(Journal of Leukocyte Biology. 2002;71:401-409.)
© 2002
by Society for Leukocyte Biology
Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system
Annette Fox-Marsh and
Leonard C. Harrison
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Correspondence and current address: Annette Fox-Marsh, MRC Laboratories, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia, West Africa. E-mail: annettemarsh5@hotmail.com or afox{at}mrc.gm.rt
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ABSTRACT
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The innate immune system existed prior to the emergence of adaptive
immunity in sharks and higher vertebrates. Homologues of many mammalian
innate immune-system elements such as the toll-like receptors exist in
species as distant as Drosophila. Selective pressure has
led to the development of highly conserved, soluble, and cell-surface
receptors that recognize functionally essential molecules shared by
microbial pathogens. It is thought that molecular patterns that
exquisitely distinguish pathogenic cells from mammalian cells are
recognized. Therefore, it would seem unlikely that innate immune-system
elements should recognize mammalian tissues. However, there is
increasing evidence to suggest that this is the case and that innate
immunity promotes rejection of transplanted mammalian tissues,
particularly those from other species (xenografts). Evidence for innate
recognition of mammalian grafts, the nature of this recognition, and
the bi-directional interactions between innate and adaptive immunity
that contribute to graft rejection are discussed in this review,
with the emphasis on nonvascular xenografts.
Key Words: PAMP • macrophage • neutrophil • NK cell • complement
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OVERVIEW OF COMPONENTS AND FUNCTIONS OF THE INNATE IMMUNE SYSTEM
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Physiology: role and organization
The innate immune system serves the extremely important function
of rapidly responding to and controlling infection. This is achieved by
the widespread and constitutive occurrence of cells and soluble factors
that recognize pathogens and elicit antimicrobial compounds and
cellular activities, such as phagocytosis. The importance of the innate
immune system in this regard is exemplified by the severity and
frequency of infection in people with genetic abnormalities in various
innate immune-system components [1
2
3
4
5
].
It is well established that the innate and adaptive immune systems
interact. For instance, B cells bear complement receptors, and T cells
activate Møs [6
]. There is also increasing evidence to
support the suggestion originally made by Janeway [7
]
that an innate immune response is essential for the generation of an
effective, adaptive response. This was based on the sound reasoning
that T and B cells with their randomly rearranged receptors cannot
discern whether an antigen is associated with a dangerous pathogen.
Thus, a reliance on signals from the innate system for effective
priming would focus responses on pathogens. Further, it is clear that
different pathogens elicit distinct responses. Again, because T and B
cells cannot discriminate different pathogens, it was suggested that
the innate immune system was responsible for shaping the adaptive
response.
Cellular components
The main specialized, cellular components of innate immunity
include macrophages (Møs), neutrophils, natural killer (NK) cells, and
mast cells. Epithelial cells, generally being the first cells to
encounter pathogens, are also important in innate defense. For
instance, the process of bacterial attachment to epithelial cells can
occur through glycolipid receptors such as toll-like receptor (TLR) 4
leading to interleukin (IL)-8 and IL-6 production and neutrophil
recruitment [8
, 9
].
Soluble components
The innate immune system also encompasses a diverse array of
soluble components. Some of these, including the complement molecules,
C-reactive protein [10
], mannan-binding lectin, and
other collectins, are clearly important in pathogen recognition
[11
12
13
]. The latter act largely as opsonins for
complement and hence cells bearing complement receptors. Others have
microbiocidal activity including the peptide defensins (also referred
to as broad-spectrum antibiotics), lysozyme, phospholipase A2,
serprocidins, and iron-binding lactoferrin [14
15
16
].
Molecules involved in recognition: receptors and ligands
The ligands, recognized by innate immune receptors, are referred
to as pathogen-associated molecular patterns (PAMPs). In addition to
the soluble recognition molecules mentioned, various cell
surface-expressed PAMP receptors or pattern-recognition receptors
(PRRs) have been identified (reviewed in ref. [17
]).
These include the TLRs [18
19
20
21
], scavenger receptors
that binds sialic acid ligands [22
], a Mø mannose
receptor [12
], a ß-glycan receptor, a fucose-binding
protein, and galactose-specific lectin [23
]. The
distinctive molecular patterns borne by pathogens are often essential
lipid and carbohydrate moieties, presumably because they are major
constituents of microbial cell walls. Well-known PAMPs include
lipopolysaccharide (LPS), techoic acid, double-stranded RNA, and
unmethylated CpG dinucleotides that are common in bacterial DNA
[24
, 25
]. Ligand specificity has been
well-described for the mannan-binding lectin that binds microbial
cell-surface sugars and activates complement [4
].
Mannan-binding lectin contains a carbohydrate-recognition domain that
discriminates between self and nonself by preferentially recognizing
glucans, lipophosphoglycans, and glycoinositol phospholipids with
mannose, glucose, fucose, or n-acetylglucosamine as terminal
hexoses [11
12
13
].
Recent studies describing the ligands and receptors involved in innate
pathogen recognition demonstrate that the innate immune system has the
capacity to discriminate between different pathogens. For Mø-mediated
innate immunity, recognition involves cooperation of two classes of
innate immune receptors: the phagocytic receptors, such as the mannose
receptors, and the TLRs that sample the contents of the vacuole
[26
]. TLR4 recognizes LPS on gram-negative bacteria
[26
, 27
]. TLR2 can also recognize LPS
[28
, 29
] but appears to be more specialized
for recognition of gram-positive bacteria. Peptidoglycan of
gram-positive bacteria is recognized by the combination of TLR2 and
TLR6, whereas lipopeptide is recognized by TLR2 alone, indicating that
TLR2 can discriminate between lipopeptides [30
31
32
33
].
TLR2 also recognizes yeast [26
], gram-negative bacterial
glycoproteins yet to be characterized [34
],
glycosylphosphatidylinositol anchors from the protozoan parasite
Trypanosoma cruzi [35
], and mycobacterial
lipoarabinomannan [36
]. TLR5 recognizes flagellin, a
virulence factor for gram-positive and -negative bacteria that
stimulates innate immunity in organisms as diverse as plants and
mammals [37
]. TLR9 recognizes CpG DNA
[38
].
Mode of action
One well-established way in which innate immunity drives adaptive
immunity is through the production of cytokines. Thus, in response to
many bacteria, dendritic cells and particularly Møs produce IL-12,
which induces activation of T-helper cell type 1 (Th1) T cells and
interferon-
(IFN-) production [39
,
40
]. For some pathogens, the molecules that induce IL-12
production by Møs have also been identified. These include microbial
lipoproteins and bacterial CpG DNA, both acting via TLRs
[24
, 41
]. In turn, TLR binding and
signaling, which require the MyD88 adapter molecule
[38
], are linked to activation of nuclear factor-
B
(NF-B), a transcription factor for an array of cytokines
[42
]. Various innate stimuli also up-regulate expression
of the CD40, CD80, and CD86 costimulation molecules on dendritic cells
[17
, 38
, 43
].
Positive-feedback loops also operate within the innate immune system.
IL-12, produced by phagocytic cells within a few hours of infection,
activates NK cells to produce IFN-, which in turn enhances the
phagocytic and bactericidal activity of phagocytic cells and their
ability to release cytokines including IL-12 [44
]. Given
that PRRs largely seem to induce IL-12 and Th1-type responses, Th2
responses are suggested to occur by default when microbial constituents
are not available and involve increased costimulatory molecule
interaction between the T cell and the antigen-presenting cell (APC;
reviewed in refs [45
, 46
]). Support for
this suggestion comes from the finding that mice lacking the MyD88
adapter molecule required for signalling through the TLRs have
defective Th1- but not Th2-type responses [46
]. However,
the existence of PAMPs and PRRs, other than the TLRs that actively
stimulate Th2-type responses, has not been ruled out.
|
INNATE IMMUNITY AND TRANSPLANTATION
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This review presents various studies, showing that mammalian
tissue grafts and mammalian molecules are recognized directly by
components of the innate immune system, and focuses on xenografts.
Innate recognition of allografts appears to be limited to NK cells or
to require tissue damage. The role of innate immunity in rejection is
discussed largely in terms of nonvascular xenografts rather than
solid organ grafts. Discordant, solid-organ, or vascular xenografts are
rejected hyperacutely within minutes because of the presence of
preformed antibodies specific to the endothelial cell carbohydrate,
Gal
(1,3)Gal [47
, 48
]. This carbohydrate
is discussed later. It is clear that the innate immune system, in
particular complement, acts in concert with preformed antibodies (Abs)
to transform xenograft endothelium into a prothrombic state, such that
grafts are rejected hyperacutely through a lack of blood supply
[49
, 50
]. This hyperacute response is so
strong, rapid, and hard to prevent that it is difficult to determine
the role of innate immunity, independent of preformed antibody. In
particular, the independent role of complement cannot be determined,
because complement depletion is required to prevent hyperacute
rejection. In xenotransplant models in which hyperacute rejection is
prevented, delayed xenograft rejection or acute vascular rejection is
observed. Again, it is thought that antibody mediates this but in the
absence of complement, is the result of endothelial cell activation
[51
]. It does not require adaptive cellular immunity but
may involve cells of the innate immune system, including monocytes and
NK cells [52
, 53
]. Organ allografts are
also subject to acute vascular rejection as a result of antibodies
specific for human leukocyte antigen (HLA) [51
].
Møs and neutrophils
It has been clear for many years that nonvascular xenograft
rejection requires T cells, particularly CD4 T cells (reviewed in ref.
[54
]). However, Møs are the dominant infiltrating cells
in xenografts undergoing rejection [55
56
57
], which
indicates that they could contribute substantially to rejection. Mø
depletion with clodronate-loaded liposomes provided the first evidence
that Møs promote T-cell infiltration and rejection of nonvascular
fetal pig pancreas (FPP) xenografts [57
]. Similar
effects of clodronate-mediated Mø depletion on pig-islet graft
rejection and T-cell infiltration have been demonstrated recently
[58
]. Further, granulocyte macrophage-colony stimulating
factor (GM-CSF)-deficient mice have impaired Mø infiltration of
xenografts with a concomitant impairment in T-cell infiltration
[59
]. Although these studies indicate that Møs
contribute to rejection and enhance the T-cell response, they do not
indicate whether Mø-mediated effects occur in the absence of
activation by T cells. This was important to investigate, because we
had found that Mø infiltration of FPP grafts in T-cell-deficient,
severe combined immunodeficiency (SCID) mice is reduced greatly
compared with that in immune-competent mice [60
].
Investigation of the response to foreign cells injected
intraperitoneally (i.p.) into T- and B-cell-deficient SCID mice showed
that pig xenografts and, to a lesser extent, allografts elicit
T-cell-independent neutrophil and Mø responses [61
].
Recruitment of both cell types was seen within 1 day, and neutrophils
appeared marginally earlier than Møs. Similarly, in immune-competent
mice, it was clear that neutrophil and Mø infiltration preceded T-cell
infiltration, which started from day 3. Others have demonstrated that
human naïve neutrophils [62
] and monocytes
[63
] can activate xenoendothelium in vitro,
independently of xenoreactive natural antibodies and complement,
indicating direct recognition. Together with studies on NK cells and
complement discussed in the sections to follow, these findings indicate
that foreign mammalian cells, particularly those from a different
species, are recognized by the innate immune system.
The mechanism(s) by which xenogeneic cells stimulate Mø and neutrophil
recruitment is unknown. Møs and neutrophils express PRRs, including
TLRs 1, 2, 4, and 5 [64
], triggering receptor expressed
on myeloid cells (TREM-1) [65
], complement receptors
[66
67
68
], and lectin-type receptors for other
carbohydrates [22
, 23
]. Carbohydrates on
the surface of neutrophils (neutrophil-glycoprotein receptors) also
bind directly to lectin-like molecules of bacteria in the absence of
serum opsonins [69
70
71
]. As with the TLRs, different
neutrophil-glycoprotein receptors bind different bacterial species
[71
]. Neutrophils appear to be the first cells to
infiltrate xenografts and may therefore have a role in Mø recruitment.
Neutrophils release Mø and T-cell chemoattractants, such as tumor
necrosis factor (TNF-), macrophage-inflammatory protein-1
(MIP-1), monokine induced by IFN- (Mig), and IFN-inducible
protein 10 (IP-10) [72
73
74
]. Neutrophil
chemoattractants, IL-8 and KC, followed by Mø chemoattractants,
monocyte chemoattractant protein-1 (MCP-1), MIP-1, and MIP-1ß, are
detected in skin allografts prior to the induction of alloreactive T
cells [75
76
77
]. More recently, defensins and other
pre-stored granules in neutrophils have been shown to attract
monocytes, dendritic cells, and T cells [78
]. Others
have similarly suggested that neutrophils respond directly to pathogens
and initiate cell-mediated immunity [73
]. Supporting a
role for neutrophils in initiating infiltration of grafts
administration of KC antiserum or neutrophil-depleting monoclonal
antibody (mAb) RB6.8C5 to allograft recipients within 30 min of cardiac
transplantation attenuates intragraft expression of T-cell
chemoattractants IP-10 and Mig and reduces cellular infiltration and
rejection [77
]. Similarly for xenografts, we recently
found that administration of RB6.8C5 significantly reduced Mø
infiltration in response to xenogeneic pig cells injected i.p.
(unpublished results). Preliminary findings using microarray also
indicate increased mRNAs for JE, monocyte chemoattractant protein
(MCP)3, MCP5, migration inhibitory factor-related protein 8 (MRP8),
CCR1, CCR5, and TNF-receptor II/p80 in FPP xenografts 2 days after
transplantation (unpublished results). These results need to be
confirmed by RNase protection assay or Northern blotting, and it would
also be desirable to demonstrate changes in protein expression.
Cellular or soluble intermediates may be involved in neutrophil and/or
Mø recruitment. Complement is able to bind foreign carbohydrates.
Complement activation through the release of cytokines and chemokines,
especially the anaphylatoxins C3a and C5a, is a major mediator of
neutrophil migration [79
80
81
]. Acute phase-response
elements such as serum amyloid A are also chemotactic for
polymorphonuclear cells and monocytes [82
]. The
acute-phase response is induced particularly by IL-1, IL-6, and
TNF-, which in turn may be induced by ligation of PRRs on stromal
cells or cells of the innate system. Inflammatory mediators such as
leukotrienes and prostaglandins contribute to cell migration and
leakage of serum molecules into inflammatory sites and may also be
involved. Finally, local stromal or innate immune-system cells may also
initiate inflammation via PRRs and release cytokines and chemokines
that directly stimulate neutrophil and/or Mø recruitment.
Complement
Various studies indicate that complement can bind to xenogeneic
pig cells in the absence of Ab. First, pig cells are killed by
complement-mediated cytotoxicity in the presence of normal and
agammaglobulinemic human serum, but killing is abolished by
heat-inactivating serum [83
]. Second, fetal and adult
pig-islet cells bind C3c after incubation with serum, although human
immunoglobulin (Ig)M, IgG, and IgA binding was undetectable
[84
]. This has also been demonstrated in a more direct
manner in preliminary flow cytometry and histology studies showing that
pig epithelial PK15 cells and FPP exocrine and parenchymal cells are
coated with C3 after in vitro incubation with SCID mouse serum
(unpublished results). Further studies are required to determine
whether this will be the case with other pig cell types and other
species combinations to determine the degree of tissue or carbohydrate
disparity required for complement binding. Whether Ab-independent
binding involves direct interaction of complement with xenogeneic
carbohydrates, as with the alternative pathway for complement
activation by pathogen, or is mediated by mannan-binding lectin is not
known. Nevertheless, we found that complement depletion with the cobra
venom factor had no appreciable effect on neutrophil or Mø recruitment
in response to xenogeneic cells in SCID mice (unpublished results).
Complement appears to contribute to allograft rejection in some
settings. The reduced success of clinical pancreatic islet
transplantation compared with whole pancreas transplantation coincides
with the demonstration that collagen-isolated islets elicit binding and
activation of platelets, binding of leukocytes, and activation of the
coagulation and complement systems [85
]. These events
can be prevented by the addition of complement inhibitor
[85
]. Therefore, islets transplanted into the liver by
injection into the portal vein may well be treated like foreign
particles with collagen and other matrix molecules, normally hidden by
endothelial cells, now exposed to the host blood. In contrast to work
with xenografts, it is clear that even in this setting, complement
activation is not triggered by the allogeneic islets themselves but is
secondary to platelet activation thought to occur in response to
extracellular matrix proteins including collagens.
NK cells
NK cells bear PRRs such as complement receptors
[66
] and express inhibitory receptors specific for
self-major histocompatibility complex (MHC) class I molecules, which
has sparked interest in their role in allograft rejection in
particular. Inhibitory receptor binding by self-MHC class I molecules
inhibits the cytolytic activities of NK cells [86
,
87
]. NK cells infiltrate organ allografts
[88
, 89
], vascular xenografts
[52
, 53
], and nonvascular xenografts
[55
, 61
]. Similar to neutrophils, Møs, and
complement, it has been shown that NK cells directly recognize
oligosaccharides on pig endothelial cells [53
,
90
, 91
]. It appears that this recognition is
sufficient to activate in vitro lytic activities of mouse NK cells
against pig cells and that pig MHC class I is not able to stimulate
inhibitory signals, because pig endothelial cells expressing a mouse
MHC I transgene were not lysed [92
, 93
].
Additionally, NK cells exert nonlytic effects such as induction of
endothelial-cell procoagulant activity, which may contribute to acute
vascular rejection [53
]. Although NK cells appear to
inhibit engraftment of allogeneic and especially xenogeneic bone
marrow, NK cell depletion alone has had no detectable impact on solid
allograft or nonvascular xenograft rejection [55
,
88
, 94
]. However, it has been demonstrated
recently that NK cell depletion enhances the effects of Mø depletion
in prolonging pig-islet xenograft survival [58
].
Recently, we investigated the effect of NK cell depletion on neutrophil
and Mø responses to i.p. pig cells in SCID mice (unpublished results).
Treatment of mice with antiasialo GM1 to specifically deplete NK
cells prevented the usual influx of NK cells in response to pig cells
and significantly reduced neutrophil and Mø infiltration, indicating
that the NK cells promote their infiltration. As mentioned in the
overview, NK cells respond to IL-12 produced by Møs, which in turn
respond to IFN- produced by NK cells. Furthermore, NK cells have
been found to be responsible for early chemokine production in
allografts [89
], providing a mechanism for these
results. NK cell depletion in concert with inactivation of
CD28-mediated T-cell costimulation prevents rejection of cardiac
allografts in mice, whereas these interventions on their own are
ineffective [95
]. Thus, there is growing evidence that
although NK cells cannot reject allografts or nonvascular xenografts
single-handedly, they can promote adaptive responses and ultimately
rejection, alone or in concert with Møs.
|
IDENTITY OF XENOGENEIC MAMMALIAN MOLECULES RECOGNIZED BY
THE INNATE IMMUNE SYSTEM
|
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We used microarrays to compare fresh FPP with FPP recovered 2 days
after transplantation into mice to identify PRRs that might be involved
in the innate response to xenografts. Various relevant mRNAs were
induced, including a TLR, lipid A-binding protein, CD14, galectins,
killer inhibitory receptor (KIR) p91, Mø scavenger receptors, and Mø
C-type lectin (unpublished results). These results are preliminary and
need to be confirmed via other means. Scavenger receptors can bind
microbial polyanions such as LPS and lipotechoic acid and can mediate
binding and ingestion of gram-negative and -positive bacteria
consistent with the demonstration that scavenger receptor-deficient
mice have enhanced susceptibility to Listeria infection
[22
, 96
]. Mø C-type lectin binds bacterial
carbohydrates [97
].
PRRs, including those identified in xenografts, recognize carbohydrates
and lipids predominantly. The greater stimulation of various components
of the innate immune system by xenogeneic cells compared with
allogeneic cells is also likely to be related to the increased level of
carbohydrate and lipid disparity between rather than within species.
There are some clear carbohydrate differences among species. Humans and
Old World monkeys express polymorphic ABH-blood group antigens but not
Gal(1,3)Gal, whereas New World monkeys, other mammals, and
marsupials do not express ABH-blood group antigens but express large
amounts of Gal(1,3)Gal [98
]. This difference in
Gal(1,3)Gal expression has been identified as the basis of
hyperacute rejection of xenografts in these species combinations.
Preformed Abs reactive against pig cells exist in humans, apes, and Old
World monkeys, even without prior transplantation of pig tissues
[47
, 48
]. These Abs are largely directed
against Gal(1,3)Gal [99
, 100
], a
carbohydrate related to the blood group A and blood group B antigens,
and constitute approximately 1% of circulating IgG in human serum
[47
]. The antigenic source for the constant production
of Gal(1,3)Gal-specific Abs seems to be the -galactosyl-like
epitopes found on many bacteria of the gastrointestinal flora
[101
, 102
]. It has also been found that
human NK cells directly recognize Gal(1,3)Gal [90
,
103
] expressed by pig endothelial cells but can also bind
xenogeneic endothelium independently of Gal(1,3)Gal
[53
]. Together, these findings indicate that even if
PRRs evolved to distinguish between pathogens and self, they may have
cross-reactivity for xenogeneic-mammalian cells, particularly those
from phylogenetically distant mammalian species.
|
BIDIRECTIONAL INTERACTIONS BETWEEN INNATE AND ADAPTIVE
IMMUNITY—IMPACT OF INNATE IMMUNITY ON GRAFT REJECTION
|
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In brief, evidence is emerging that xenograft rejection depends on
bidirectional interactions between innate and adaptive immunity. It is
clear that innate immunity is not sufficient for nonvascular xenograft
rejection because xenografts are not rejected in various models of
T-cell deficiency [104
]. It also appears that various
components of innate immunity can stimulate adaptive immunity to
xenografts such that it may prove difficult to examine how rejection
proceeds in the absence of innate immune activation.
The local innate response stimulates T-cell
infiltration of grafts
We showed that Møs and neutrophils induced by i.p. injection of
xenogeneic cells into SCID mice would stimulate T-cell recruitment when
purified and transferred to immune-competent mice [61
].
As discussed earlier, T-cell infiltration of xenografts is impaired in
the absence of Møs, and Møs are able to respond rapidly to grafts as
part of an innate response. Thus, it would appear that the innate Mø
(±neutrophil) response greatly enhances T-cell infiltration and
therefore rejection of xenografts. As depicted in Figure 1
such a relationship between the innate response and T-cell
infiltration of inflammatory sites is logical and indeed obligatory.
Naïve T cells traffic through lymph nodes, where they will be
primed if stimulated by specific antigen delivered and presented by
dendritic cells draining the site of infection or inflammation. Once
activated, T cells enter the circulation and require signals to
extravasate to the site of infection or inflammation to perform
function there. It is logical that the innate response that occurs more
or less immediately at the site of foreign antigen provides these
signals. The capacity of neutrophils and Møs to induce T-cell
recruitment is also well-supported by other adoptive-transfer studies
and by the ability of these cells to produce T-cell chemoattractant
chemokines and cytokines such as IP-10 and TNF- [73
,
74
, 105
106
107
108
]. Møs recruited within 1 day
of injecting xenogeneic cells express TNF- protein such that there
is an increase in the absolute number of TNF-+ Møs at
this time [61
]. Furthermore, it has been demonstrated
that blockade of locally produced chemokines prevents allograft
infiltration by alloreactive T cells, although the latter are found in
increased numbers in the periphery after transplantation
[77
, 109
]. NK cells may also be an
important source of T-cell chemoattractants, particularly for
allografts. NK cell infiltration of allografts often occurs before that
of T cells [110
], and depletion experiments have
demonstrated that NK cells are a source of chemokines such as KC,
MIP-1, and MIP-1ß expressed early within grafts
[89
]. Recently, we found that depletion of NK cells with
anti-asialo-GM1 also significantly decreased the number of CD8 T cells
induced by i.p. pig cells in mice, although the effect was only
transient (unpublished results).
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|
Figure 1. Scheme depicting the role of innate immunity in promoting T-cell
infiltration of xenografts. Molecular patterns expressed or induced by
xenografts are recognized by elements of the innate immune system
leading to rapid neutrophil and Mø infiltration. Dendritic cells
draining the graft site present xenogeneic antigens to T cells within
the local lymph node. T cells then enter the circulation and require
signals to extravasate to the graft/inflammatory site. These signals
are provided by the innate response, which occurs locally and prior to
T-cell activation. Innate immune responses are known to induce
chemokine and adhesion-molecule expression on endothelial cells.
|
|
Xenograft rejection is far more aggressive and difficult to
prevent than allograft rejection [111
], which coincides
with a stronger innate immune response to xenografts. Thus, innate
immunity may contribute to the strength and complexity of the xenograft
response by driving and shaping adaptive immunity, as proposed for
pathogen responses [7
, 17
,
112
]. However, it is yet to be determined whether innate
responses to grafts induce costimulatory signals for activation of
adaptive responses.
Preformed Abs stimulate innate immunity
As discussed, preformed Abs reactive with pig cells exist in
humans, apes, and Old World monkeys even without prior transplantation
of pig tissues [48
, 101
]. We and others
have demonstrated that Ab-transfer accelerates the inflammatory
response to xenografts in immune-deficient mice, indicating that
preformed Abs may impact the initial innate response to xenografts.
Thus, coinjection of hyperimmune serum raised against xenogeneic pig
PK15 cells, together with PK15 cells into the peritoneal cavity of SCID
mice, increased neutrophil and Mø infiltration compared with injection
of PK15 cells alone [113
]. Similarly, passive transfer
of hyperimmune serum raised against pig-islet-like cell clusters
enhanced mononuclear cell infiltration of transplanted islet-like cell
clusters [114
, 115
].
T cells induce Mø infiltration and activation
The innate and adaptive immune systems appear to operate in
a feedback manner. Not only do Møs promote T-cell responses but T
cells also promote infiltration and activation of Møs, as demonstrated
by adoptive-transfer experiments [60
, 61
].
Thus, although Møs in immune-deficient mice cannot reject xenogeneic
pig cells, Møs from xenograft-primed, immune-competent mice express
MHC class II and transfer prompt xenograft rejection. The requirement
for T cells to stimulate certain Mø functions is long-established
[6
] and is classically associated with the provision of
IFN- [106
, 116
]. Thus, the sites at
which Møs can exert destructive activities appear to be controlled by
T cells. Others have similarly demonstrated that T cells are required
for Mø infiltration (particularly CD8 T cells) and Mø activation
(particularly CD4 T cells) in allografts [117
].
|
HOW TRANSPLANTATION FITS WITH THEORIES ABOUT COSTIMULATION OF
ADAPTIVE IMMUNITY—INNATE PATHOGEN RECOGNITION VERSUS DANGER
|
|---|
The innate model for induction of costimulatory signals focuses
adaptive responses on pathogens and thus appears far more efficient
than the earlier self-nonself model for control of adaptive immunity.
The latter did not predict that foreign and harmful antigens would be
distinguished from foreign but inert antigens, such that energy would
not be wasted on unnecessary adaptive responses. Although, there is
much evidence that pathogens trigger the innate immune system to
produce costimulatory signals for lymphocyte activation, evidence that
adaptive immunity is obligatorily controlled by innate pathogen
recognition is somewhat lacking. As suggested by Matzinger
[118
], this model may not account for the transplant
response. Matzinger has also argued that the innate/pathogen model
still does not distinguish between harmful and harmless foreign
pathogens. However, if innate recognition developed through selective
pressure from pathogens, it is likely to be directed toward harmful
pathogens. The alternative danger model proposed by Matzinger argues
that an immune response is only initiated if an antigen is associated
with endogenous signals from cells that are stressed, damaged, or die
messily [118
, 119
]. This model shifts the
reliance on exogenous foreign molecules to endogenous danger signals.
In light of the identification of PRRs, Matzinger has suggested that
PRRs actually recognize endogenous molecules and that bacteria have
evolved to recognize and use them for the infectious process. That
tolls are involved in development supports this suggestion. A few
endogenous ligands for PRRs have been identified so far. The mannose
receptor and the scavenger receptors are good examples of receptors
that recognize exogenous and endogenous ligands [96
,
120
].
The investigation of innate and adaptive responses to grafts raises
several issues about these models for regulation of costimulation and
adaptive immunity. First, xenogeneic mammalian cells, which are neither
pathogens nor tissue that has been experienced through evolution,
except perhaps as self, stimulate innate immunity. Second and related,
adaptive responses to grafts occur in the absence of pathogens,
implying that innate immunity is stimulated by nonpathogenic ligands or
that costimulation from innate immunity is not required. It is unclear
how innate recognition of xenografts fits with the view that the ligand
specificity of the innate system developed through pressure from
pathogens or with the danger theory, suggesting that innate immunity
evolved to recognize endogenous stress or damage signals. Matzinger
[118
] has suggested that the transplantation response
fits better with the danger model—the source of danger being the
surgical procedures that result in tissue damage and ischaemic cell
death. This is supported by findings that the reduced survival of liver
allografts from cadaver donors compared with living donors is linked to
the occurrence of stressed and ischaemic cells that activate components
of the innate immune system (reviewed in ref. [110
]).
Various studies are described that demonstrate stimulation of NK cells,
complement, and other innate components by ischaemic mammalian tissues.
In conflict, however, are findings using various transplant models. The
i.p. model of transplantation does not involve surgical trauma (just a
simple injection), such that there is no obvious danger signal. It is
also hard to envisage the presence of a danger signal when transplants
are rejected upon withdrawal of immunosuppression. Clear evidence of
transplant tolerance after withdrawal of immunosuppression is lacking,
and in most cases, this leads to T-cell-mediated rejection in humans
(reviewed in refs. [121
122
123
]). Further, the danger
model does not explain why xenogeneic cells induce greater innate
stimulation compared with allogeneic cells, unless the xenogeneic cells
in some way undergo more necrotic death or damage host cells. The
disparity between xenogeneic and allogeneic cell recognition supports
the idea that the innate system recognizes a degree of foreignness.
Perhaps there is some overlap between pathogenic and foreign mammalian
molecules. Finally, it must be noted that stimulation of an effective,
adaptive response to transplanted tissue may occur in the absence of
innate immune activation such that neither damage nor pattern
recognition is required. As discussed in detail elsewhere (reviewed in
ref. [60
]), T-cell responses to grafts may be less
dependent on costimulatory signals as a result of the unusual situation
of direct presentation of an enormous array of graft-derived
self-peptides by graft APCs. It would be interesting to examine graft
rejection in models in which innate recognition is impaired, such as in
MyD88 or TLR knockout mice.
In summary, there are several ways in which responses to grafts could
occur in the absence of pathogens. Innate immunity may be stimulated by
foreign (exogenous), graft-associated ligands, perhaps because they
resemble pathogen-associated molecules; innate immunity may be
stimulated by endogenous danger signals induced by the transplantation
procedure or in the case of xenografts by toxic substances released by
nonphysiologic cells; or innate costimulation may not be required for
transplant responses.
|
CONCLUDING REMARKS
|
|---|
It has now been demonstrated in various ways that foreign
mammalian tissues can stimulate innate immunity. Stimulation may be
greatest with the most disparate tissues but can also occur with
self-tissues if they are placed in a nonphysiologic environment.
Although there is no doubt that innate immune receptors recognize
pathogenic molecules, these findings inspire questions regarding the
confines and evolution of ligand recognition. Further work is required
to identify the molecules that stimulate the innate response to
mammalian tissues and determine whether they are endogenous, exogenous,
or a combination of both. Innate responses to grafts appear to
stimulate T-cell infiltration and may promote other aspects of the
adaptive response. This is supported by the increased severity of the
rejection response to grafts that induce a greater innate response. The
interdependent nature of innate and adaptive immunity is also
demonstrated, and adaptive immunity is emerging as an important
feedback regulator of innate effector mechanisms. Therefore, therapies
that target elements of innate immunity should be investigated as a
means of enhancing graft survival.
Received August 7, 2001;
revised December 10, 2001;
accepted December 10, 2001.
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