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Lung Transplant Rejection – A Review

Lung transplantation presents the possibility of replacing the respiratory component of the body devoid of any chronic pulmonary disease, which a recipient may have had. However, this involves the transfer of tissues or cells between individuals that are genetically diverse, and stimulates an adaptive and specific immune response, orchestrated by T cells that recognize antigens bound to major histocompatibility complexes (MHCs) expressed on donor cells – with the implication of two main recognition pathways: direct and indirect.

Effector responses ultimately result in the mediation of acute and chronic rejection. The indirect pathway of allorecognition, where adaptive immune system cells recognize MHC alloantigen-derived peptides on self-MHC molecules, seems to greatly contribute to the induction of allograft rejection. The indirect pathway, however, may also be involved in promoting the generation of regulatory T cells – thought to be crucial suppressors of the alloresponse. Recently shifts of perception have favoured the idea of dendritic cells being crucial for the regulation of immunity, including tolerance inductive and maintenance capabilities. Advances in our understanding of these types of cells and our ability to manipulate their development and maturation, will allow us to exploit their inherent tolerogenicity for therapeutic purposes.

Although the use of immunosuppressive drugs in transplantation has been standard practice for decades, the marked morbidity from their use in addition to poor long-term survival of grafts, remain important limitations. Developing transplant tolerance biomarkers will undoubtedly improve the maintenance and care of organ allograft recipients, providing potential monitoring capabilities and therapeutic applications, and advancing our understanding of immune responses to both self and foreign antigens in humans.


Introduction


The hope for the many individuals with incurable pulmonary diseases such as cystic fibrosis, pulmonary fibrosis, and chronic obstructive pulmonary disease, is lung transplantation. Despite the many significant immunological advances, many challenges still remain and lung transplant recipients are faced with the worst survival statistics following transplantation (except small bowel) – acute rejection incidences remain above 50% in the first year, with five year survival of grafts being less than 50% due to chronic rejection and graft dysfunction1.

Rejection of grafts can be mediated by mechanisms that are antigen-dependent or -independent (i.e. acquired immune system and innate immune response, respectively), and usually categorized according to the tempo at which it occurs. Hyperacute (minutes to hours), acute (days to weeks) and chronic (months to years) rejection are terms used to describe graft damage occurring at respective tempos following transplantation2.

However, mechanisms responsible for these types of rejection are not by any means confined by their ‘supposed’ time of action; such that (in some recipients) acute rejection may proceed late after transplantation with characteristic changes of chronic rejection being observed very early after transplantation. Accordingly, it is more appropriate to think in terms of the underlying mechanisms and appreciate that the immune system will make every effort; using almost every specific and nonspecific mechanism it can mobilize, to destroy the transplanted tissue. If steps are not taken to overcome these rejection mechanisms, there would be a rapid loss of a majority of grafts.

Hyperacute rejection occurs when preformed antibodies in the recipient bind graft antigens, which bind to endothelial cells, activating complement-dependent cell lysis and subsequent intravascular thrombosis and coagulation – catastrophic for the graft. A dramatic blockage of blood supply to the organ rapidly darkens the previously pink organ, followed by swelling. The rapid and severe manifestation of hyperacute rejection prompt immediate treatment by removal of the organ – but it is the acute and chronic forms of rejection that present more problems.

Alloreactive T and B cell mediated acute rejection has been found to be an important risk factor of chronic rejection, but may be treated with immunosuppression. The manifestation of bronchiolitis obliterans syndrome (BOS), subsequent to obliterative bronchiolitis (OB), characterises chronic rejection, and has no effective treatment. While previous studies supported an alloreactive T and B cell role in BOS development, recent studies seem to highlight an autoimmune role in the pathogenesis of the rejection response – with many of the specific mechanisms still unknown.


Acute Rejection


Infiltrating (in perivascular and peribronchiolar lung regions) CD4+ and CD8+ T cells and mononuclear cells characterise the acute rejection which, quite frequently, occurs in the first year following lung transplantation 3. Acute rejection can occur even in the absence of lymphatics draining donor APCs to secondary lymph nodes (proposed sites of alloreactivity), though, removal of these in animal models has been demonstrated to prevent acute rejection of allografts 4. However, in mouse models of orthotopic lung transplantation, secondary lymphoid organs have been shown to be unnecessary in acute rejection of allografts 5. Such data highlights the distinction of the lung from other solid organs and suggests that the primary activation site of naïve allogeneic T cells (immediately following transplantation) is the lung 4.

Within the immune system, which has a vast capacity for expansion, there are large numbers of T cells with the ability to recognize and respond to a transplant. In the average human there are 5 × 1011 T cells, and it is remarkable that, of these present, up to 1 in 1000 can directly recognize a transplanted organ 6. Given that each cell has the capacity to rapidly divide and double in numbers every 8 to 18 hours, it is possible (in theory) for each T cell to produce between a thousand to a million graft-antigen-specific daughter cells.


Major histocompatibility complex molecules and their normal function


The normal function and physiology of T cells is heavily dependent on MHC molecules. Foreign antigen peptide fragments, held in the MHC binding groove, are bound by T cell receptors. There is very strong binding of T-cell receptors to the combined peptide-MHC molecule, but very weak to either peptide or MHC molecule alone.

Protein-derived peptides from cells on which MHC molecules are expressed, occupy peptide-binding grooves of the MHC molecules on normal tissues (Figure 1). In a process called ‘negative selection’, potentially self-reactive T cells are deleted in the thymus and this usually causes avoidance in the recognition of self-peptide antigens presented by MHC molecules. The simultaneous positive selection (by the thymus) of T cells that weakly bind MHC molecules allows their recognition of self MHC-presenting foreign peptide complexes 8. During virus infection, for example, viral peptides replace the self-peptides in self MHC molecules; and since T cells can ‘see’ the self MHC-foreign peptide complex, they can respond and destroy the cells infected with virus 9.

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Antigen Presenting Cells


Activation of T cells for graft destruction cannot occur through recognition of MHC molecules alone – presentation of the MHC-peptide complex (the antigen) on the surface of leukocytes or endothelial cells is also required. ‘Professional antigen presenting cells’ are just one set of leukocytes that are especially good at activating T cells 10. Arguably, all nucleated cells can be regarded as antigen presenting cells (APCs) due to their expression of MHC class I antigens and, if infected virally, can display a variety of MHC class I-virus peptide complexes. Professional APCs, however, have the distinct ability to create MHC-peptide complexes displayed on cell surfaces, by acquiring foreign antigens and processing them into peptide fragments.

Additionally, the professional APCs carry surface molecules (‘costimulation molecules’), which interact with corresponding T cell surface molecules, and are necessary for their proper activation 11,12 (Figure 2). Costimulatory interactions, such as these, involve B7.1 and B7.2 (CD80 and CD86) molecules on the APCs and CD28 and CTLA-4 on T cells 14. Alternatively, interactions may involve CD40 on APCs and its ligand CD40L (CD154) on T cells 15.

Macrophages, epithelium, endothelium and dendritic cells are all contained within the normal lung, where they contribute to immunological defences of the organ. Although professional APC activity is also exhibited by macrophages and B cells, the major APC type is the dendritic cell 16,17 – which, either by activation of T cells or migration to draining lymph nodes, induce the alloimmune response following lung transplantation. Depletion of dendritic cells in animal models and kidney transplant patients (human) resulted in significant abrogation of allografts, suggesting an essential role played by these cells in acute rejection – also supported by orthotopic lung transplant models in mice 5.

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By responding to stimuli or antigens (from allografts and environment) the dendritic cells migrate to lymph nodes where they mature and upregulate the necessary costimulatory markers to efficiently activate T cells 16. Three subsets of cytokine secretion – Th1 (interferon γ, lymphotoxin), Th2 (IL-4, IL-5 and IL-13), including the recently recognised Th17 (IL-17, IL-22) – determine the type of response; mobilization of cytotoxic T cells and macrophages, B cell mediated antibody production, and recruitment of neutrophils, respectively 18.


Direct and indirect Allorecognition


The two distinguishable ways, in which, T cells recognize transplanted tissues are known as direct and indirect allorecognition 19,20. One of the major differences between the two is their relative capacity of reactive cells (the number of T cells with receptors that are available for the recognition of the graft); 1 in 1000 to 1 in 10 000 for direct allorecognition, and 1 in 100 000 to 1 in a million (about two orders of magnitude fewer cells) for indirect allorecognition.

Direct allorecognition

The immune system has an inherent capacity for recognition and response to transplanted tissues, and this phenomenon is direct allorecognition. Introduction of a transplant leads to recipient T cell recognition of unmatched MHC molecules on the graft because of:

(a) The ‘high determinant density’ concept of allorecognition: In the thymus, all T cells are programmed for the recognition of MHC antigens and only those with receptors for self MHC-self peptide complexes are eliminated. The vast numbers that remain will contain T cells capable of binding MHC-foreign peptide complexes with sufficient affinity to respond. Moreover, on most cells there is a dense expression of MHC antigens, which provides an abundance of antigen for avid binding and recognition 21.

(b) The ‘cross-reactivity’ or ‘multiple binary complex’ concept of allorecognition: Different ranges of tissue peptides are expressed by the donor and recipient due to the differences in peptide-binding grooves of the unmatched MHC molecules. Foreign MHC–foreign peptide complexes appear to resemble, to the T cells of the recipient, self MHC molecules presenting, for example, foreign peptides derived from viruses. Recognition of virus-infected self-cells; by T cells will indeed result in an appropriate response by many T cells 22.

The two possibilities of explaining the high alloreactive cell numbers are not mutually exclusive, and to a large extent, overlap. In either case, quite critical, is the very large numbers of T cells which may be activated by a transplant.

Minor histocompatibility antigens

In addition to major histocompatibility, minor histocompatibility antigens have also been identified, and are peptides (albeit presented by MHC molecules) 23,24. As previously outlined, an MHC-peptide complex is present on the surface of normal cells, with variations in normal proteins within individuals (allelic variants, for example). Accordingly, the same MHC molecule on cells from different individuals having different alleles, expresses MHC–peptide complexes that T cells can distinguish (that is, MHC plus peptide from either allele variant). These minor histocompatibility antigens (MHC molecules with allelic peptides) contribute to allorecognition in such a way that their differences lead to triggering of the rejection response, even if donor and recipient are very closely matched for their MHC antigens.

Indirect allorecognition

In contrast to direct allorecognition (which is only relevant in the non-physiological context of transplantation or in pregnancy, if there is exposure of the maternal immune system to paternal foetal antigens), indirect allorecognition occurs according to physiologically normal antigen recognition (by T cells) pathways 25,26. As previously alluded, pathogenic peptides (virally-derived peptides, for example) are taken up in the grooves of MHC molecules and presented to T cell receptors. In this case self MHC plus foreign (viral) peptides are seen by T cells because the APCs presenting the MHC-peptide complex and the T cells are both the same 27. In essence, the same occurs with donor antigens that are shed from grafts and taken up and presented by recipient APCs – self MHC plus foreign (donor) peptide are seen by recipient T cells (Figure 3) – hence, indirect allorecognition is identical to normal physiological foreign antigen recognition, by T cells.

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Effector responses in acute rejection


Experiments showing the incompetence of rodents to reject allografts, following depletions or deficiencies, demonstrate that responses to transplants are heavily dependent on T cells. Antigen-specific receptors allow T cells to recognize grafts as foreign, though the mechanisms of graft destruction may occur specifically, via antibodies or cytotoxic T cells, or non-specifically, via inflammation or delayed-type hypersensitivity. The degree of histoincompatibility between the recipient and donor, in addition to graft type, dictate whether response mechanisms contribute to acute graft damage 28,29.


Role of CD4+ T cells


The various studies that have transferred subpopulations of T cells into animals devoid of them to determine those with the capability to reject transplants, have shown (very clearly in some cases) that CD4+ T cells play a central role in the destruction of grafts 30 (Figure 4). Damage to grafts can occur in four ways. Firstly, CD4+ T cells can be cytotoxic by acting as cytotoxic (killer) T cells. Although they are unlikely to be a major mechanism of parenchymal cell damage, such cells may be responsible for endothelialitis, due to their direct recognition of MHC class II antigens (only present on activated endothelium and nowhere else) in transplanted organs.

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CD4+ T cells can, alternatively, act as ‘helper’ T cells by activating B cells and inducing their differentiation into plasma cells so that antibodies are produced against grafts. This is only possible if helper cells interact with MHC class II molecules on recipient B cells, following activation by the indirect allorecognition pathway. There are two subsets of CD4+ T helper cells (Th1 and Th2), which release cytokines, providing help for B-cell activation. It is the Th2 subset, however, which is responsible for making the necessary cytokines (including interleukin IL-4, IL-5 and IL-6) to promote the production of antibodies 31.

The other mentioned Th1 cytokine, IL-2, also majorly influences graft rejection; and being a growth factor for T and B cells, it dramatically increases their survival and proliferation. The use of calcineurin inhibitors (ciclosporin 33 or tacrolimus 34) to block IL-2 production, monoclonal antibodies to CD25 (a chain of the IL-2 receptor) to block IL-2 uptake by IL-2 receptors 35, or sirolimus (rapamycin) to block intracellular signalling through IL-2 receptors 36,37 all result in suppression of graft rejection. The CD8+ cytotoxic T lymphocyte (CTL) is one of the cell types that depend on IL-2 for activation.In contrast, the CD4+ Th cells of the Th1 subset make IFN-γ and IL-2, and can be activated by either direct or indirect allorecognition pathways. IFN-γ can increase the expression of adhesion molecules from graft endothelium to facilitate adhesion of circulating leukocytes to the walls of blood vessels and aid their transmigration into graft tissue. IFN-γ can also elevate the level of expressed MHC class II molecules from endothelial cells and graft parenchyma, which expands the T cell activating capacity of APCs by increasing their abilities in the processing and presentation of antigen as well as the expression of costimulatory molecules. Moreover, IFN-γ can activate and induce macrophages to release enzymes, free radicals and other noxious agents along with inflammatory cytokines such as IL-1 and tumour necrosis factor alpha (TNF-α). Essentially, the manner in which graft-specific T cells are activating macrophages is analogous to type IV (or delayed-type hypersensitivity) – and this pathway seems central to graft damage 32.


Role of CD8+ T cells


There is still a lot debate amongst immunologists regarding the role of the CTL in graft rejection 30. For graft damage to occur CTLs must recognize and kill the donor tissue, and this necessitates their activation by the direct pathway of allorecognition. The opportunity to recover and remove highly activated CTL from grafts undergoing rejection 38, allows their subsequent injection into tissues, which causes cell death and necrosis at the site of injection 39. On the basis that CTLs are present in rejection and have tissue damaging potential, it would seem reasonable to suggest that CTLs probably do play a part in acute graft rejection.

However, rejection may occur irrespective of any absence of histological evidence regarding the lysis of graft cells, given that the transfer of naive CD8+ T cells (without other T cells) into a transplant recipient does not activate them and brings about graft rejection 40,41,42. This, however, only suggests that the cells cannot grow or differentiate in the absence of Th1 cells which produce IL-2. Graft damage did not seem to occur following intravenous transfer of pre-activated CD8+ T cells into graft recipients either 41, and may be due to cells not homing into the graft or dying very quickly – the latter being supported by an experiment that adopted the protocol, of transferring activated CD8+ T cells into recipients who were given regular doses of IL-2 to maintain CD8+ CTL viability, which led to organ graft rejection 43. Seemingly, the CD8+ CTL which recognises MHC class I molecules (expressed on the majority of nucleated cells) might and perhaps does contribute to graft damage.

CTLs incur damage to target cells through induction of lytic or apoptotic cell death 44,45. The directed release onto target cell surfaces of two molecules (perforin and granzyme) causes death by lysis. Perforin permeates the target cell membrane and granzyme enters the cell to initiate the lytic programme, resulting in the bursting of the cell and release of its contents into the environment (and in the case of a viral infection, may lead to the promotion of a local inflammatory response to clear remaining virus particles). Appropriately, perforin and granzyme expression in transplant biopsies 46 and in peripheral blood cells 47 is being studied as a potential molecular marker of acute rejection.

Being part of a pathological process, lytic cell death is not part of cell turnover in normal tissues. Cell death is also possible by apoptosis, where macrophages rapidly phagocytose small cell fragments following chromatin degradation and cell break-down, without releasing target cell contents. This physiologically normal process allows the regulation of overall cell population sizes, and is essential for tissue remodelling (such as in in embryogenesis). Apoptosis (programmed cell death) is induced in target cells by cytotoxic T cells interacting (through the Fas-Fas ligand (FasL)), with the target cell 44,45. Both types of cell death are believed to play a part in rejection of grafts; the apoptotic pathway, in particular, may explain how CTL can cause graft damage with no histological evidence of tissue cell lysis.


Role of Antibody


Alloantibodies usually accompany acute rejection in experimental models, though, these antibodies may not be damaging. The use of genetically modified mice, devoid of antibodies but with an otherwise intact immune system, showed the main effectors of acute graft rejection to be T cells; however, if T cells are compromised, it is the antibodies that become important effectors of graft rejection 48. Experimental studies which showed treatment for suppression of rejection also reduced antibody binding in the graft, seem consistent with a role for antibodies in acute rejection; and additionally, in adoptive transfer models it appears that some Th cells bring about rejection of grafts by assisting B cells in the production of antibodies 49,50.

However, it is not always straightforward to interpret antibody responses following transplantation. Another line of evidence suggests that allografts (organs and tumours) can be protected from acute rejection, by antibodies 51. Contrary to expectation – through an effect called ‘passive immunological enhancement’ – rats that were recipients of organ grafts were protected from rejection by the passive transfer of antidonor antibodies into them, which only caused damage when rabbit complement was also injected 52. Thus, as well as not being detrimental, the very low levels of circulating anti-graft antibodies may also be of benefit to the graft.


Chronic Rejection


In the first few months following transplantation, infiltrating mononuclear cells cause parenchymal damage, which is prevented or limited by use of immunosuppressive drugs. As time progresses, however, an insidious process damages the graft such that its main conduits are obliterated. The proliferation of myofibroblasts and deposition of collagen and extracellular matrix result in the main pathology of small and large airway occlusion, observed after lung transplantation – known as obliterative bronchiolitis (OB) or bronchiolitis obliterans syndrome (BOS).

Such a progression in disease has to be explained by immunologists in the face of potent immunosuppressive agents, which strongly inhibit a type 1 response. It is clear, however, that chronic rejection comprises of both antigen-dependent and antigen-independent components. Ross proposed the hypothesis of endothelial response to injury in 1993 to explain non-transplant atherosclerosis 53 – applicable to BOS. He suggested that the activation of endothelial cells and up-regulation of cytokines, chemokines and adhesion molecules results from an initial ‘insult’ – leading to the trans-endothelial migration of monocytes that can be modified further by modified low density lipoproteins (LDLs) in vessel walls, where subsequent release of cytokines and growth factors, leads to the proliferation and migration of smooth muscle cells.

Accordingly, it would seem reasonable to suggest that, in the case of lung transplantation, the up-regulation of cytokines, chemokines and macrophages that occurs as a consequence of epithelial cell damage is initiated by an initial insult. Contained within the damaged lungs are many neutrophils, macrophages and T cells 54; thus, three phases of the disease process may be considered (Figure 5) – the first of which is an antigen-independent phase, primarily consisting of damage incurred by neutrophils and free radicals 56. This is followed by the lymphocytic infiltration of bronchiolar structures in an alloimmune phase, and finally, the partial or total occlusions of the airway lumen in a chronic fibroproliferative phase.

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These macrophages, neutrophils an NK (‘Natural Killer’) cells in the lung modify the adaptive immune response, and have been implicated in transplantation. Macrophages play a homeostatic and pathogen defence role within the lung with studies showing that they are the source of growth factors thought to mediate the fibroproliferative characteristics observed in OB 57. Macrophage depletion in a heterotopic tracheal transplant rat model prevented the development of OB, suggestive of a causative role for macrophages in OB lesions 58. Depletion of lung allograft macrophages also led to a diminished Th1 immune response 59. Macrophages may also be related to the bridge between innate and adaptive immunity. Recent studies have highlighted the role of Th17 cells in the pathogenesis of OB 60, and monocytes/macrophages have been suggested to have the key role of inducing Th17 immunity 61.

Although not much is known about the role played by NK cells in lung transplant rejection, it is known that they are resistant to calcineurin inhibitor–mediated immune suppression. The MHC class I expression on resident donor-derived NK cells could, therefore, be a strong enough stimulus to cause the immune responses in transplant recipients who are immunosuppressed – so NK cells may be a future therapy target in OB prevention 62.


Role of CD4+ T cells


CD4+ T cells have been extensively implicated in incidences of experimental parenchymal and vascular rejection, and can contribute (as in acute rejection) to chronic rejection in three ways: (1) provision of signals promoting the generation of CD8+ CTLs, (2) provision of signals promoting the differentiation and activation of alloantibody-producing B cells; and (3) activation of antigen-independent effector leukocytes that damage tissue. The activated macrophages are probably the best known of the effector leukocytes, releasing such mediators as reactive oxygen intermediates, nitric oxide and degradative enzymes to cause tissue damage. The cytokines released by macrophages (such as TNF-α) or T cells (IFN-γ) can directly damage parenchymal cell grafts 63,64. The injection of severe combined immunodeficiency (SCID) mice, bearing human aortic grafts, with human IFN-γ caused aortic smooth muscle cell proliferation as well as vessel remodelling 64 – so it is not surprising that great interest surrounds IFN-γ, particularly, as an effector mechanism of chronic rejection.

It should be mentioned that in non-transplant settings, host responses function protectively to eradicate foreign microbes. Activation of the same effector mechanism by one which is not associated with a pathogenic microbe, results in a tissue injury known as ‘delayed-type hypersensitivity’ (DTH) 65 – the acute form of which (acute DTH) remains as a potential effector mechanism in acute allograft rejection. When the DTH evoking antigen is not eliminated, it seems reasonable to postulate that persistently activated macrophages and CD4+ T cells release cytokines and growth factors, which promote stromal cell growth and fibrosis by acting on mesenchymal cells. It is thus likely that a contributing factor to chronic rejection is chronic DTH.


Pathways of Antigen Presentation


An ‘antigen presenting cell’ is one that can present antigen and activate resting T cells, and only specialized cells (such as dendritic cells) are able to activate these T cells. The discovery that T cells directly engage and respond to allogeneic molecules, was key to understanding alloreactivity (Figure 3) 26. Such form of antigen recognition (the direct pathway) accounts for the observed strong proliferative responses of alloreactive CD4+ T cells in vitro (the mixed lymphocyte response) and perhaps for the vigorous acute rejection observed in particular experimental strain combinations. However, it is also known that T cells, in the same manner as nominal antigen recognition, can recognize allogeneic peptides presented and processed by host APCs within self MHC (or derived from parenchymal tissue) (Figure 6).

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Much experimental and clinical evidence exists in support of the hypothesis that indirect presentation drives chronic rejection. It may, therefore, be assumed that in a gradual progression, the donor-derived parenchymal cells release antigens which are then captured in secondary lymphoid tissues by dendritic cells. Some studies of lung transplant patients 67,68 investigated the frequency of CD4+ T cells to indirectly presented peptides from the hypervariable region of mismatched MHC class I 67 or class II antigens 68, with results showing a significantly higher precursor frequency (3–24-fold higher) in BOS recipients (hyperresponsive to antigens presented via the indirect pathway) than recipients without BOS.

Emerging as a significant contributor to the development of OB/BOS in human lung transplantation is autoimmunity. Located within the lung interstitium, is type V collagen [col(V)], expressed by airway epithelial cells, with ischemia/reperfusion (I/R) injury and interstitial remodelling enhancing its expression 69. Acute rejection was found to be exacerbated by the reactivity of T cells to col(V) in rat allografts, suggestive of graft failure that may be promoted by autoreactive T cells 70. CD4+ T cells reactive to col(V) cells were associated with a near 10-fold increased risk for the development of BOS in clinical lung transplantation – considerably greater than that associated with acute rejection episodes, HLA mismatch, or anti-HLA antibodies 60. Cellular immune responses to col(V) were mediated by IL-17A, TNFα, and IL-1β, but not IFN-γ – and while dendritic cells are key in the initiation of cellular immunity, reactivity to col(V) seemed to be dependent on monocytes (CD14+) 60. These data collectively provide evidence of a new paradigm where an effector response is produced by coordination of monocytes with CD4+ T cells, and BOS is mediated by autoreactive Th17 cells.


Role of CD8+ T cells


CD4+ T cell activation results in maturation of other immune damage effector mechanisms (including antigen-specific cytotoxic CD8+ T cells). If CD4+ Th cell frequency were reduced during chronic rejection, the same would be applicable to cytotoxic T cell frequency – as is the case following transplantation of heart and kidney, with long-term patients becoming hyporesponsive for direct target cell recognition by cytotoxic CD8+ lymphocytes 71. This is a confirmation that, although long term immunosuppression cannot inhibit the indirect pathway of antigen recognition, patients do become anergic with respect to the direct pathway.

Whether or not the direct pathway of antigen recognition is rendered hyporesponsive following lung transplantation, is yet to be investigated. It may be possible to carry out an investigation where the extent of donor-specific CD4+ Th (or cytotoxic CD8+ T cell) response is measured against that of a third party. However, considering that lung transplant patients observe a heightened indirect response, it would not be reasonable to assume the occurrence of hyporesponsiveness (in the direct pathway) in lung recipients, even if such is the case for heart and kidney allograft recipients.

It may be argued that cytotoxic T cell mediated damage occurs subsequent to lung transplantation. A mucosal epithelia study (including those of the gut and lungs) identified a particular CD8+ T cell population, correspondingly expressing the adhesion molecule αEβ7 (an integrin expressed by only 2% of peripheral lymphocytes and identified via monoclonal antibodies to the CD103 antigen on the αE subunit). The αEβ7 integrin only binds the E-cadherin molecule (expressed constitutively by most epithelial cells) with high affinity 72,73. In a study of renal biopsies that showed signs of acute rejection, accumulation of CD103+ CD8+ T cells within the tubular epithelial layer of the biopsies was demonstrated to occur, which may suggest that the differentiation of infiltrating CD8+ T cells to CD103+ is promoted by TGF-β1 (already expressed in renal tubules in acute rejection). Tissue-specific damage to epithelial cells (by T cells), may therefore, be a possibility that may also apply to epithelial cells that line the bronchi.

Immediately, following experimental tracheal transplantation, donor epithelial cells are destroyed and replaced by recipient cells 74 – with integrally developed epithelium being shown to be crucial in preventing BOS development 75. In this study, rat epithelium was removed by protease digestion, using tracheal syngeneic graft transplantations within the omentum. Luminal occlusion developed in the syngeneic grafts and this could be inhibited with epithelial cell reseeds. A comparison of different immunosuppressive drugs on BOS development, carried out by the same group, showed a direct relationship between drugs preserving epithelial cell integrity and those preventing airway obliteration 76 – suggestive of a discouraging or inhibiting effect exerted on mesenchymal proliferation, by an intact epithelium; the mechanisms of which, are yet to be explicated.

Indirect allorecognition may dominate chronic lung rejection, but a contribution may also be made by the direct recognition of MHC by T cells following depletion of donor APCs 77,78. Unlike CD4+ T cells (MHC class II), the CD8+ T cells can recognize MHC class I presented antigens (present on all cells). Mouse models where transplantation of tracheal allografts have been implicated, demonstrate that the involvement of CD8+ T cells with direct alloreactivity of class I MHC to the graft is persistent and contributes to chronic destruction and subsequent obliterative airway disease 79. It has also been shown that MHC class II molecules are upregulated on lung allograft epithelium and endothelium, following transplantation in rat models 80 – also reported in lung transplant patients with chronic rejection 81.

The persistence observed with direct allorecognition may be explained by the ‘semi-direct pathway’ of alloantigen presentation 82, which describes the process where donor MHC-peptide complexes are acquired by recipient APCs via exosomes or cell-cell contact 83. Although this pathway may enable simultaneous interaction of recipient APCs with CD4+ and CD8+ T cells, and account for the potential uptake of donor MHC fragments by recipient APCs that present to alloreactive T cells (following acute rejection injury), no proof has yet been reported of the pathway in lung transplantation.


Role of Antibody


Many clinical and experimental studies have demonstrated an association between chronic antibody production (to HLA class I antigens) and the development of chronic rejection or transplant vasculopathy, following cardiac transplantation 84,85. T cell-dependent antibody responses may be inhibited by calcineurin inhibitors (ciclosporin and tacrolimus), but such is not the case with secondary immune responses involving antibody production. Multivariate analysis of BOS-related risk factors, following lung transplantation, have demonstrated that HLA mismatches at the class I locus (principally, the HLA-A locus) and antibodies to HLA-A antigens to be significantly independent, as predictors of disease development 86.

The mechanisms allowing antibodies (to MHC class I antigens) to activate parenchymal cells within grafts is a potential way in which they can contribute to chronic rejection. Patient derived monoclonal and anti-HLA class I antibodies activate nuclear factor kappa beta (NF-ҡβ) in human macrovascular and microvascular endothelial cells, leading to fibroblast growth factor receptor expression and cell proliferation, in vitro 87,88. Tyrosine phosphorylation, production of fibroblast growth factor and cell proliferation are all induced by the ligation of MHC class I antigens on smooth muscle cells 89. Relevant to lung transplantation; anti-MHC class I antibody mediated activation of airway epithelial cell lines, produces the fibrogenic factors that allow the proliferation of adjacent fibroblasts 90. It is thus probable that fibroproliferative lesions of BOS are exacerbated by chronic antibody production.


Overcoming Rejection


Strategies implemented to overcome acute and chronic rejection aim to reduce immune activation and recipient T cell counts, prevent T cell activation and proliferation, and suppress inflammation. Immunological graft tolerance (long-term acceptance without continued immunosuppression) would be the ultimate achievement.

Immunosuppression

The human body can distinguish between native and non-native tissues, thus immunosuppressive drugs (Table 1 and Figure 7) are required to minimize the subsequent response of the immune system to the non-native tissue, permitting organ viability. Lung transplantation presents many issues. The accompaniment of donor human leukocyte antigen with the transplant requires vigorous immunosuppression, while the exposure of the lung to an array of infectious organisms presents a conflict to this – making immunosuppression a predicament. It is no surprise therefore, that patients require careful monitoring, particularly when significant side effects are also associated with these drugs.

Although the immunosuppression regimens implicated in lung transplantation are highly aggressive, high rates of acute and chronic rejection still exist. For this population, other strategies to augment immunosuppression have been considered. One of these is the use of aerosolized ciclosporine, where the delivery of the calcineurin inhibitor cyclosporine is altered to directly enhance its concentration in the lung. A decreased incidence of death and rejection has been observed in patients undergoing this type of treatment (in addition to their immunosuppression regimen) 92, but larger randomized trials are currently in progress to confirm its benefits in lung transplant recipients.

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Another strategy, extracorporeal photopheresis (ECP), the removal of peripheral blood mononuclear cells and their exposure to psoralen (UVADEX), facilitates apoptosis following ultraviolet radiation 93 treatment. APCs which process apoptotic cells may then adopt a “silent” phenotype, promoting tolerance. The mechanisms of such tolerogenesis are unclear, but could be the result of reduced costimulatory molecule expression, respective suppression and production of IL-12 and IL-10, and modulation of regulatory T cell activity 94,95. Clinical studies are on-going to define the therapeutic potential of ECP in modulating immune responses and tolerance induction. Compared with non-treated patients following conventional immunosuppressive therapies, those who are ECP treated develop higher regulatory T cell percentages, though clinical trials are still on-going 69.

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Immune Tolerance

As crucial as immunosuppression may be, it ultimately limits the overall success of transplantation. Immune responses of patients are supressed at the cost of serious side effects and increased vulnerability to infection (the leading cause of mortality following lung transplantation). Achievement of graft tolerance without chronic immunosuppression (donor-specific immune tolerance) has been possible experimentally but is rare in clinical contexts – and despite tolerance mechanisms not being fully clarified, the whole phenomenon is referred to as the “holy grail” of transplantation 1.

The indirect recognition of graft derived HLA antigens (processed by recipient dendritic cells) drives chronic rejection. The constant release of graft antigens that are not cleared contribute to the chronic immune response. Dendritic cells play a fundamental role in transplant tolerance because they have the capacity to induce a regulatory T cell phenotype. When recipient dendritic cells are loaded with donor MHCs, infiltrating tolerogenic CD4+Foxp3+ T regulatory cells within the graft is favoured, with induction of donor reactive T cell deletion 96. The plasmacytoid dendritic cell, for example, is a distinct subset of “tolerogenic” dendritic cell that has been proved to be necessary for the development and tolerance induction of Tregs (regulatory T cells) in therapeutic adoptive transfer studies 57. Other dendritic cell types similar to the plasmacytoid may also be implicated in future in vivo and clinical tolerance protocols.

A possible hypothesis for the difficulty of autoimmune and alloimmune suppression could be the absence or dysfunction of Tregs following transplantation, with some studies reporting a correlation between the incidence of BOS and decreases in Tregs in lung transplant recipients 97. In addition, collagen-V (a major extracellular matrix component in fibrotic lungs and an autoantigen candidate in the pathogenesis of BOS) reactive T cell lines were found to produce IL-10 and had the ability to supress proliferation and secretion of IFN-γ from autoreactive T cells 98. Subjects developing BOS, however, seemed to exhibit an associated decline of IL-10 producing T-cell clone frequencies 98. These data suggest that autoimmune responses to collagen-V, in recipients of lung transplants, may either be dampened through natural Tregs or adaptive Tregs. A recent study suggests that the lung epithelium may be a major regulator of induced Tregs, as alveolar epithelial cells induced lung antigen specific Tregs during inflammation 99.

Of course, col(V) is not the only autoantigen identified in recipients of lung transplants. Antibodies to K-α1 tubulin (an epithelial specific protein) were found in a significant number of BOS patients 100. In a study, profibrotic growth factors were found to be induced from airway epithelial cell lines by sera positive for anti-K-α1 tubulin antibodies – suggesting that autoreactivity (and not just alloimmunity) may induce fibrosis 101. The same study also found that, in a mouse model, col(V) and K-α1 tubulin autoreactivity may be promoted by an acute alloimmune response in the lung – with IL-17 involvement in the subsequent airway injury and fibrosis 101. Further support for the role of IL-17 in BOS was provided by a study where the production of IL-8 (induced by IL-17) from human smooth muscle cells was suppressed by azithromycin, a macrolide important for treating a subset of BOS patients 102. Alloimmune-mediated damage may, therefore, result in an autoimmune response that is initiated by epitope – with IL-17, potentially, mediating this characteristic response.

Immunosuppression and alloimmunity both undermine normal homeostatic mechanisms of the lung. The induction of tolerance is a broad and active area of research encompassing such studies as tolerogenic Toll-like receptor activity 100, T-cell immunoglobulin mucin (TIM) membrane glycoproteins 102, and significance and role of mast cells 97. The strategies promoting immune tolerance to autoantigens and alloantigens (and unidentified antigens), along with the identification of biomarkers of tolerance, provide the potential to clinically identify and monitor tolerance and hold promise in tackling such devastating complications as BOS 98,99,103.


Conclusion


The lung could be envisaged as a “lymph node with alveoli” – one, with high susceptibility to local immune homeostatic perturbations – making it immunologically distinct from other organ allografts (kidney, heart, or liver). Immunocompetent cells within the lung; airways, interstitium and alveoli, as well as within bronchus associated lymphoid tissue (BALT) are sufficient for mediation of local immune responses even when systematic secondary lymphoid tissues are absent. T and B cells within the lung interact with other immunologically active components such as extracellular matrix, epithelial and endothelial cells, and cells of the innate immune system.

During transplantation, the lung may encounter insults such as ischemia/reperfusion (I/R) injury or infection, which lead to recruitment of lymphoid cells as well as promoting acute and chronic rejection, and the development of BALT. BALT may be a site of continued proliferation of T and B cells and antigen presentation, where alloimmune responses are perpetuated and an autoimmune prone environment is provided. Although distinct mechanisms of immune maintenance occur simultaneously with those of gas exchange (with additional mechanisms to prevent one impacting the other), these can be catastrophically affected by (even the most optimal) chronic immunosuppressive immunomodulation, necessitated in lung transplantation.

Substantial improvements in lung recipient survival rates will undoubtedly occur, when distinct interactions between immune and non-immune cells that impact the physiology of the transplanted lung are fully understood, and their underlying mechanisms fully elucidated. For now, optimal immunosuppressive regimens accompanied by augmentative strategies, under careful monitoring will have to suffice – but just as antibiotics alone cannot be relied upon for defence against pathogens, progress in lung transplantation cannot occur with only general immunosuppression.

Studies of immune cells implicated in tolerogenesis, and their therapeutic use, do seem very promising; as do other potential options, such as the implication of artificial lungs.

Cite this article as: Ali Hamidi, "Lung Transplant Rejection – A Review," in Projmed, October 20, 2015, https://www.projmed.com/2015/10/lung-transplant-rejection-a-review/.


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