Immunologically Privileged Sites in Transplantation Immunology and Oncology

IMMUNOLOGICALLY PRIVILEGED SITES IN TRANSPLANTATION IMMUNOLOGY AND ONCOLOGY JUDITH R. HEAD and RUPERT E. BILLINGHAM* Transplantation immunity is that branch of immunology that deals with the familiar destruction or rejection of grafts exchanged between genetically disparate individuals [I]. The successful employment of allografts , such as kidneys and hearts, for therapeutic replacement purposes currently requires ongoing treatment of the host with immunosuppressive drugs to hold in abeyance his immunological response against the alien cell surface histocompatibility antigens of the graft, especially those determined by the major histocompatibility complex (MHC). Tissue typing can reduce somewhat the magnitude of this histoincompatibility barrier , so that less immunosuppression is needed. The immune response that an allograft elicits in a normal or inadequately immunosuppressed host is the consequence of a complex interaction between the foreign antigens of the graft and various subsets of host lymphocytes and antigen -presenting cells (APC). The effectors generated during this host response, which mediate graft rejection, are various lymphocytes and antibodies, depending on the type of graft involved. Well before the science of immunogenetics emerged, allografts of both normal and malignant tissues were transplanted to heterotopic sites for different reasons [2]. These included technical convenience (as in the propagation of malignant tissues), confirmation of endocrine function, ability to observe grafts directly by transplanting to the anterior chamber of the eye or to the wall of the hamster's cheek pouch, and possibly the hope that they might serendipitously escape rejection altogether or at least thrive better than in other sites. The results obtained, together with the relatively high proportion of successes that has long been obtained with full- or partial-thickness therapeutic corneal allografts in nonimmunosuppressed patients, indicated that some sites do behave as if they ?University ofTexas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.© 1985 by The University of Chicago. All rights reserved. 003 1-5982/86/2901-0462$01.00 Perspectives in Biology and Medicine, 29, 1 ¦ Autumn 1985 \ 1 15 are immunologically privileged or favored, in the sense that allografts fare better when transplanted to them than when transplanted to more conventional sites in the body. Some privileged sites have been studied systematically to determine their modus operandi. This work, the principal subject matter of this article, is important for the light it has shed on (1) the pathophysiology of allograft rejection; (2) the anomalous success of corneal grafts; (3) the possibility of being able to create privileged sites artificially; (4) the potential use of such sites to sustain therapeutic endocrine-tissue allografts without the need for chronic immunosuppression; and (5) the concept of a natural immunologic tumor-surveillance mechanism. A recent additional incentive is evidence that exposure of one particular site, the anterior chamber of the eye, to foreign tissue may specifically weaken a host's capacity to destroy subsequent allografts from either the original donor or another donor of similar genetic makeup (i.e., a syngeneic donor) that are transplanted to nonprivileged sites [3]. The Lymphatic System: The Host's Encounter with Foreign Antigens Foreign antigens, such as microorganisms, that gain entry to the body by penetrating the skin or other protective surfaces are usually conveyed by draining lymphatic vessels through one or more lymph nodes. These latter are remarkably efficient filters, removing particulate material, including cells, bacteria, and tissue debris, primarily through phagocytic activity. Because they contain abundant antigen-reactive lymphocytes, lymph nodes are sites of immune reactions. The swelling, inflammation, and tenderness of a lymph node are a crude indication that it is engaged in an immunological response. Antigenic material that is injected into or otherwise gains access to the bloodstream directly, thereby bypassing the lymph nodes, is filtered out principally by the spleen and processed in a manner that can also lead to the generation of an immunologic response, or it may lead to a depression of response, reflecting the fact that this is an immunoregulatory organ. It has long been known that the principal site of a host's response to most types of free allografts (i.e., grafts, such as skin, that are naturally revascularized, as compared with more complicated organ allografts, which have to have their blood supply restored surgically) is the regional or draining lymph node...