. These cells or their prod ucts may then create a local inflammatory re sponse as noted above. Polack25 showed experimentally that a single intravenous injec tion of antigen (in this case, Shigella endotoxin) can induce a mild uveitis with graft haziness within 24 hours. The possibility also exists that immunization may stimulate the production of T effector cells that can cross react with allomajor histocompatibility complex antigens of the corneal button. Recently, this has been reported in culture involving cloned T helper cells that recognize class II antigens and cross react with tetanus toxoid antigen 26 and cloned T cells that cross react with influenza-A viral antigens. 27 We can only speculate on the marked differ ence in elapsed time between immunization and both episodes of rejection reported in Pa tient 1. The response to a tetanus toxoid boost er may well have been a secondary (or anam-
nestic) response, reflecting previous antigenic sensitization. The rapid response after the hep atitis B immunization could again reflect previ ous sensitization via a previous subclinical in fection. Although the association between graft rejec tion episodes and immunization was temporal only, immunization is a controllable situation and patients should be forewarned that the procedure may potentiate a threat to the health of their corneal transplant. We suggest that allograft patients be treated with increased top ical corticosteroids both before and after immu nization. Ophthalmologists should also ques tion patients with corneal grafts about recent immunizations or viral syndromes in the pres ence of an acute rejection epsisode. ACKNOWLEDGMENT
Frank M. Polack, M.D., provided the case histories for Patient 4 and Patient 5.
References 1. Chandler, J. W., and Kaufmann, H. E.: Graft rejections after keratoplasty for keratoconus. Am. J. Ophthalmol. 77:543, 1974. 2. Khodadoust, A. A.: The allograft rejection reac tion. The leading cause of late failure of clinical corneal grafts. In Porter, R., and Knight, J. (eds.): Corneal Graft Failure, CIBA Foundation Symposium. Amsterdam, Elsevier, 1973, pp. 151-163. 3. Stark, W. J., Maumenee, A. E., and Kenyon, K. R.: Intermediate term corneal storage for pene trating keratoplasty. Am. J. Ophthalmol. 79:795, 1975. 4. Tuberville, A. W., Foster, C. S., and Wood, T. O.: The effect of donor cornea epithelium removal on the incidence of allograft rejection reactions. Ophthalmology 90:1351, 1983. 5. Fabre, J. W., Milton, A. D., Spencer, S., Settaf, A., and Houssin, D.: Regulation of allo-antigen ex pression in different tissues. Transplant. Proc. 19:45, 1987. 6. Whitsett, C. F., and Stulting, R. D.: The distri bution of HLA antigens on human corneal tissue. Invest. Ophthalmol. Vis. Sci. 25:519, 1984. 7. Young, E., Stark, W. J., and Prendergast, R. A.: Immunology of corneal allograft rejection. HLA-DR antigens on human corneal cells. Invest. Ophthal mol. Vis. Sci. 26:571, 1985. 8. Mayer, D. J.: Tissue typing. In Brightbill, F. (ed.): Corneal Surgery. St. Louis, C. V. Mosby, 1986, pp. 158-177. 9. Young, E., Stark, W. J., and Prendergast, R. A.: Modulation of cell-surface service antigen exprès-
AMERICAN JOURNAL OF OPHTHALMOLOGY
sion in cultured human corneal cells. ARVO Ab stracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1985, p. 316. 10. Donnelly, J. J., Li, W., Rockey, J. H., and Prendergast, R. A.: Class II (IA) alloantigens in duced on corneal endothelium in vivo and in vitro. ARVO Abstracts. Supplement to Invest. Ophthal mol. Vis. Sci. Philadelphia, J. B. Lippincott, 1985, p. 316. 11. Gillette, T. E., Chandler, J. W., and Greiner, J. V.: Langerhans cells of the ocular surface. Oph thalmology 89:700, 1982. 12. Vantrappen, L., Geboes, K., Missotten, L., Maudgal, P., and Desmet, V.: Lymphocytes and Langerhans cells in the normal human cornea. In vest. Ophthalmol. Vis. Sci. 26:220, 1985. 13. Klempanuer, J., Steiniger, B., Wonigeit, K., and Günther, E.: Genetics of heart allograft rejection in the rat. Transplant. Proc. 17:1897, 1985. 14. Tsuchimoto, S., Mizuno, K., Matsuno, Y., Niiyama, T., Cramer, D., Natori, T., and Aizawa, M.: The effects of RTI subregion differences on liver allograft survival in the rat. Transplant. Proc. 17:1900, 1985. 15. Pescovitz, M. D., Thistlethwaite, J. R., Jr., Sharp, T., Auchincloss, H. A., Jr., Ilstad, S. T., Terell, R. E., and Sachs, D. H.: Class II major histocompatibility complex-matched renal allografts in swine. Summary of current results and continuing studies. Transplant. Proc. 17:686, 1985. 16. Mone, T., Albrechtsen, D., Flutmak, A., Jakobsen, A., and Jervell, J.: Importance of HLA-DR matching and cadaveric renal transplantation. N. Engl. J. Med. 303:850, 1980. 17. Stiller, C. R., and Keown, P. A.: Immunologie monitoring. Current prospectives and clinical impli cations. Transplant. Proc. 13:1699, 1981. 18. Theodore, R. H., and Lewson, A. C : Bilateral
iritis complicating serum sickness. Arch. Ophthal mol. 21:828, 1939. 19. Wong, V. G., Anderson, R. R., and McMaster, P. R. B.: Endogenous immune uveitis. Arch. Oph thalmol. 85:93, 1971. 20. Lopez, C , Simmons, R., Mauer, S. M., Najarian, J., and Good, R.: Association of renal allograft rejection with virus infections. Am. J. Med. 56:280, 1974. 21. Kumar, S. S., Ventura, A., and VanderWert, B.: Influence of vaccination in renal transplant recipi ents. JAMA 239:840, 1978. 22. Briggs, J. D., Timbury, M., Paton, A., and Bell, P.: Viral infection and renal transplant rejec tion. Br. Med. J. 4:520, 1972. 23. Gabriel, R., Selwyn, S., Brown, D., Crossland, J., Loughridge, L., Morgan, M., Prosser, D., and Snow, M.: Viral infections and acute renal transplant rejection. Nephron 16:282, 1976. 24. David, D. S., Millian, S. J., Whitsell, J. C , Schwartz, G. H., Riggio, R. R., Stenzel, K. H., and Rubin, A. L.: Viral syndromes and renal homograft rejection. Ann. Surg. 175:257, 1972. 25. Polack, F. M.: The effect of ocular inflamma tion on corneal grafts. Am. J. Ophthalmol. 60:259, 1965. 26. Umetsu, D. T., Yunis, E. J., Matsui, Y., Jabara, H. H., andGeha, R. S.: HLA-DR-4-associated alloreactivity of a HLA-DR-3-restricted human tetanus toxoid specific T-cell clone. Inhibition of both reactivities by an allo-antiserum. Eur. J. Immunol. 15:356, 1985. 27. Gomard, E., Henin, Y., Sterkers, G., Masset, M., Fauchet, R., and Levy, J. P.: An influenza-A virus specific in HLA-DR-W8-restricted T-cell clone cross reacting with a transcomplementation product of the HLA-DR-2 and DR-4 haplotypes. J. Immunol. 136:3961, 1986.