Biomedical subjects
Publications and source records attributed to G A Wilbanks.
A 39-year-old man with a 3-week history of an enlarging mass protruding from his right cornea is presented. Clinical and pathologic findings were compatible with a large corneal pseudocyst. Causes of corneal cyst and pseudocyst formation, as well as a proposed mechanism for the giant pseudocyst formation presented here, are discussed.
Perfluorodecalin is a perfluorocarbon liquid used intraoperatively in retinal detachment repair. It is usually removed at the end of the procedure; however, residual amounts may be retained when poor corneal clarity or intraocular hemorrhage obscures the view. No clinical reports exist on the consequences of retained perfluorodecalin in the anterior segment. We report five cases in which perfluorodecalin was in prolonged contact with the cornea. The period of time for corneal pathology to occur and the role perfluorodecalin played in the etiology of such changes is discussed. A total of 348 patients with retinal detachments in one retinal practice underwent repair using pars plana vitrectomy combined with intraoperative perfluorodecalin between January 1992 and May 1994. Postoperatively, residual perfluorodecalin was observed in the anterior chamber in contact with the corneal endothelium in five patients. The patients were followed clinically for a period of up to 18 months. Four of five patients developed corneal changes from prolonged contact with perfluorodecalin. Corneal edema developed in the area perfluorodecalin-endothelial contact in three of five eyes. The period of perfluorodecalin-endothelial contact before corneal decompensation occurred ranged from 4 to 13 weeks. Two eyes required penetrating keratoplasties for progressive corneal edema. Corneal edema was reversed in one eye after removal of perfluorodecalin from the anterior chamber via multiple paracentesis. One of the remaining eyes developed deep corneal vascularization without edema in the area of perfluorodecalin contact after 12 months. These observations suggest that corneal toxicity may be induced by intraocular perfluorodecalin if it is allowed direct contact with the corneal endothelium for periods as short as 1 month. Some of these changes may be reversible if perfluorodecalin is aspirated from the anterior chamber. Further investigations are required to examine perfluorodecalin-induced corneal toxicity.
Two corneal suction trephination systems currently in use are the Barron-Hessburg and the Hanna trephine. This study assessed the outcome of patients who received penetrating keratoplasty using these two systems. One hundred twenty-four eyes (62 with the Hanna system, 62 with the Barron-Hessburg system) from 98 patients undergoing penetrating keratoplasty were evaluated retrospectively. Best corrected spectacle acuity and corneal astigmatism were assessed 6 and 12 months after surgery. No significant difference was noted between the groups 6 months after surgery. At 12 months, a significant improvement in spectacle acuity was present with 55% of the Hanna group having visual acuity of 20/40 or better compared with 33% of the Barron-Hessburg group (p < 0.005). This difference was greater if eyes having the best visual prognoses were separately evaluated: 74% of the Hanna group had 20/40 vision or better compared with 41% of the Barron-Hessburg group (p < 0.005). In eyes having a good visual prognosis, a significant improvement in visual acuity was present, with 33% of the Hanna group improving nine or more lines compared with 9% of the Barron-Hessburg group (p < 0.05). Postoperative keratometric and refractive astigmatism were not different at 6 or 12 months. We found that visual recovery at 1 year is better using the Hanna system, especially in eyes with good visual prognoses.
Immunization with bovine interphotoreceptor retinoid-binding protein induces autoimmune uveitis in B10.A mice. We have examined whether this soluble retina-specific Ag can induce anterior chamber-associated immune deviation when injected into the anterior chamber (AC) of the eye, and whether this deviant immune response has any effect on uveitis is susceptible mice. The results of these experiments indicate that interphotoreceptor retinoid-binding protein (IRBP) injected intracamerally altered the subsequent immune response of B10.A mice such that a) they were not able to develop IRBP-specific delayed hypersensitivity, nor (b) were they able to express significant autoimmune uveitis following a uveitogenic regimen. Moreover, spleen cells from mice that received IRBP in the AC suppressed uveitis when adoptively transferred into naive recipients. The splenic suppressor cells were able to prevent autoimmune uveitis in recipient mice when administered after the uveitogenic regimen. Most important, IRBP-specific splenic cells from mice treated with IRBP in the AC when injected into mice with established uveitis caused an abrupt cessation of the intraocular inflammation. The ability of intracamerally-injected soluble Ag to induce suppressor T cells that act on the efferent limb of the immune response suggests that the anterior-chamber-associated immune deviation phenomenon may have physiologic relevance in terms of preservation of the integrity of ocular tissue and renders this approach particularly suitable for treating already established experimental autoimmune diseases of this type. These results are discussed in terms of other methods that have been devised experimentally to suppress and prevent autoimmune uveitis and encephalomyelitis.
Delayed hypersensitivity (DH), the prototypical form of cell-mediated immune responsiveness, is mediated with the participation of considerable nonspecific inflammation which necessarily disrupts the anatomic integrity of involved and adjacent tissues. Damage of this type is of minor consequence to many visceral and cutaneous organs, but is of devastating consequence for organs such as the eye and the brain. At least in the case of the eye, the organ is remarkably adept at regulating the immune system's ability to respond to intraocular antigens by selectively down-regulating both the induction and expression of delayed hypersensitivity while leaving other effector modalities intact. This ability of the eye to selectivity down-regulate systemic DH responses to intracamerally inoculated antigens is known as anterior chamber-associated immune deviation (ACAID) and is mediated in part by antigen-specific regulatory T cells. Recent work suggests that macrophages (M phi) that reside in the iris and ciliary body can migrate out of an antigen-bearing eye and activate regulatory T cells within the spleen. In an effort to understand the mechanism by which intraocular M phi interact with antigen in the anterior chamber of the eye (AC) and subsequently induce splenic regulatory cells in ACAID, we have investigated what role, if any, the AC microenvironment itself plays in ACAID induction. The results reveal that CD45- parenchymal iris/ciliary cells secrete a soluble factor(s) locally and into the aqueous humor which endows resident, mature M phi with ACAID-inducing capabilities. Mice receiving infusions of these altered, antigen-pulsed M phi are incapable of mounting a significant DH response following immunization with antigen in adjuvant. Importantly, the ACAID-inducing effect is achieved when conventional, extraocular M phi are exposed in vitro to a soluble factor present in aqueous humor or culture SN from iris and ciliary body cells. Further investigations into the identity of this factor reveal it to be transforming growth factor-beta (TGF-beta). The role of TGF-beta in the generation of ACAID, as well as the implications of these findings to an understanding of immunologic privilege in general, are discussed.
The eye, brain, and fetoplacental unit within the pregnant uterus are immunologically privileged sites that contain unique fluids with suspected immunoinhibitory properties. Aqueous humor, which is normally present within the anterior chamber (AC) of the eye, has been shown to suppress antigen-driven T cell activation, and to contain significant amounts of transforming growth factor beta-2 (TGF-beta). Antigens injected into the AC of normal mice induce a deviant form of systemic immunity, termed anterior chamber-associated immune deviation (ACAID), which is characterized by a selective inability to display antigen-specific delayed hypersensitivity. It has recently been reported that eye-derived macrophages appear in the blood following AC injection of a soluble antigen, and that these cells can induce antigen-specific ACAID when injected into naive, syngeneic recipients. Moreover, antigen-pulsed peritoneally derived macrophages that are exposed in vitro to aqueous humor, supernatants of cultured iris and ciliary body cells (I/CD), or TGF-beta have been found to assume ACAID-inducing properties. In the present experiments, amniotic fluid and cerebrospinal fluid from mice, rats and humans, as well as supernatants from cultured I/CB cells, have been examined for their capacity to confer ACAID-inducing properties on peritoneal macrophages. It was found that each of these biologic fluids, but neither normal mouse serum nor rat thoracic duct lymph, was able to endow antigen-pulsed peritoneal macrophages with ACAID-inducing properties. Moreover, fluids from these immune privileged sites were found to contain latent and/or active TGF-beta, as determined by bioassay, using neutralizing anti-TGF-beta antibodies. It is concluded (a) that the immune privileged states of the eye, the brain, and the fetoplacental unit share common features, and possess unique fluids with a similar capacity to force macrophages to present antigens in a "deviant" manner and (b) that this capacity is mediated, at least in part, by TGF-beta. These results are discussed in terms of the potential physiologic and pathophysiologic significance of immune privilege in these three specialized tissues.
Immune-privileged sites, such as the the internal compartments of the eye, and perhaps the brain, are physiological adaptations that act to modify systemic immune responses such that effector mechanisms that invoke locally destructive inflammation are suppressed. In the case of the eye, the parenchymal cells of the iris and ciliary body create an intraocular microenvironment that alters both the induction and expression of immunity to antigens placed within the eye. The immunosuppressive properties of the intraocular microenvironment are mediated by cytokines, especially transforming growth factor-beta (TGF beta). This cytokine has been demonstrated to endow intraocular antigen-presenting cells with the capacity to induce an atypical or deviant form of immunity to intraocular antigens which is selectively deficient in T cells that mediate delayed hypersensitivity. Moreover, TGF beta, along with other intraocular factors, can impair the intraocular expression of pre-existing cell-mediated immunity by inhibiting antigen-driven activation of primed T cells. The strategies employed by the eye to engender specialized immune responses appropriate to its physiological functions are discussed in terms of other privileged sites such as the brain.
The normal aqueous humor contains a variety of soluble immunosuppressive factors, including transforming growth factor-beta, alpha-melanocyte stimulating hormone, and vasoactive intestinal peptide. These factors are largely the secretory products of parenchymal cells of the iris and ciliary body. TGF beta has recently been shown to alter the functional capacity of intraocular antigen presenting cells, such that they are capable of inducing Anterior Chamber Associated Immune Deviation (ACAID). This deviant systemic immune response is characterized by an impaired capacity to mount an effective cell-mediated immune attack directed at antigens that are placed in, or arise within, the eye. A second property of immunosuppressive factors in aqueous humor is to suppress directly the expression of delayed hypersensitivity in the anterior chamber. In fact, even when the intraocular microenvironment is disturbed by local instillation of gamma-interferon, making it possible for limited expression of cell-mediated immunity in the eye, the microenvironment of the anterior chamber remains profoundly immunosuppressive. In this latter instance, prostaglandins replace TGF beta as the major molecular mediators of suppression in the aqueous humor. In the aggregate, factors present in the normal (or perturbed) intraocular microenvironment have the capacity to modify both the afferent and efferent limbs of the systemic immune response, and this accounts for the longstanding observation that the anterior chamber is an immunologically privileged site. Since evidence suggests that the eye can mobilize more than one molecular mechanism in its effort to limit the sight-destroying potential of immunogenic inflammation, we believe that elucidation of intraocular cytokines and factors that create and maintain an immunosuppressive microenvironment will contribute to a better understanding of the pathogenesis of the acute and chronic uveitides, especially those of autoimmune and infectious etiology.
Despite an ever increasing body of information concerning general in vivo immune reactivity to exogenous Ag, relatively little is known concerning regional tissue influences on these responses. One expression of regionally distinct immune regulation is the deviant form of systemic immunity induced after the introduction of Ag, such as BSA, into the anterior chamber of the eye--anterior chamber-associated immune deviation (ACAID). ACAID is characterized by a selective, systemic immune deficiency in which both Ag-specific delayed hypersensitivity (DH) and complement-fixing antibody production are impaired by populations of Ts lymphocytes, although other immune effector modalities are preserved. Recent evidence demonstrates that the blood of mice that receive an anterior chamber injection of BSA 48 h earlier contains leukocytes capable of inducing cell-mediated Ag-specific efferent suppression of DH similar to that seen in mice with ACAID. Additional analysis of these bloodborne suppression-inducing leukocytes revealed them to express the mature macrophage/monocyte marker F4/80. On the basis of these findings, we wished to determine the source of the ACAID-inducing cells present in the peripheral blood of mice after anterior chamber inoculation of BSA. The data reveal that cells harvested from the normal eye are capable of selective induction of DH suppressive activity similar to that seen in ACAID. Interestingly, this property is unique to F4/80 expressing cells of the iris and ciliary body (I/CB). F4/80- I/CB cells do not possess this property. Although the F4/80 expressing cells that are present in extraocular sites do not constitutively possess ACAID-inducing properties, exposure of these cells to the anterior chamber microenvironment endows them with this ability. Finally, I/CB cells exposed to Ag in situ, via direct anterior chamber Ag inoculation, induce suppressed Ag-specific DH reactivity when infused into naive syngeneic recipients--a form of systemic immune deviation similar to that seen in mice with ACAID. The results presented here represent the first in vivo description of APC, altered by factors in a local microenvironment, that can initiate a systemic immune response characterized by Ag-specific immune suppression.
The anterior chamber of the eye is an immunologically privileged site. Recent evidence indicates that this privilege is an actively acquired immune state in which a unique form of systemic immune deviation exists, anterior chamber-associated immune deviation (ACAID). ACAID is characterized in part by the generation of Ag-specific splenic T lymphocytes that mediate suppression of induction and expression of delayed hypersensitivity and that suppress production of C-fixing antibodies. Delayed hypersensitivity and C fixation are usually associated with extensive nonspecific inflammation and innocent bystander tissue injury. It is, therefore, believed that ACAID represents physiologic adaptations of the immune system that mitigate wanton destruction of the anatomically delicate visual axis, thereby preserving sight, while at the same time providing selective immune protection. As a means of examining the potential contribution of the eye to ACAID induction, we have studied the immune properties of blood harvested from mice that had received BSA into the anterior chamber 48 h earlier. We found that an Ag-specific "signal" is present in the blood of these mice; when blood was transfused into naive syngeneic mice, regulatory cell populations were induced and the recipients were unable to display BSA-specific delayed hypersensitivity. Further analysis of this signal revealed it to be associated with the leukocyte fraction, but not with either the plasma or RBC components of whole blood. Among leukocytes, the suppression-inducing activity correlated positively with cells bearing the mature macrophage marker F4/80 and negatively with cells bearing Thy-1, surface Ig, and class II MHC molecules. These findings are discussed with regard to the potential intraocular sources of the ACAID-inducing signal and the possible mode of action of this factor.
A large body of information exists describing the inability of animals receiving inoculations of antigen either intravenously (i.v.) or via the anterior chamber of the eye (AC) to mount delayed hypersensitivity (DH) responses to the injected antigen. Evidence indicates that the deviant humoral and cellular immunity that follows AC and i.v. inoculations of antigen is mediated, in part, by active suppression. Because of these similarities, it has been argued that immune deviation resulting from the AC inoculation [anterior chamber-associated immune deviation (ACAID)] of antigen represents nothing more than deviant immune responses known to be induced by the i.v. inoculation of antigens. Since circumstantial evidence suggests that AC injections may have unique immune effects, we wished to test the hypothesis that AC exposure to antigen elicits a unique form of systemic immune regulation. We have studied and compared the functional and phenotypic properties of suppressor cell populations induced by AC and i.v. inoculations of a soluble antigen, bovine serum albumin (BSA). Results indicate that AC inoculations of BSA (but not i.v. inoculations) activate antigen-specific. CD8+, I-J+ T lymphocytes which suppress the expression of DH responses, i.e. efferent suppression. We further report that AC and i.v. injection routes both activate antigen-specific afferent suppressor cell populations which impair the inductive phase of the immune response. However, the i.v.-induced afferent suppressor cells are CD8+ I-J+, whereas the AC-induced afferent suppressor cells are CD4+. We conclude that AC and i.v. exposures to soluble antigens are not immunologically equivalent, and that ACAID represents a uniquely regulated systemic immune response to intraocular antigens.
Inoculation of soluble antigen into the anterior chamber (AC) of the eyes of mice and rats induces a distinctive form of immune deviation known as anterior chamber-associated immune deviation (ACAID). Similarly, intravenous injections of soluble antigen induce immune deviation. In both instances, a selective impairment of delayed hypersensitivity (DH) is observed, whereas humoral immunity is said to be preserved. Recently, we noted that radiolabelled bovine serum albumin (BSA) was not eliminated in an immune fashion from the blood of animals pretreated with this antigen via AC and intravenous (i.v.) routes of inoculation. This was puzzling because the sera of these animals contained easily measurable anti-BSA antibodies. We have examined the characteristics of the anti-BSA humoral responses of mice following i.v. and AC inoculation of BSA in order to understand the reason for the lack of immune elimination. The results indicate that AC and i.v. recipients fail to eliminate antigen in an immune fashion because they produce insufficient amounts of complement-fixing (IgG2) antibodies, even though the other isotypes of immunoglobulins are well represented in the humoral anti-BSA response. The pattern of antibody isotype production, especially after boosting with BSA in complete Freund's adjuvant (CFA), implies that activation of IgG2-secreting, BSA-specific B cells is suppressed. Evidence is presented demonstrating this suppression to be antigen-specific and mediated by CD8+ T lymphocytes. These data are compatible with the hypothesis that interleukin-4 (IL-4)-secreting T helper (Th) cells are selectively activated in ACAID, whereas interferon-gamma (IFN-gamma)IL-2-secreting Th cells are actively suppressed.
Antigens injected into the anterior chamber of the eye generate a deviant immune response (Anterior Chamber Associated Immune Deviation--ACAID) characterized by impaired delayed hypersensitivity and lack of complement-fixing antibodies. Both the antigen-containing eye and an intact spleen are required for ACAID induction. The eye's contribution takes the form of an antigen-specific, ACAID-inducing signal associated with blood-borne F4/80+ macrophages. Macrophages capable of carrying an ACAID-inducing signal can be harvested directly from the iris and ciliary body, or can be created by exposing F4/80+ peritoneal exudate cells to aqueous humor or to supernatants of cultured iris and ciliary body cells. In the present study, F4/80-bearing macrophages from the peritoneal cavity were exposed in vitro to supernatants of cultured iris and ciliary body cells and then labelled with PKH-2 prior to intravenous infusion into naive, syngeneic recipients. The pattern of distribution of these cells in spleen, lymph nodes, and blood was compared with similarly labeled cells exposed in vitro to medium alone. The results reveal that, compared to conventional peritoneal exudate cells, macrophages that are endowed with ACAID-inducing properties (by exposure to supernatants of iris and ciliary body cell cultures) preferentially migrate to the spleen following their intravenous inoculation into syngeneic recipients. Moreover, when injected intravenously into asplenic mice, macrophages with ACAID-inducing potential accumulate excessively (compared to their conventional counterparts) in the peripheral blood.(ABSTRACT TRUNCATED AT 250 WORDS)
The route by which antigen is administered plays an important role in dictating quantitative and qualitative characteristics of systemic immune responses. Antigens such as BSA injected into the anterior chamber (AC) of the eye evoke a deviant systemic immune response (anterior chamber-associated immune deviation--ACAID) characterized by a selective deficiency of delayed hypersensitivity (DH). It has been claimed that the deviant immunity which follows an AC injection is related to the uniqueness of the route of antigen administration. However, others have argued that since the aqueous humor which fills the AC of the eye drains directly into the venous circulation, and since the anterior chamber lacks demonstrable lymphatic drainage pathways, an AC injection is a de facto intravenous (i.v.) injection. To determine which of these proposals is correct, we have studied the kinetics of antigen retention and release following inoculations of 125iodine-labeled BSA into the AC, into the subconjunctival space (SC), and into the blood stream. The results indicate that both AC and the SC inoculation sites function as antigen depots: significant amounts of BSA are retained within the eye in both situations for at least 4 weeks. Moreover, BSA was released from the eyes into the blood stream for greater than 21 days post-inoculation. Sites of i.v. inoculation exhibit no such properties. Interestingly, removal of the eye of AC inoculated groups, but not the site of i.v. inoculation in i.v. recipients, up to 5 days post-inoculation prevented the induction of immune deviation.(ABSTRACT TRUNCATED AT 250 WORDS)