Studies on the Nature of the Privilege Enjoyed by Corneal Allografts
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Studies on the nature of the privilege enjoyed by corneal allografts Ali A. Khodadoust* and Arthur M. Silverstein The orthotopic corneal allograft enjoys a degree of immunologic privilege due in part to the usual avascularity of the recipient bed. It has been demonstrated that the absence of vasculari- zation interferes with both the afferent limb of host sensitization and, in the previously sensitized host, with the efferent limb of graft rejection. Even when vascularized, however, the graft may only inadequately sensitize the host. Data are presented illustrating such other peculiarities of corneal graft rejection as the leisurely rate at which the cornea may reject as compared with skin, the consequences for the rejection process of the absence of donor vascular endothelium, and the occasional sparing of one or another of the corneal cell layers during rejection. Key words: keratoplasty, corneal allograft, transplantation, privileged site, lamellar graft, penetrating graft Elarly experiences with clinical kerato- inert or provides inadequate stimulus. More- plasty suggested, and clarification of the over, demonstration that specific graft re- immunologic aspects of transplantation jection might be induced months or even confirmed, that allografts onto the cornea years after implantation argues against enjoy an immunologic privilege not shared some form of graft adaptation with conse- by other sites.1"3 The demonstration that quent attenuation of its ability to sensitize any or all of the donor cells of the graft the host. Thus, any privilege ascribed to might survive indefinitely on the cornea'1"7 the corneal graft must be due rather to and the demonstrable antigenicity of these some qualities of the recipient corneal bed cells in ectopic locations8-9 rule out the than to those of the graft itself. possibility that the corneal graft is either It is the avascularity of the cornea that is usually identified as the factor respon- sible for the immunologic protection of From The Wilmer Institute, The Johns Hopkins University School of Medicine, Baltimore, Md. the graft, and indeed one of the major Supported in part by United States Public Health prognostic clinical criteria for graft suc- Service Research Grant EY-00217 from the cess is the degree of vascularization of the National Eye Institute, by an unrestricted gift recipient bed. What has not been clear, from the Alcon Laboratories, Inc., and by an however, is whether the avascularity of Independent Order of Odd Fellows Research Professorship. the cornea acts primarily on the afferent limb of the immunologic response to pre- Manuscript submitted Jan. 21, 1972; manuscript vent initial sensitization of the host, on accepted Feb. 7, 1972. the efferent limb to prevent rejection once Reprint requests to The Johns Hopkins University sensitization has been achieved, or on both School of Medicine, Baltimore, Md. 21205. components of the graft-host interaction. "Present address: Department of Ophthalmology, Pahlavi University Medical School, Shiraz, Iran. Billingham and BoswelP concluded in their 137 Downloaded from iovs.arvojournals.org on 10/02/2021 138 Khodadoust and Silverstein Investigative Ophthalmology March 1972 classic study that lack of vascularization per cent technical success rate with 8 mm. absolutely prevents the efferent rejection penetrating allografts and substantially 100 per cent technical success rate with 5 mm. pene- process, even in the sensitized host, but trating grafts.13 Even when the larger graft is this leaves unexplained how any vascular- placed centrally and the sutures are removed ized comeal graft may survive, a phe- at the earliest possible time (ten days after nomenon often encountered in both clini- grafting), vessels were found occasionally to cal and experimental situations. The limited reach the margin of the graft. In the present study, therefore, the smaller graft size was em- data in this field are further complicated ployed to assure long-term maintenance of an by differences in the sensitivity to the avascular bed insofar as possible. At the time rejection process of penetrating and lamel- of suture removal on the tenth postoperative day, lar corneal grafts. Thus, Maumenee10 found vascularization of the recipient cornea was limited rejection of over 90 per cent of success- to 1 to 2 mm. near the limbus. These vessels collapsed soon after removing the sutures and ful penetrating grafts following additional became ghost vessels visible only by slit lamp sensitization of the recipient with skin examination. from the same donor as the cornea, while 11 The vascularized lamellar graft. As described Komblueth and Nelken observed that in an earlier communication,14 two techniques lamellar grafts were spared from any con- are available to encourage vascularization of the sequences of this type of added sensitiza- corneal transplant. The graft may either be tion of the host. placed eccentrically upon the recipient cornea within 1 to 1.5 mm. of the limbus or the sutures In the present study we have examined may be left in place, since they have been the difference between the avascular and found to encourage vascularization. In the pres- the vascularized graft in their ability to ent study, both of these approaches have been sensitize the recipient host and, follow- employed. The 8 mm. deep-lamellar graft was placed eccentrically on the superior region of the ing host sensitization by means of an ortho- recipient cornea and the sutures left in place topic skin graft from the same donor, the until the tenth postoperative day. At the time ability of the avascular or vascularized of suture removal, blood vessels had, with vary- corneal bed to support the rejection pro- ing severity, invaded the recipient corneal stro- cess. ma from the limbus and had penetrated 1 to 3 mm. into the donor graft itself. Materials and methods The vascularized penetrating graft. In order to encourage and ensure vascularization of the All experiments were performed on five- to penetrating graft, 8 mm. donor buttons were seven-pound adult albino rabbits of the New placed centrally to avoid undue technical compli- Zealand giant strain. The animals were always cations. Rather than remove the sutures on the operated on in pairs, each serving simultaneously tenth postoperative day, however, vascularization as donor and recipient of a corneal graft of a was further induced by leaving the sutures in size, position, and type (lamellar or penetrating) place until the fourteenth to sixteenth day after appropriate to the particular experimental de- transplantation. At the time of suture removal sign. The corneal buttons were secured in place under these circumstances, vessels from the lim- with interrupted or continuous edge-to-edge su- bus had extended through the recipient corneal tures, employing 8-0 virgin silk. stroma and penetrated the peripheral 1 to 2 mm. The avascular lamellar graft. With the tech- of the donor button. nique described earlier,12 8 mm. deep-lamellar Skin transplantation. In order to ensure ade- corneal grafts were placed centrally upon the quate sensitization of the host and simultaneously prepared recipient bed and sutured in place. to assess the degree of pre-existing sensitization, The sutures were removed on the seventh day 2x3 cm. pieces of ear skin were transplanted after grafting, at which time a small brush of orthotopically at the desired time after corneal vessels extended only some Vz mm. from the transplantation. In each instance the donor of limbus into the recipient cornea. Upon removal the skin was the same animal that had provided of the sutures the vessels retreated, and the the initial graft of cornea. The skin grafts were graft remained clear and uncomplicated thence- examined daily, and standard criteria were used forth. More than 400 such allografts have been to evaluate initial take and the timing of graft performed, with a technical success rate of 98 rejection. per cent. Clinical observations. All eyes were examined The avascular penetrating graft. We have pre- at intervals and for durations appropriate to the viously described a technique permitting a 90 different experiments, as outlined in the Results Downloaded from iovs.arvojournals.org on 10/02/2021 Volume 11 Privilege enjoyed by corneal allografts 139 Number 3 section. Initial gross examination was by hand the grafts proved to be technically suc- light, followed by slit lamp examination where cessful and uncomplicated, and in no in- required. Occasional eyes were taken for histo- stance did host vessels extend more than pathologic confirmation of clinical impressions, comparing these reactions with earlier descrip- 1 mm. in from the limbus, the minimal tions of the histopathology of corneal allograft vascular ingrowth which did occur quick- rejection.11"10 ly retreating following suture removal. All Since we had earlier noted7- 14 that the first grafts remained clear for the entire eight- involvement of the cornea in the rejection pro- week period, and no sign of a rejection cess might be the slow destruction of the epi- thelium, at times so subtle as to escape normal process involving either epithelium or stro- clinical observation, grafted eyes were routinely ma was observed. stained with 0.5 per cent methylene blue ap- The effect of added sensitization on the plied topically. In our experience this technique avascular lamellar graft. At the end of does not fail to disclose even the most mild the eight-week observation period, the ani- progression of an epithelial rejection, revealing in this situation a linear defect in the donor epi- mals described above were all grafted on thelium which may be followed day by day the ear with 2x3 cm. full-thickness skin as it travels across the surface of the corneal grafts derived from the same donor which graft. had provided the initial corneal graft. Re- In each instance in which graft rejection was jection of the skin allografts occurred in noted, pains were taken to determine clinically all animals between the eighth and twelfth which of the layers of the donor cornea were involved, since the separate layers (epithelium, day after grafting, with an average of stroma, and endothelium) are sometimes rejected nine and one-half days.