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W2068763413 abstract "There are a number of well-established paradigms in transplantation immunology. Transplants of organs or skin across a complete MHC mismatch are rejected unless the recipient is immunosuppressed. Passenger leukocytes within the graft are the main stimulators of this rejection (1, 2). A local increase in the cytokines interleukin (IL*)-2 and interferon(IFN)-γ occurs in rejection of a transplant, whereas a reduction in their expression is associated with graft tolerance(3-5). Liver transplants across major barriers break these paradigms because they are often not rejected, even in the absence of immunosuppression (6, 7). Moreover, liver passenger leukocytes seem to be required for this spontaneous form of graft acceptance (8-10), which is accompanied by rapid immune activation shortly after liver transplantation(11, 12). Surprisingly, up-regulation of IL-2 and IFN-γ in the lymphoid tissues of tolerant animals is much greater than in rejecting animals (12). Similar to liver allografts, multiple heart and kidney grafts to a single recipient are accepted, although when transplanted singly they are rapidly rejected (13). These paradoxical findings are consistent with activation-associated or high-zone tolerance akin to the high-zone tolerance to soluble antigens(14, 15) or alloantigens(16, 17) reported many years ago. SPONTANEOUS TOLERANCE OF TRANSPLANTED LIVERS For nearly thirty years it has been known that a transplanted liver is often spontaneously accepted across a major histocompatibility barrier(6). This occurs without a requirement for immunosuppression of the recipient and is unique to the liver as other transplanted organs such as kidneys or hearts are rejected under the same conditions (18). Spontaneous acceptance of transplanted livers has been described in all mouse strains examined(19), many low-responder rat strains(20), outbred pigs (6), and primates(6). Even in humans, immunosuppression can sometimes be completely withdrawn in liver transplant recipients with a long-term stable course (21). Acceptance of a transplanted liver leads rapidly to subsequent specific tolerance to other grafts of liver donor origin, including skin grafts in some rat (7) and mouse (19) strain combinations, despite the fact that it is very difficult to induce tolerance to skin grafts. Moreover, liver transplantation can reverse ongoing rejection of a transplanted heart of liver-donor strain (22), and livers may in some cases be spontaneously accepted in presensitized recipients(7, 19). Such rapid induction of tolerance, reversal of ongoing rejection, and graft acceptance in some presensitized recipients across a complete MHC mismatch in the absence of immunosuppression make this the most powerful model of peripheral tolerance to transplanted organs. Understanding the mechanism is therefore of great potential significance to clinical transplantation in general. Adoptive transfer studies from animals that have accepted a transplanted liver show that donor-reactive T cells are rendered tolerant(20). The mechanism of the initial T-cell unresponsiveness is unclear, and it has not been possible to distinguish between anergy and deletion, although T cell-dependent suppression has been excluded. Thus, cells with suppressive activity have not been detected in the first month after liver transplantation (20) despite the fact that, in common with models of heart (23) and kidney transplantation (reviewed in 24), such cells do appear at later times (25). The nature of the tolerogenic stimulus also remains to be identified unambiguously. NATURE OF THE LIVER TOLEROGEN Soluble class I antigen has long been proposed as a possible tolerogen in liver transplantation due to the fact that it is mainly produced by the liver, and the bulk of soluble class I antigen in the serum of liver transplant recipients is of liver donor origin (26, 27). In theory, class I antigen in soluble form may prevent rejection by neutralizing graft-specific antibodies (26) or by inhibiting graft-reactive cytotoxic T cells (28). Prevention of rejection by its administration to the recipient has, however, met with limited success and studies to date have shown only slight prolongation of survival (29) or no prolongation(30). Furthermore, transplantation of livers from MHC class I-deficient donors does not prevent acceptance of the liver(31). It has recently been proposed that donor leukocytes derived from the liver play a major role in liver transplant tolerance (32). Transplants of chimeric livers, which have passenger leukocytes of recipient origin and parenchyma of donor origin, do not induce tolerance to subsequent skin grafts (33). Furthermore, reduction in the number of donor leukocytes by irradiation of the liver donor 1 week before transplantation results in rejection (8-10). In this case, reconstitution of donor leukocytes by brief parking of the liver in a normal donor (8) or by injection of liver or spleen leukocytes (9, 13) reconstitutes acceptance of the liver. The association between liver passenger leukocytes and liver transplant tolerance is paradoxical, as passenger leukocytes can be the main immunological stimulus for transplant rejection, as shown for thyroid(1), pancreatic islet (reviewed in 2), and kidney (34) grafts. Two possible explanations have been proposed for this apparent paradox. First, it has been suggested that liver leukocytes induce a limited graft-versus-host (GVH) reaction resulting in engraftment of stem cells of donor origin and development of microchimerism(32, 35). The other is that the large number of leukocytes present in the transplanted liver leads to overstimulation or abnormal activation of recipient T cells followed by exhaustive differentiation and a deletional form of tolerance(12, 13). LIMITED GVH REACTION LEADING TO MICROCHIMERISM This process involves migration of leukocytes from the transplanted organ to the recipient tissues. Here, under cover of immunosuppression, leukocytes establish a limited GVH reaction that counteracts the rejection(host-versus-graft) response (36). This enables the considerable numbers of hemopoietic stem cells from the graft(37) to survive in the recipient, where they establish long-term microchimerism. Consistent with this mechanism is the well-documented migration of donor passenger leukocytes to recipient tissues, particularly the spleen (38-40), although it is possible that such movement is associated with rejection rather than tolerance (38, 39). Much of the research on the role of microchimerism in organ acceptance has concentrated on demonstrating whether microchimerism accompanies long-term acceptance. Also, attempts to promote acceptance of liver(41, 42) or nonliver grafts(41) have concentrated on administration of donor leukocytes such as bone marrow cells, which are rich in stem cells. There has thus been an emphasis on the end result of microchimerism and not on the immune process by which this result is obtained. Hence there is a need for evidence to show whether a limited GVH reaction is, in fact, occurring in the recipient after liver transplantation. In contrast, there is evidence that liver leukocytes are responsible for aberrant activation of recipient T cells in recipient lymphoid tissues, which leads to their inability to reject the graft (11, 12). In common with microchimerism, a key element in this tolerance is leukocyte migration to recipient lymphoid tissues. ACTIVATION-ASSOCIATED TOLERANCE IN RECIPIENT LYMPHOID TISSUES After liver transplantation, there is rapid migration of large numbers of donor leukocytes into the recipient lymphoid tissues, notably the spleen(11, 39, 43) and draining (celiac) lymph nodes (12). Donor leukocytes constitute approximately 2% of recipient spleen leukocytes at the peak of cell migration, which occurs 1 day after transplantation (12). There is greatly reduced donor leukocyte migration to lymphoid tissues in the recipients of leukocyte-depleted livers, which reject their grafts(12). Central tolerance does not seem to play a role, as thymectomy does not prevent liver tolerance (44) and there is little migration of donor leukocytes to the recipient thymus(11, 12, 44). Donor cell migration to recipient lymphoid tissues is accompanied by rapid up-regulation of mRNA for the cytokines IL-2 and IFN-γ at these sites(12). Paradoxically, much greater increases in cytokine mRNA occur in tolerant strain combinations such as a PVG liver donor grafted to a Dark Agouti (DA) recipient (PVG→DA) or Lewis (LEW)→DA than in combinations such as PVG→LEW or DA→LEW, which reject(12). The cytokine up-regulation seen in lymphoid tissues of animals in the process of becoming tolerant to their transplanted liver is rapid and transient, reaching a peak at 24 hr and rapidly disappearing thereafter (12). There is also proliferation of recipient cells in close association with donor cells in the splenic periarteriolar lymphoid sheath during liver transplant acceptance(11). There is thus a close temporal and physical correlation between the migration of donor leukocytes to recipient lymphoid tissues, recipient T-cell activation, and up-regulation of IL-2 and IFN-γ in these tissues, and subsequent tolerance to the transplanted liver. This process is shown in detail in Figure 1. Transplants of skin, heart, or irradiated liver, which have few passenger leukocytes, lead to low levels of migration to recipient lymphoid tissues (12, 38). These grafts are rejected. By contrast, transplants of liver in the DA→LEW or PVG→LEW strain combination are rejected in spite of the migration of large numbers of graft donor leukocytes to recipient lymphoid tissues (12). In these grafts, there is little or no up-regulation of IL-2 and IFN-γ associated with donor cell migration to lymphoid tissues (12), which suggests that the recipients have not mounted an early, exhaustive T-cell response. Tolerance thus entails migration of donor leukocytes to recipient lymphoid tissues, where they induce a rapid and abortive immune response of the recipient donor-reactive T cells, indicated by expression of high levels of cytokine mRNA. This is supported by a close association between migration of donor leukocytes to recipient lymphoid tissues and subsequent proliferation of recipient leukocytes (11, 39). Furthermore, IL-2 and IFN-γ mRNA present in spleen and lymph nodes of tolerant animals are produced by recipient and not donor cells (S. Shastri, manuscript in preparation). Although rapid up-regulation of proinflammatory cytokines in tolerant animals seems to be counter intuitive, it accords well with several in vitro and in vivo models in which tolerance is associated with activation of responder T cells. These activation-associated models of tolerance include unresponsiveness to mls superantigen (45), soluble protein antigen (46), HY antigen(47), activation-induced T-cell death (reviewed in48), propriocidal killing (49), and anergy of responder T cells resulting from presentation of antigen by activated T cells (reviewed in 50). Activation-induced tolerance, which is primarily a recipient response, should be contrasted to the hypothesis of limited GVH-induced tolerance associated with microchimerism(36). According to the latter concept, the donor cells and not the recipient cells would be activated. Prevention of tolerance in liver allografts by injection of IL-2 early after transplantation (10, 51) seems to contradict the model depicted in Figure 1. It implies that liver tolerance is associated with insufficient IL-2 production rather than overstimulation of T cells. One explanation that can reconcile this contradiction is that the early and exhaustive activation observed in the spleen and lymph nodes of tolerant animals may lead to large numbers of activated recipient T cells, which require IL-2 for continued growth and differentiation. Evidence for this comes from the observation of greater numbers of IL-2 receptor-expressing cells in tolerant, compared with rejecting, livers (52). Perhaps this large cohort of activated cells requires more IL-2 than can be produced, leading to their exhaustion and subsequent deletion. Administration of exogenous IL-2(10, 51) might fulfill their requirement for IL-2, thereby promoting their proliferation and maturation to effector cells, capable of destroying the transplanted liver. EFFECT OF IMMUNOSUPPRESSION ON LIVER TOLERANCE Evidence in support of the suggestion that the immune activation seen in liver tolerance is not an epiphenomenon but is central to induction of the unresponsive state comes from studies in which tolerance was inhibited by high-dose immunosuppression. Treatment of rat liver graft recipients for the first 2 days after transplantation with methylprednisolone, at dosage levels similar to human transplants, significantly reduced the development of tolerance to subsequent skin transplants of liver donor origin(12). This finding is reminiscent of experiments performed many years ago, which showed that corticosteroid immunosuppression prevented induction of tolerance to tumor allografts(53). The early immune response associated with activation-induced tolerance poses a dilemma for management of patients. Early high-dose steroid treatment may interfere with possible liver tolerance induction in humans, whereas immunosuppressive treatment is necessary to control rejection. One possible way of obviating the problem is to exploit the apparent difference in tempo of up-regulation of proinflammatory cytokines in tolerance compared with rejection. As mentioned previously, tolerance-associated cytokine production in lymphoid tissues peaks early, at 1 day after transplantation, whereas cytokine production in a rejecting graft seems to peak later, at approximately 5 days (3, 4, 54). Similarly, the small amount of available data on the tempo of cytokine expression in lymphoid tissue during graft rejection also shows partial early up-regulation(12) or a delay of 4-5 days before peak levels are reached (55). By delaying administration of immunosuppressive drugs for a short time after liver transplantation, it might therefore be possible to avoid their adverse effects on tolerance-associated immune activation while still preventing the late upregulation of cytokines associated with rejection. Such an effect of immunosuppressive therapy on tolerance is not predicted by the hypothesis of a limited GVH reaction. On the contrary, immunosuppression has been suggested to be a necessary requirement in those circumstances in which the transplanted organ is not able to mount a sufficiently strong GVH response to protect itself (36). HIGH-DOSE TOLERANCE MODEL FOR ALLOGRAFTS Further evidence in support of a role for early immune activation in liver tolerance comes from models of high-dose tolerance to virus or protein antigens. Infection of mice with low doses of virus leads to sustained development of cytotoxic T cells, which eliminate the virus. In contrast, high doses of virus lead to rapid activation and subsequent deletion of virus-specific T cells, resulting in viral persistence(56). Such a phenomenon has been termed “tolerance by exhaustion” (57). Similarly, in a model of experimental allergic encephalomyelitis, high doses of disease-inducing myelin basic protein lead to activation of responder T cells and production of IL-2. Neverthless, disease does not develop in these animals and there is clonal deletion of myelin basic protein-reactive T cells (58). A common feature of these models of high-dose tolerance is that activation of responder T cells, measured by proliferation or cytokine production, precedes deletion or inactivation of the responding clone. High-dose tolerance can account for some, but not all, aspects of liver transplantation tolerance. It is consistent with the size of the liver, which weighs about 9 g in a rat, compared with 1 g for a heart or kidney. A scheme depicting the relationship between antigen dose and graft outcome is shown inFigure 2. At low levels of stimulation there is little or no response, corresponding to immunological indifference (ignorance). Increasing antigenic stimulation increases the response and culminates in rejection of the allograft. At very high levels of stimulation, exhaustion of the immune response occurs, resulting in tolerance of allo-reactive T cells, which are presumably deleted. This pattern of high-dose tolerance has been observed previously for spleen cell-induced acceptance of subsequent skin allografts (16) or tumor grafts across minor histocompatibility barriers (17). The large parenchymal cell mass of the liver is not sufficient by itself to induce high-dose tolerance. An additional role is played by donor passenger leukocytes as demonstrated by the occurrence of rejection after they are depleted from the transplanted liver. Irradiation of the liver donor leads to a decrease in levels of passenger leukocytes to approximately 30% of normal(8), thereby reducing the antigenic stimulus and moving the response to the left along the curve shown in Figure 2, which results in rejection (8). Conversely, reconstitution of passenger leukocytes to the irradiated liver, which increases the antigenicity of the graft and moves the response to the right along the curve, restores spontaneous liver acceptance(8, 13). Prolonged survival of irradiated heart (59), kidney(60), or lung grafts (61), although contrasting with the decreased survival of irradiated liver grafts, is consistent with the proposed model. Reducing the antigenicity of a heart or kidney graft moves it to the left along the curve in Figure 2, resulting in a decrease in the rejection response. The model also predicts that increasing the antigenicity of heart or kidney grafts should move them to the right along the curve in Figure 2, into a lower response region. This is supported by experimental data that show that an increase in the number of transplanted organs leads to their prolonged survival (13, 62). Single heart or kidney transplants in the PVG→DA strain combination are rejected in about 8 days, whereas double-heart transplants exhibit prolonged survival of 15.5 days and double-kidney transplants have a median survival of about 60 days(62). Survival of two hearts plus two kidneys is also markedly prolonged, with continued cardiac function being demonstrated at 60 days, even though there is evidence of chronic rejection(13). Injection of 1.5×108 donor leukocytes into recipients of two hearts and two kidneys results in indefinite graft survival, with no evidence of chronic rejection after 200 days(13). This progressive increase in survival time with increasing dose of transplanted tissue contrasts with early studies of skin transplants (63). The requirement for a large dose of both donor tissue and donor leukocytes, although consistent with the model of high dose tolerance shown inFigure 2, still fails to explain the occurrence of liver tolerance in certain situations. For example, PVG strain donor livers are rejected in LEW, but accepted in DA, strain recipients, despite the fact that there is no difference either in the amount of tissue transplanted or in the number, type, or distribution of donor leukocytes in recipient lymphoid tissues (12). Furthermore, injection of large numbers of donor leukocytes at the time of transplantation has little effect on heart or kidney transplant survival (13, 64-66). Similarly, increasing the amount of donor tissues, without additional donor leukocytes, does not lead to long-term acceptance of multiple heart and kidney grafts (8). It thus seems that additional donor leukocytes together with a large mass of donor parenchyma are required for complete acceptance, a phenomenon that was first demonstrated using chimeric liver grafts (33). The identity of the population of cells of donor origin that contributes to tolerance induction is of central importance. If this population could be identified, then it might be possible to administer these cells to promote specific tolerance in the absence of nonspecific immunosuppression. Donor dendritic cells are the major allostimulatory population in the graft(34), and it is possible that they cause the rapid and exhaustive immune activation that we describe in liver tolerance. Liver dendritic cells home to recipient lymphoid tissues, with significant numbers present in the spleen 1 day after injection (67, 68), and liver dendritic cells propagated in vitro are strong stimulators of alloresponses (69). Thus donor dendritic cells are possible candidates for induction of high-dose/activation-associated tolerance in recipient lymphoid tissues. Alternatively, nitric oxide induced by IFN-γ has been shown to inhibit alloactivation by dendritic cells(70), and high expression of IFN-γ in recipient lymphoid tissues during tolerance induction (12) might interfere with ongoing stimulation of the immune response in these tissues. There is conflicting evidence for the role of liver dendritic cells in transplant tolerance. Administration of dendritic cells can prolong survival(71), although increasing the number of dendritic cells in donor livers results in rejection (72). Donor T cells may also be involved in liver transplant tolerance as reconstitution of acceptance of irradiated donor livers with donor leukocytes is less effective if T cells are removed from the donor inoculum (13). CONCLUSIONS The paradoxical survival of fully mismatched liver allografts in recipient strains that normally reject other organs of liver donor origin seems to be due to high-dose and/or activation-associated tolerance. There are four lines of evidence that support this mechanism: liver tolerance is associated with greater cytokine production than liver rejection; reduction of the immunostimulatory cells of the graft, the passenger leukocytes, causes rejection of livers that are otherwise tolerated; treatment of tolerant strain combinations with high-dose steroids at the time of transplantation reduces tolerance; and increasing the amount of kidney and heart tissue and donor leukocytes leads to acceptance of these organs. These findings are of potential importance for treatment of liver transplant patients. Early immunosuppressive treatment of these patients may interfere with liver allograft acceptance, and it is possible that a delay of therapy for 1 or 2 days may well improve outcome. Further experiments are required to define whether there is a “tolerance window” in the first day or two after liver transplantation in which immunosuppressive drug use should be minimized to allow natural liver tolerance to develop. Finally, the precise mechanisms underlying tolerance induction need to be identified, particularly the nature of the donor cells that mediate tolerance, their activation state and expression of cell surface molecules and cytokines, and the contribution of donor parenchymal tissue to the tolerogenic process. Acknowledgements. The authors thank Professor A. Basten for critical review of the manuscript and for helpful discussions.Figure 1: Model of sequential processes involved in the spontaneous acceptance of transplanted organs. The spontaneous acceptance of liver allografts in the strain combinations PVG→DA or LEW→DA is dependent on migration of donor passenger leukocytes to recipient lymphoid tissues followed by rapid immune activation in these tissues. If migration does not lead to early immune activation as in liver allografts in the PVG→LEW or DA→LEW combination, or if there is little or no migration as occurs with skin, heart, kidney, or irradiated liver donor allografts, then rejection occurs.Figure 2: A proposed stimulus-response curve for transplanted organs showing high-dose tolerance. Increasing the antigenic stimulation increases the rejection response up to a point. Further increases in antigenic stimulation lead to overstimulation of the immune response, resulting in clonal exhaustion and a decreased rejection response." @default.
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W2068763413 title "High-Dose/Activation-Associated Tolerance" @default.
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