Allograft Tolerance

Allograft Tolerance G Benichou and T Kawai, Massachusetts General Hospital, Boston, MA, USA ã 2014 Elsevier Inc. All rights reserved.

Abbreviations ACAID APC CTLA4 DCs MDSCs

Anterior chamber-acquired immune deviation Antigen-presenting cell Cytotoxic T lymphocyte antigen 4 Dendritic cells Myeloid-derived suppressor cells

Introduction Tolerance of our own cells and tissues is initially achieved during ontogeny via elimination of autoreactive T- and B-cell clones whose antigen receptors exhibit a high affinity for self-peptide determinants presented along with self-major histocompatibility complex (MHC) molecules in the thymus and bone marrow, respectively (central tolerance). On the other hand, lymphocytes whose antigen receptors display a low affinity for self-antigens are allowed to survive, expand, and leave the thymus to form the adult T-cell repertoire (positive selection). Therefore, substantial numbers of autoreactive lymphocytes escape central elimination and can potentially initiate autoimmune disorders in the periphery. However, the development of autoimmune pathology by peripheral autoreactive T cells is consistently prevented through a series of mechanisms including ignorance, anergy, exhaustion, and presumably peripheral clonal deletion (peripheral tolerance). Multiple cells, soluble mediators, and cell surface receptors have been implicated in the maintenance of peripheral tolerance to self-antigens. On the other hand, after transplantation of allogeneic organs and tissues, peripheral lymphocytes exposed to foreign MHC molecules present on donor cells react vigorously and initiate an inflammatory process resulting in the rapid destruction of the foreign tissue, a process known as acute allograft rejection. Immunosuppressive agents such as calcineurin inhibitors, which inhibit nonselectively lymphocyte activation, have been used successfully to prevent such acute rejection process, thus allowing large-scale transplantation and significant improvements in organ transplantation. However, chronic use of immunosuppressive drugs results in significantly increased risks of cardiovascular disease, infection, malignancies, and other metabolic derangements, such as de novo diabetes and dyslipidemia. Most importantly, current immunosuppressive therapies fail to prevent development of chronic rejection, which leads to an inexorable loss of previously functioning transplanted organs at an annual rate of about 5–7% with no significant improvements of renal graft half-life in the last 10 years (Figure 1). Therefore, induction of allograft tolerance remains an important goal of organ transplantation.

Tolerance Induced During Ontogeny Transplantation tolerance is naturally achieved during pregnancy, a period during which the mother’s immune system

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MHC Mreg MSCs NK cells TMEM Tregs

Major histocompatibility complex Regulatory macrophage Mesenchymal stem cells Natural killer cells Memory T cell Regulatory T cells

fails to reject the fetus despite the presence of paternal allogeneic MHC antigens. On the other hand, while the mother is tolerant of her own fetus, the fetus’ immune system itself becomes somewhat tolerant to the noninherited maternal antigens to which it is exposed during pregnancy and breastfeeding. In fact, the first evidence of transplant tolerance derived from the seminal observation by Ray Owen of mixed chimerism in dizygotic cattle twins, so-called freemartin cow. Owen discovered red cell chimerism in these cows resulting from placental fusion, which allows cross-circulation between twins in their early development (Figure 2). This seminal study suggested that tolerance of allogeneic cells can occur naturally when the immune system is exposed to alloantigens during development. Around the same time, Peter Medawar independently found that skin grafts exchanged between twin calves are invariably accepted. Subsequent studies on neonatal tolerance actually demonstrated that immunologic tolerance to an allograft can be artificially induced by exposing the fetus to the alloantigen, before maturation of the immune system (Figure 3). Based upon these principles, later studies have focused on the elucidation of the cells and physiological mechanisms involved in the suppression of inflammatory alloimmune reactions in vivo in an effort to design selective methods to achieve immune tolerance of various allogeneic transplants in patients.

Allograft Tolerance and Immune Privilege It is clear that certain organ and tissue transplants are less prone to rejection than others and/or more susceptible to tolerance induction. On the other hand, allografts placed in selected anatomical sites of the recipient enjoy long-term survival with no or minimal immunosuppression. The concept of immune privilege initially stemmed from studies performed with tumors injected into the anterior chamber of the eye or the brain of rabbits or the cheek pouch of hamsters. These tumors underwent rapid growth, while they were invariably rejected when placed elsewhere in the body. Likewise, Medawar et al. showed that allogeneic skin grafts placed in the anterior chamber of the eye, which remained unvascularized, enjoyed longterm survival and failed to sensitize the host’s immune system in a fashion that typically leads to accelerated rejection of a second graft placed orthotopically. The term ‘immune privilege’

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Figure 1 Long-term results of deceased donor kidney transplantation. No significant improvements in the half-life of the kidney allograft in the last decade. Reproduced from Meier-Kriesche, H.U., Schold, J.D., Srinivas, T.R., Kaplan, B., 2004. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am. J. Transplant. 4 (3), 378–383.

Sixteenth to seventeenth day CBA fetus

Skin graft from (CBAXB10)F1

Control

Figure 2 In 1917, Frank Lillie of Chicago University discovered vascular connection between male and female placentas, allowing the exchange of blood between fetuses. Reproduced from Buergelt, C.D., 1996. Color Atlas of Reproductive Pathology of Domestic Animal, Mosby, with permission.

Cellular suspension Spleen, kidney liver, testis

(CBAXB10)F1

was subsequently introduced by Billingham and Boswell in 1953 based on observations of spontaneous acceptance of corneal allografts. Since then, it has become clear that leukocyte recognition of alloantigens in immune-privileged sites leads to systemic immune unresponsiveness, as described in the phenomenon of anterior chamber-acquired immune deviation (ACAID) described by Streilein et al. In addition to physicochemical barriers protecting such sites from inflammatory cell infiltration, immune privilege is ensured through intrinsic mechanisms including the presence of immunomodulatory cytokines (IL-10 and TGF-b) and hormones, downregulation of MHC expression, and expression of Fas-ligand, causing apoptosis of activated T cells (CD95þ). Furthermore, immune privilege is also mediated via antigen-specific regulatory mechanisms contributing to extend tolerance to external nonimmune-privileged sites. Such regulation involves antigenpresenting cells (APCs) displaying alloantigens in a tolerogenic fashion and the activation of regulatory T cells (Tregs) suppressing inflammatory T cells via mechanisms described later in this article. Finally, it is important to note that while certain tissues are naturally immune-privileged, others can adopt this property following manipulations of the alloimmune recognition and

Figure 3 Neonatal tolerance. Exposure to cellular suspension of MHC despaired mouse (CBAXB10)F1 to sixteenth- to seventeenth-day CBA fetus rendered the CBA mouse tolerant to the CBA antigen, allowing to accept a skin allograft from (CBAXB10)F1. Reproduced from Billingham, R.E., Brent, L., Medawar, P.B., 1953. Activity acquired tolerance of foreign cells. Nature 172 (4379), 603–606.

response. For instance, studies from Waldmann’s group have shown that CBA/ca mice can be rendered tolerant of minor antigen-mismatched B10.BR skin allografts via treatment with anti-CD4 and CD8 antibodies. Remarkably, accepted skin grafts retransplanted in a second untreated host were not rejected and even conferred tolerance to a second skin allograft derived from a nontreated B10.BR donor but not from a thirdparty donor. Therefore, following antibody administration, the accepted skin allograft had become an immune-privileged site. Circumstantial evidence was provided that, in this model, the immune-privileged property of skin allografts was ensured by intragraft FoxP3þ regulatory CD4þ T cells. Similarly, in a miniature swine model, MHC class I disparate kidney allografts accepted following a short-course immunosuppressive treatment conferred tolerance to heart transplants from the same donor. Interestingly, removal of the kidney allograft led to the

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rejection of cardiac allografts, a result suggesting that the presence of the renal transplant was necessary not only for induction but also for maintenance of tolerance. These studies show that under appropriate circumstances, immune-privileged properties can be acquired by a given tissue/organ. Alternatively, the immune-privileged status of a tissue can be lost under appropriate circumstances. For instance, ‘naturally’ immune-privileged corneal allografts placed in an inflamed bed in the so-called high-risk recipients are acutely rejected due to neovascularization, induction of MHC class II expression on local APCs, and activation of inflammatory direct T-cell alloreactivity. As we gain insights into the mechanisms by which immune privilege is acquired and maintained, we will be able to design strategies promoting tolerogenicity of any tissue or organ transplant regardless of its immunogenic characteristics.

Immune Cells and Mechanisms Involved in Peripheral Suppression of Innate and Adaptive Alloimmunity Associated with Allograft Rejection Central deletion of developing alloreactive T and B cells in primary lymphoid organs plays a critical role in shaping the alloimmune repertoire involved in allograft rejection and tolerance. It is likely that similar mechanisms are essential to the establishment of tolerance induced via mixed- or full-donor hematopoietic chimerism achieved through bone marrow transplantation in rodent models. On the other hand, peripheral suppression of inflammatory alloimmunity by selected ‘regulatory’ leukocyte subsets and cytokines is required to trigger and maintain tolerance to allogeneic transplants in adults. While many different recipient leukocyte subpopulations of the innate and adaptive immune systems can mediate or contribute to allograft rejection or graft-versus-host reactions, virtually all of these cells have also been shown to participate in peripheral induction or maintenance of tolerance. This apparent contradiction is explained by the facts that leukocytes can differentiate into proinflammatory ‘rejectogenic’ or antiinflammatory ‘tolerogenic’ effector cells depending upon the environment in which they become activated either in lymphoid tissues or in the graft itself. This phenomenon involves interactions with other leukocytes, the context in which leukocytes encounter their antigen (nature of the APCs and costimulation signals), and the presence of particular soluble mediators including cytokines, chemokines, and non-immune molecules such as hormones and neuromediators. All of these factors influence the nature of the intracellular signaling pathways and genetic programs engaged in the differentiation of resting leukocytes into ‘rejectogenic’ or ‘tolerogenic’ cells.

Immune Cells of the Innate Immune System Innate immune responses are regularly elicited following reperfusion injury, inflammation, tissue damage, and opportunistic microbial infections taking place at the time of transplantation. Various cells of the innate immune system participate in the allograft rejection process via secretion of soluble factors, killing of donor cells, and triggering and promoting adaptive inflammatory alloimmunity, while preventing the differentiation and activation of regulatory cells.

Likewise, different cells and molecules associated with innate immunity have been shown to alter processes involved in the maintenance of tolerance to allografts and xenografts. On the other hand, different cell populations of the innate immune system are known to favor tolerance either by killing or inactivating inflammatory cells or by delivering signals contributing to regulatory T- and B-cell activation. Most importantly, a number of innate immune cells expressing MHC class II such as certain macrophages and dendritic cells (DCs) (either donor or recipient-derived) can present alloantigens either directly (direct allorecognition) or as peptides (indirect allorecognition) in a tolerogenic fashion and tilt the balance of alloimmunity toward tolerance.

Natural killer cells Although natural killer (NK) cells do not express bona fide antigen receptors, they can discriminate between cells of self and nonself origins using receptors recognizing specifically autologous MHC class I glycoproteins. Interaction of these receptors with self-MHC class I triggers the delivery of negative signals by inhibitory receptors on NK cells, a process designed to prevent autoimmunity. Alternatively, in the absence of selfMHC class I recognition, NK cells become activated, release inflammatory cytokines, and kill their targets, a phenomenon referred to as ‘missing self.’ This mechanism is used by NK cells to eliminate virally infected cells and tumor cells. Additionally, NK cells can attack allogeneic cells lacking self-MHC class I molecules and thereby cause the rejection of skin grafts from b2-microglobulin KO mice and semiallogeneic F1 donors. Activated alloreactive NK cells acquire cytolytic effector functions and release proinflammatory cytokines including gIFN and TNFa, thereby promoting the rejection of solid organ allografts directly and/or indirectly by enhancing type 1mediated adaptive alloimmunity. In addition to their role in skin and bone marrow transplantation, it is now well established that NK cells also contribute to the cell-mediated alloresponse involved in acute and chronic rejection of solid organ transplants. NK cells have been shown to suppress inflammatory adaptive alloresponses and promote tolerance of allografts in recipients treated with donor-specific transfusion and immunosuppressive drugs. Likewise, NK cells can prolong skin graft survival by killing donor DCs, thus impairing direct allorecognition by T cells secreting inflammatory cytokines. This process actually enhances the activation of TH2 alloreactive cells and the infiltration of transplanted organs by eosinophils. Additionally, NK cells have been shown to facilitate tolerance of renal transplants in rats injected with anti-CD28 monoclonal antibodies. In fact, some studies show that NK cells may be absolutely required for tolerance induction. For example, depletion of NK cells abrogated tolerance of pancreatic islet allografts induced with anti-CD40L or anti-LFA-1 antibodies. In this model, the tolerogenic properties of NK cells were shown to rely on perforin expression, which is associated with their cytotoxic functions. Indeed, NK cells exert their tolerogenic effects via different mechanisms including leukocyte cytotoxicity and cytokine secretion. During chronic inflammation, activated NK cells secrete the anti-inflammatory cytokine IL-10. IL-10 cytokine production by NK cells present in the uterine decidua contributes to protect the fetus from rejection by maternal allospecific T cells. The secretion of IL-10

Transplantation Pathology | Allograft Tolerance

by NK cells is also known to dampen inflammatory reactions in the central nervous system and the eye. Subsequently, NK cells are essential to the activation of Tregs involved in ACAID associated with the immune-privileged status of the eye. Finally, NK cells have been shown to extend allograft survival by decreasing effector memory T-cell (TMEM) expansion presumably through competition for IL-15 cytokine.

Dendritic cells DCs represent the principal link between innate and adaptive immunity owing to their exceptional ability to efficiently process and present antigen determinants and deliver essential costimulation signals to naive T cells. Following transplantation, the adaptive alloimmune response is initiated by CD4þ T cells recognizing donor MHC class II molecules displayed on donor DCs in the recipient’s secondary lymphoid organs (direct allorecognition). In addition, recipient DCs regularly process donor MHC and minor antigens and present them in the form of peptides bound to self-MHC molecules to recipient T cells (indirect allorecognition). While direct presentation by donor DCs is probably short-lived, it triggers a massive inflammatory T-cell response causing early acute rejection of transplants. The indirect alloresponse is a much weaker response but is long-lived, being perpetuated via continuous presentation of donor peptides by recipient APCs. Although the indirect alloresponse by T cells is sufficient to cause acute rejection of skin allografts, the extent of its contribution to acute rejection of vascularized solid organ transplants remains unclear. Alternatively, the indirect alloresponse clearly plays an important role in alloantibody production and vasculopathy associated with chronic allograft rejection. Based upon their documented role in the initiation of T-cell-mediated inflammatory alloimmunity, depletion of donor DCs was originally expected to delay or even prevent allograft rejection. Actually, DC depletion has resulted in diverse and often opposite outcomes depending upon the nature of the tissue transplanted and its anatomical site of placement in the host. It was observed that absence of recipient- or donorderived DCs did not consistently achieve significant prolongation of graft survival. On the other hand, depletion of DCs often impaired transplant tolerogenesis in mice. These observations indicated that DCs are necessary for antigen presentation involved in both T-cell-mediated rejection and tolerance of allografts. This apparent paradox has now been partially solved by the discovery that DCs consist of a diverse population of cells differing by a series of surface markers and functional characteristics. For instance, elimination of Langerhans cells or dermal DCs from skin allografts resulted in opposite effects with regard to rejection. In addition, DC functions vary considerably depending upon their degree of maturation. Myeloid immature DCs (iDCs), which have not been stimulated via damage-associated molecular pattern molecules (DAMPs), pathogen-associated molecular patterns (PAMPs), or cytokine exposure, express low levels of MHC class II and costimulatory receptors and do not present antigen peptides in a fashion that achieves productive activation of proinflammatory T cells. In fact, presentation of alloantigens by these iDCs is regularly associated with T-cell anergy resulting in peripheral tolerance and immune privilege. In contrast, matured DCs (mDCs) uptake and process antigens in an

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inflammatory cytokine environment. In the presence of PAMPs and DAMPs, mDCs display high levels of MHC class II and selected costimulation receptors and elicit potent inflammatory alloimmune responses by recipient T cells after transplantation. Plasmacytoid DCs, corresponding to a small population primarily located in the peripheral blood, have been shown to contribute to graft protection following Inducible T-cell COStimulator (ICOS) costimulation and IL-10 secretion associated with Treg responses. Based upon these findings, longterm survival to the allografts has been achieved by transferring DCs of which regulatory properties were promoted through physical or chemical modifications.

Macrophages Activated macrophages are typically found in inflammation sites including allografts where they secrete proinflammatory cytokines such as TNFa, IL-12, IL-1, and IL-6, thus enhancing both innate and adaptive immune responses. Macrophages are involved in antibody-dependent cellular cytotoxic reactions causing the destruction of opsonized allogeneic target cells during acute allograft rejection. Macrophages also contribute to the maintenance of chronic inflammatory processes involved in transplant vasculopathy and fibrosis. In addition, macrophages express MHC class II constitutively and can process and present alloantigens to inflammatory CD4þ T cells, thus enhancing T-cell-mediated responses and rejection. It is, however, important to note that different types of macrophages can be found in kidney allografts including FoxP3þ cells referred to as regulatory macrophages (Mregs), which have been implicated in attenuation of inflammation either directly or through activation of Tregs. Whether these Mregs significantly contribute to transplant tolerance is a subject of current investigation.

Myeloid-derived suppressor and mesenchymal stromal cells Both myeloid-derived suppressor cells (MDSCs) and mesenchymal stem cells (MSCs), which migrate to inflammatory sites, exhibit some immunoregulatory properties and promote tolerance to heart and islet allografts. MDSCs are progenitor cells expressing CD11b and Gr1 in mice and producing inducible nitric oxide synthase and arginase following activation. MDSCs suppress the proliferation of T cells and inflammatory cytokine production by effector T and B cells while promoting the differentiation of Tregs in the presence of gIFN and IL-10. MSCs are multipotent cells found essentially in the bone marrow whose primary role is to support hematopoiesis. MSCs are believed to enhance the generation of regulatory cells in transplanted tissues through their production of TGF-b and prostaglandin E2 and via direct cell–cell contact. In addition, there is some evidence indicating that DCs exposed to MSCs tend to remain in an immature state, thereby presenting donor antigens in a tolerogenic fashion to alloreactive T cells.

Immune Cells of the Adaptive Immune System T cells recognizing donor antigens either directly or indirectly play a key role in cellular and humoral acute rejection of allografts primarily through the secretion of inflammatory cytokines, the induction of delayed-type hypersensitivity responses, the differentiation of cytotoxic T cells, and the

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activation of B cells producing donor-specific antibodies. B cells contribute to the alloimmune response and rejection through the production of alloantibodies capable of killing or opsonizing donor cells and by presenting donor antigens to T cells and governing their differentiation into TMEMs. It is noteworthy that laboratory rodents, which are bred in germfree environments, are essentially devoid of preexisting alloreactive TMEMs at the time of transplantation and therefore particularly susceptible to tolerance induction via donor hematopoietic chimerism and leukocyte costimulation blockade. In contrast, significant frequencies of preexisting long-lived allospecific TMEMs are regularly found in primates. These TMEMs are exceptionally resistant to costimulation blockade agents and suppression by regulatory cells and represent a major barrier to allograft tolerance induction. Alternatively, it has long been known that both T- and B-cell populations contain subsets contributing to transplant tolerance induction and maintenance. This conclusion was originally based upon the observations that an adoptive transfer of lymphocytes from tolerant mice was often sufficient to confer tolerance to naive recipients. Recent identification of cytokines, genes, transcription factors, and cell membrane receptors involved in regulation of immunity has allowed to isolate and study some regulatory T and B cells involved in transplant tolerance.

Regulatory T cells CD4þ Tregs are comprised of two distinct populations: (1) natural or thymic-derived Tregs are T cells continuously generated in the thymus through high-affinity interactions with autologous peptides bound to self-MHC molecules and (2) induced or peripheral-derived Tregs generated from naive T cells encountering antigens presented by APCs in secondary lymphoid organs and possibly in allografts and other sites. Both Treg cells are characterized by a high expression of the alpha subunit of the IL-2 receptor (CD25) and the transcription factor forkhead box P3 (FOXP3). Thymic Tregs present in healthy individuals are thought to suppress autoreactive inflammatory T cells in the periphery, thus preventing the onset of autoimmune disorders. On the other hand, peripheral Tregs are generated and activated during the course of an immune response by selected APCs presenting antigens in a tolerogenic environment. Following allotransplantation, Treg activation/expansion and graft infiltration is always observed. However, it is clear that these cells normally fail to suppress the overwhelmingly potent inflammatory innate and adaptive responses causing rejection. In contrast, in the case of MHC-matched transplants and transplants placed in immune-privileged sites, the balance of immunity can be shifted toward regulation and the graft spontaneously accepted. This is due to the presence of local anti-inflammatory factors (immune-privileged sites), the lack of direct proinflammatory T-cell responses (due to MHC matching), and presumably the presence of self-MHC class II on donor cells, which promotes Treg activation. Indeed, while the mechanisms by which these CD4þ Tregs recognize alloantigens are still unclear, there is ample evidence showing that they recognize donor antigens in an indirect fashion, that is, in the form of donor peptides presented by self-MHC class II molecules. Accordingly, recipient MHC class II expression on donor cells (from partially MHC-matched donors) can promote the expansion/activation of some Tregs.

It is noteworthy that some studies have shown the tolerogenic effects of host bone marrow cells (BMC) transduced with donor MHC class II genes. In this model, evidence has been provided supporting that Treg activation relies on the presentation of donor MHC class II-derived peptides by self-MHC class II molecules on recipient APCs. Recent studies have shed some light on the mechanisms involved in Treg-mediated suppression of ‘rejectogenic’ effector T cells. Tregs express elevated levels of cytotoxic T lymphocyte antigen 4 (CTLA4 or CD152) receptors, which bind with high affinity to B7.1 (CD80) and B7.2 (CD86) present on APCs. Binding of CTLA4 to B7 molecules on APCs prevents costimulation of T effector cells via CD28 (which binds to B7 with a lower affinity) and stimulates the enzyme indoleamine 2,3 synthase (IDO). IDO activity causes tryptophan deprivation and the release of kynurenines and IL-10 cytokine both suppressing the activity and expansion of proinflammatory T cells. Tregs also suppress inflammatory reactions through their production of different immunoregulatory cytokines such as IL-10, IL-35, and TGF-b, which can inhibit APC activation and promote the conversion of T cells into Tregs (Figure 4). In addition, Tregs have been shown to suppress inflammatory T-cell immunity by killing effector T cells and depriving them from IL-2 cytokine, thus rendering them anergic. It is still unclear whether Tregs mediate their tolerogenic effects essentially by suppressing the sensitization of alloreactive T cells in secondary lymphoid organs or their effector functions in the graft itself. In addition to their role in transplant tolerance induction, some evidence has been provided by Colvin et al. supporting the contribution of Tregs in tolerance maintenance. In these studies, it was observed that mice having spontaneously accepted kidney allografts for more than 100 days rejected their transplants within days following in vivo depletion of Tregs. In addition to the ‘conventional’ CD4þCD25þ FoxP3þ Tregs, other T cells, such as CD4þFOXP3 Tr1 cells, CD8þCD25highFoxP3þ, CD4CD8 Tregs, and NKT cells, have been identified to be capable of suppressing inflammatory responses. Tr1 cells are derived from peripheral antigen-specific T cells exposed to IL-10 produced by tolerogenic APCs or Tregs (Figure 4). These cells have been shown to prevent allograft rejection and graft-versus-host disease (GVHD) through their production of IL-10 and TGF-b. CD8þCD25highFoxP3þ cells (CD8þ Treg) represent a very small subset of peripheral blood T cells (1–3% of CD8þ T cells), which suppress the functions of effector T cells and follicular T helper cells via secretion of CCL4 and IL-10. Finally, some double-negative CD3þCD4CD8 Tregs, which express the ab TCR but not NK1.1, have been found essentially in the spleen of tolerant mice and in humans. These cells inhibit inflammatory responses involved in allograft rejection, GVHD, and autoimmune disorders presumably by killing inflammatory T cells through the CD95–CD95L pathway and by suppressing the expression of CD80 and CD86 on DCs. Finally, some NKT cells, which recognize glycolipids associated with CD1, have been shown to promote tolerance to alloantigens by secreting anti-inflammatory cytokines and facilitating Treg expansion. In addition, NKT cells are essential to the maintenance of immune-privileged properties in the anterior chamber of the eye.

Transplantation Pathology | Allograft Tolerance

Generation of regulatory T cells

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Figure 4 CD4þ regulatory T cells and their suppressive functions. Tolerogenic DCs, Bregs, and ‘natural’ thymic Tregs can convert naive T cells into FOXP3þ Tregs or FOXP3 regulatory T cells or Tr1, which suppress effector functions by proinflammatory T cells through various mechanisms.

Regulatory B cells Some mouse studies suggest the contribution of regulatory B cells (Bregs) in resolving inflammation and promoting tolerance to allografts. These cells express CD1d, CD21, CD24, and IgM and are also characterized by their low CD19 expression. The main feature of Bregs is their ability to produce IL-10 anti-inflammatory cytokine following antigen stimulation and signaling through CD40 coreceptors. Some evidence has been provided that Bregs can suppress inflammatory responses in autoimmune models. Whether Bregs contribute significantly to the differentiation/activation of Tregs and the establishment of transplant tolerance remains to be determined.

Preclinical Studies in Nonhuman Primates During the last two decades, significant progresses have been made in understanding the cellular and molecular mechanisms underlying the regulation of immunologic responses. Based on this knowledge, long-term allograft survival without maintenance immunosuppression has been achieved in nonhuman primates (NHP) using different strategies including (1) profound depletion of lymphocytes, (2) costimulatory blockade, (3) induction or infusion of regulatory cells, and (4) induction of mixed hematopoietic chimerism.

Profound Lymphocyte Depletion T cells are major players in rejecting the allograft. However, in primates, although transient depletion of peripheral blood T cells is possible, it has been difficult to efficiently deplete T cells from lymphoid tissue using monoclonal antibodies. However,

recent development of an anti-CD3 immunotoxin (IT), which is a conjugate of the anti-rhesus CD3 mAb and the mutant diphtheria toxin protein, has rendered profound depletion of T cells possible in NHP. Severe lymphocyte depletion with anti-CD3 IT achieved prolonged survival of renal allograft without maintenance immunosuppression. In spite of this, activation of B cells was not prevented, resulting in anti-donor antibody production and chronic rejection.

Costimulatory Signal Blockade Among the costimulatory signals that have been identified, blockade of the CD28 or CTLA4 (CD152)/CD80, CD86, and the CD40/CD40 ligand (CD154) pathways has been tested in NHP. Blockade of the CD40/CD154 pathway has proven to be highly effective. CTLA4Ig (belatacept) has also been effective to achieve prolonged survival allograft in islet and kidney transplantation in NHP. However, induction of tolerance has never been achieved by costimulatory blockade alone in NHP.

Infusion or Induction of Regulatory Cells Successful induction of renal allograft tolerance has been reported in approximately half of recipients who were adoptively transferred with anergic T cells induced by coculture with donor alloantigen in the presence of anti-CD80/CD86 antibody. This study emphasized that recipient conditioning with cyclophosphamide was critical even in infusion of autologous regulatory cells. More recently, a group at the University of Pennsylvania demonstrated prolonged islet allograft survival by depleting T cells and B cells with rabbit antithymocyte globulin and anti-CD20 mAb (rituximab) treatments,

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Donor Third party

Figure 5 A renal allograft biopsy at 10 years from a tolerant recipient showed no evidence of rejection. Skin allograft from the kidney donor (left skin) was accepted while skins from third-party monkeys were rejected within 7 days (skin grafts in right).

respectively. Persistence of immature and transitional B cells was associated with long-term islet allograft survival in this study, an observation suggesting that these B cells can exert some regulatory functions in primates.

those patients who do not become tolerant remain to be determined. For example, a recent study from Kyoto has demonstrated high incidence of fibrosis in the liver biopsies in their pediatric liver transplant recipients who discontinued their immunosuppression.

Donor Bone Marrow Transplantation Induction of renal allograft tolerance with stable allograft function for more than 10 years (Figure 5, left) has been achieved in nonhuman primates via transient mixed chimerism. Those tolerant monkeys also accepted a skin allograft from the same kidney donor (Figure 5, right). Indeed, previous studies in rodents had demonstrated that persistent mixed chimerism is necessary to induce/maintain tolerance of MHC-mismatched skin allografts, a model in which thymic (central) tolerance is thought to rely essentially on deletion of donor-reactive T cells. Nevertheless, in our nonhuman primate studies, renal allograft tolerance was achieved even in the face of transient mixed chimerism, which implies the contribution of peripheral regulatory mechanisms in this process.

Clinical Studies Although many strategies of tolerance induction have been developed, in clinical trials, tolerance induction has so far been attempted only in liver and kidney transplantation.

Tolerance Induction in Liver Transplantation It has long been recognized that the immune response to a particular organ varies with the organ transplanted and that some ‘tolerance-prone’ allografts like the liver can confer unresponsiveness to ‘tolerance-resistant’ allografts like the skin. Originally described in porcine liver recipients by Calne et al., the liver is generally considered the most tolerogenic of transplanted organs, with its as yet undefined tolerogenic effects being apparently multifactorial. It has been assumed that spontaneous induction of tolerance following withdrawal of all immunosuppression can probably be achieved in up to 20% of liver allograft recipients. However, long-term consequences of attempted immunosuppression withdrawal in

Tolerance Induction in Kidney Transplantation In contrast to the liver allograft, tolerance induction has been difficult to achieve in other solid organ transplants. Except for liver transplantation, induction of tolerance has so far been attempted only in clinical kidney transplantation. Attempts to translate tolerance with the following strategies have been made in clinical kidney transplantation.

Profound lymphocyte depletion Similar to nonhuman primate studies with anti-CD3 IT, significant minimization of immunosuppressive medication was achieved in renal allograft recipients after profound T-cell depletion with alemtuzumab (Campath-1H, anti-CD52 mAb). Starzl et al. also attempted to induce tolerance in 90 kidney transplant recipients who were treated with alemtuzumab or rabbit thymoglobulin. In these studies, spaced weaning of immunosuppressant was achieved in selected patients, though complete withdrawal was not successful. There was no improvement in patient or graft survival compared with historic controls, and chronic allograft nephropathy progressed at the same rate in both groups. Favorable results with attempted tolerance induction using alemtuzumab have been inconsistent in other trials as well. Most investigators have now concluded that T-cell depletion alone cannot consistently induce tolerance in humans.

Costimulatory blockade Tolerance induction by costimulatory blockade has also been attempted in clinical kidney transplantation. Although CD40/ CD154 pathway blockade with anti-CD154 mAb induced prolonged renal allograft survival in nonhuman primates, similar tolerogenic effects were not observed in clinical settings and five of seven tested patients developed rejection episodes. Further clinical trials with this antibody were then suspended when an unexpectedly high incidence of thromboembolic

Transplantation Pathology | Allograft Tolerance

complications was found to be associated with this treatment in humans. CTLA4Ig (belatacept) has shown significant immunosuppressive effects in nonhuman primates and humans and was recently approved for clinical use. Belatacept is the first in these new classes of therapeutic agents to be approved for clinical kidney transplantation and its application for clinical tolerance induction might be anticipated.

Donor bone marrow Strategies using donor bone marrow (DBM) can be divided into those attempting to achieve microchimerism, detectable only by very sensitive methods, and those striving for mixed chimerism, readily detectable at a macroscopic level. These two approaches appear to operate through different mechanisms.

DBM infusion for induction of microchimerism In this strategy, DBM was infused with conventional immunosuppression with or without T-cell depletion. Levels of chimerism induced were very small (<0.1%) and were only detectable by polymerase chain reaction (PCR) (hence the term ‘microchimerism’). Barber et al. reported a clinical trial using DBM cell infusion combined with antilymphocyte globulin. Although significantly better allograft survival was observed in recipients treated with DBM, immunosuppression was not completely discontinued in any of these recipients and clear evidence of tolerance was not demonstrated in these studies. During the 1990s, different groups in Pittsburgh and Miami evaluated DBM infusion with T-cell depletion and conventional immunosuppression in various organ transplants. In these studies, although superior graft survival with less incidence of acute or chronic rejection was reported, clear evidence of tolerance induction in these recipients was never demonstrated.

DBM transplantation for induction of macrochimerism In the mixed chimerism approach, a pretransplant conditioning is necessary to achieve DBM engraftment with macrochimerism (>1%, readily detectable by flow cytometry). In HLA-matched kidney transplants, we have performed combined kidney and bone marrow transplantation (CKBMT) after a cyclophosphamide-based nonmyeloablative conditioning regimen in seven renal failure patients with refractory multiple myeloma. Either transient or durable (mixed or full) chimerism was achieved and five of seven patients remain alive at the time of this writing. Immunosuppression was successfully withdrawn in all three recipients who had transient chimerism and one with stable mixed chimerism, with the longest kidney allograft survival now exceeding 14 years. All patients with full-donor chimerism continued to be on immunosuppression for GVHD prophylaxis. Using total body irradiation and donor hematopoietic stem cell delivery, the Stanford group reported successful induction of stable mixed chimerism and renal allograft tolerance in HLA-identical kidney transplant recipients. Out of 12 patients treated with this regimen, four patients developed persistent mixed chimerism while eight displayed transient mixed chimerism. Immunosuppressive medication was

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discontinued in all four patients with persistent chimerism and four patients with transient chimerism. Immunosuppression was not discontinued in three patients who developed acute allograft rejection and in one patient who developed recurrence of his original disease focal segmental glomerulosclerosis (FSGS). In HLA-mismatched kidney transplantation, we have applied CKBMT with a nonmyeloablative conditioning regimen. In a total of 10 patients enrolled into our clinical trials, all patients developed transient mixed chimerism for 7–21 days and seven of them achieved stable renal allograft function without maintenance immunosuppression (Figure 6), with the longest kidney allograft survival exceeding 10 years. Immunosuppression was reinstituted in two of these seven patients after 7 and 5 years due to recurrent kidney disease and chronic rejection, respectively. Although the results are encouraging, further revision of the protocol is necessary to improve consistency of long-term stable tolerance and to reduce the toxicities of the treatment. As hypothesized in nonhuman primate studies, peripheral mechanisms of tolerance are likely to be involved in renal allograft tolerance observed in these patients whose chimerism was only transient. In contrast to the mixed chimerism approach, induction of full-donor chimerism, where recipient hematopoietic cells are totally replaced with donor cells, has until very recently been considered unlikely to have clinical applicability. However, a group at Northwestern University has recently reported successful renal allograft tolerance by induction of full-donor chimerism. Although the conditioning regimen was relatively intensive, no GVHD was reported, purportedly as the result of administration of novel ‘tolerogenic CD8þ/TCR facilitating cells.’ In their most recent report, 8 of 15 patients enrolled in this clinical trial developed stable full-donor chimerism and six of them so far successfully discontinued their immunosuppression with immunosuppression-free interval up to 22 months. Interestingly, unlike the patients at Massachusetts General Hospital, withdrawal of immunosuppression was not achieved in recipients who only developed transient chimerism. However, there are several serious concerns in applying fulldonor chimerism for induction of allograft tolerance. First, the risk of GVHD cannot be completely eliminated with this approach. Secondly, patients with full-donor chimerism might be expected to suffer from immunologic incompetence, since donor T cells that develop in the recipient thymus may be restricted to recipient-type MHC only as a result of positive selection. Therefore, donor-type T cells would not recognize antigens effectively when presented by the donor-type APCs, which would also be the only APCs available in full-donor chimeras (Figure 7).

Concluding Remarks Significant progress recently made in immunology has led to the development of a variety of strategies designed to tilt the balance of alloimmunity towards tolerance in laboratory rodents. However, it is now clear that transplant tolerance is more arduous to accomplish in humans who display a much higher degree of genetic polymorphism and exhibit high

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Figure 6 (a) Clinical course of the first four patients who received combined kidney and heart transplantation (x-axis: days after transplantation). Immunosuppression was discontinued at 9–14 months after transplantation (pink, cyclosporine; green, tacrolimus; gray, steroids; blue, mycophenolate mofetil). Serum creatinine levels (yellow). (b) A protocol kidney biopsy at 3 years showed no rejection (subject 1). (c) The first patient has been doing well without maintenance immunosuppression for over 10 years. Modified from a figure in Kawai, T., Cosimi, A.B., Spitzer, T.R., Tolkoff-Rubin, N., Suthanthiran, M., Saidman, S.L., et al., 2008. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358 (4), 353–361.

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Figure 7 Antigen recognition in full-donor and mixed chimerism. In both full and mixed chimerism, T cells are restricted to recipient MHC during development in the host thymus. However, there is no host APC available in full-donor chimerism, which may result in immunoincompetence.

frequencies of preexisting alloreactive TMEMs at the time of transplantation. Nevertheless, successful tolerance induction has recently been achieved in clinical HLA-mismatched kidney transplantation, and further studies to improve results with less morbidity should be pursued.

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