Allorecognition and the alloresponse: clinical implications.

Abstract

The artificial transfer of tissues or cells between genetically diverse individuals elicits an immune response that is adaptive and specific. This response is orchestrated by T lymphocytes that are recognizing, amongst others, major histocompatibility complex (MHC) molecules expressed on the surface of the transferred cells. Three pathways of recognition are described: direct, indirect and semi-direct. The sets of antigens that are recognized in this setting are also discussed, namely, MHC protein products, the MHC class I-related chain (MIC) system, minor histocompatibility antigens and natural killer cell receptor ligands. The end product of the effector responses are hyperacute, acute and chronic rejection. Special circumstances surround the situation of pregnancy and bone marrow transplantation because in the latter, the transferred cells are the ones originating the immune response, not the host. As the understanding of these processes improves, the ability to generate clinically viable immunotherapies will increase.

Full text

Page 1

Tissue Antigens ISSN 0001-2815
REVIEW ARTICLE
Allorecognition and the alloresponse: clinical implications
B. Afzali, R. I. Lechler & M. P. Hernandez-Fuentes
Department of Nephrology and Transplantation, King’s College London, Guy’s Hospital Campus, London, UK
Key words
allorecognition; alloresponses; major
histocompatibility complex; minor
histocompatibility antigens; rejection;
T lymphocytes; transplantation
Correspondence
Professor Robert I Lechler, PhD, FRCP,
FRCPath, FMed Sci
Immunoregulation Laboratory,
King’s College London
5th Floor, Thomas Guy House
Guy’s Hospital
London SE1 9RT
UK
Tel: 144 (0)20 7188 7672
Fax: 144 (0)20 7188 7675
e-mail: robert.lechler@kcl.ac.uk
Received 5 March 2007; accepted
5 March 2007
doi: 10.1111/j.1399-0039.2007.00834.x
Abstract
Theartificialtransferoftissuesorcellsbetweengeneticallydiverseindividualselicits
an immune response that is adaptive and specific. This response is orchestrated by
T lymphocytes that are recognizing, amongst others, major histocompatibility
complex (MHC) molecules expressed on the surface of the transferred cells. Three
pathways of recognition are described: direct, indirect and semi-direct. The sets of
antigensthatarerecognizedinthissettingarealsodiscussed,namely,MHCprotein
products, the MHC class I-related chain (MIC) system, minor histocompatibility
antigens and natural killer cell receptor ligands. The end product of the effector
responses are hyperacute, acute and chronic rejection. Special circumstances
surround the situation of pregnancy and bone marrow transplantation because in
thelatter,thetransferredcellsaretheonesoriginatingtheimmuneresponse,notthe
host. As the understanding of these processes improves, the ability to generate
clinically viable immunotherapies will increase.
Introduction
The complexity of multicellular organisms requires the
ability to recognize multiple different tissues each express-
ing many dissimilar genes as components of self while
maintaining the ability to eliminate foreign proteins such as
invading microorganisms. ‘Self-compatible’ tissues are re-
cognizedbytheexpressionofaseriesof‘histocompatibility’
antigens (major and minor) that engage a specific receptor
complex found on cells of the immune system [e.g. the
mammalian T-cell receptor (TCR)]. That this mechanism
provides adequate self-non-self discrimination in even very
primitivelifeforms(1)butisadaptedinhigherorganismsto
also provide immunity against environmental pathogens is
an example of how the immune system has evolved under
pressure from external challenges (2). The primacy of re-
cognizing tissues of disparate individuals within the same
species is supported by the much higher frequency of T-cell
reactivity against alloantigens (3) than other conventional
antigens (in this case keyhole limpet haemocyanin) (4).
Transplantation is the artificial transfer of cells, tissues
or organs from one individual to another. Where the graft
is syngeneic (genetically identical to the host, e.g. trans-
plantation between identical twins) or autologous (a trans-
plant from one individual into itself such as using stored
blood for autotransfusion), there is perfect histocompati-
bility and no significant immune response is elicited. In this
situation, therecipient is fully tolerant tothetransplant and
accepts it without a rejection phenomenon. Where there is
histoincompatibility, however, in general an immune re-
sponseiselicitedagainsttheforeignantigens,themagnitude
of which determines acceptance or rejection of the trans-
planted tissues. The reaction can be either an ‘alloresponse’
(if the transfer occurs between two genetically disparate
individuals of the same species) or a ‘xenoresponse’ (if the
transplant is cross-species) depending on the nature of the
donor and recipient, the target antigens being referred to as
alloantigens and xenoantigens respectively. T lymphocytes
occupy a central role in the rejection response to allogeneic
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
545

Page 2

tissues,withdepletionorsuppressionoftheirfunctionbeing
instrumental in the prolongation of transplant survival.
Immunological memory and specificity, hallmarks of T-cell
involvement, are both features of allograft rejection as
re-exposure to the same alloantigens (re-transplant from
the same or genetically identical donor) elicits an acceler-
atedandheightenedimmuneresponse(secondsetrejection)
than on first encounter (first set rejection), whereas re-
transplantation from a third party (unrelated) donor shows
only first set rejection.
The response to transplanted tissues follows a two-step
process which will be the subject of this review. ‘Allorecog-
nition’ is the term used to describe the recognition of
transplanted allogeneic tissues by the host, while ‘allores-
ponse’ denotes the effector mechanisms recruited in the re-
action totheforeigntissue andtheoutcomeofthoseeffects.
These definitions should be accepted with one caveat,
namely that experimental systems often use a clinical end-
point (graft rejection or survival) as the readout and do not
dissect out the relative contributions of allorecognition and
alloresponse to the endpoint. Nevertheless, an understand-
ing of these mechanisms may be critical to the development
of targets for therapy and translation from the laboratory
to the bedside. In addition, another important concept
needs to be borne in mind, namely that there is a signifi-
cant difference between ‘antigenicity’ (i.e. a foreign peptide
capable of eliciting immunological recognition) and ‘immu-
nogenicity’ (i.e. a foreign peptide capable of eliciting an
immune response). This distinction is the basis of the clinic-
ally applicable therapies that are enabled by anunderstand-
ing of allorecognition and alloresponses.
Allorecognition
Alloantigens can be divided into major histocompatibility
complex (MHC) and minor histocompatibility antigens
(mHAg), the former, divided into class I and class II mole-
cules, responsible for eliciting the strongest immune re-
sponses to allogeneic tissues. Thymic development of
T lymphocytes involves selective survival of thymocytes
(mediated by survival signals) capable of recognizing self-
MHC molecules. As a result, the mature T-cell repertoire is
biased towards recognition of foreign peptides associated
withself-MHCmoleculesasopposedtothoseassociatedwith
non-selfMHC,whiletheresponsetoallogeneicMHCislikely
to be as a result of cross-reactivity with allogeneic peptide-
bound MHC molecules (i.e. Allo 1 X ¼ Self 1 Y) (5).
Allorecognition can proceed via several mechanisms
(Figure 1): direct allorecognition, whereby T cells recognize
determinantsontheintactdonorMHCmoleculesdisplayed
on the surface of transplanted cells (6), indirect allorecog-
nition in which donor MHC molecules are processed and
presented as peptides by self-MHC molecules (in a similar
fashion to conventional antigen processing) (7) and
a recently described third mechanism termed semi-direct
allorecognition where trafficking recipient dendritic cells
(DC) acquire intact donor MHC:peptide complexes from
cells of the graft enabling them to then be able to stimulate
antigen-specific immune responses (8).
Direct allorecognition
Direct allorecognition was long believed to be the only
mechanism by which allogeneic antigens could be recog-
nized in the donor graft (Figure 1A). When measured, this
response to allogeneic MHC molecules is of high fre-
quency (9). Two non-mutually exclusive theories regarding
the molecular mechanisms of this high frequency have
been proposed, namely the ‘high determinant density’ and
‘multiple binary complex’ models which differ in the im-
portance they allot to the presence of peptide in the allo-
geneic MHC–peptide complex.
In the former, it has been proposed that alloreactive
Tcellsaredirectlyabletorecognizetheexposedpolymorphic
residues on allogeneic MHC, thus consigning the bound
peptidetosecondaryimportance.Thismodelpredictsthatif
every MHC molecule on a cell surface can serve as a ligand
for an allospecific T cell then the antigen density on the
cell surface would be extremely high, in marked contrast
with the density of a specific peptide plus MHC. The high
ligand density available for stimulating alloreactive T cells
implies that receptors of much lower affinities would be
able to respond to the foreign MHC, leading to a high
frequency of alloreactivity. This hypothesis is supported by
demonstration that blocking the TCR-contacting regions
of allo-MHC using synthetic peptides (10) or site-specific
mutations inhibits specific alloresponses (11), presumably
through inhibition of TCR–MHC contact (12). Addition-
ally, alloreactivity in the absence of peptide has previously
been shown (13).
The multiple binary complex model proposes that
recognition of peptide bound by allogeneic MHC is of
primary importance to direct allorecognition in a manner
akin to conventional self-restricted responses (14). Multiple
different bound peptides, in combination with one alloge-
neic MHC gene product, may produce determinants re-
cognized by different cross-reactive T cells. Although the
peptide is likely to be naturally processed and derived from
a serum or cellular protein, the set of peptides bound by an
allogeneic MHC molecule is often substantially different
from that bound by the self-MHC homologue because of
sequence variation in the peptide-binding groove. This
model predicts that if each bound peptide is an essential
component of the determinant recognized by alloreactive
T cells, each peptide–allo-MHC complex will be recognized
by a different alloreactive T cell and a single MHC in-
compatibility can stimulate a wide diversity of T cells. This
hypothesis is supported by the mutant-transfected T2-I-Ab
Allorecognition and the alloresponse
B. Afzali et al.
546
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556

Page 3

cell line that is unable to process antigen and is incapable of
stimulating allospecific responses and in which transfection
with stable peptide–MHC class II complex restores the
ability to stimulate alloresponses (15). Similarly, alloreac-
tive CD81T cells have been shown to be specific for a self-
peptide presented by foreign class I molecules, with no
evidence of peptide-independent components (3). Further-
more,displacementofendogenouspeptidesfromallogeneic
antigen-presenting cells (APCs) by incubation with exoge-
nous peptides leads to loss of allorecognition by allospecific
T cells (16). Another study looked at the peptide-complex
recognition ability of 12 cytotoxic allogeneic T-cell clones
and for all of them the allorecognition was peptide specific
whether the allogeneic MHC molecules were expressed on
normal cells or antigen-processing-deficient cells (13).
The vigorous nature of the direct alloresponse and its
immediacy in comparison with the indirect pathway (see
below) is the result of direct recognition of intact MHC by
T cells without the need for processing and presentation by
self-MHC. Mechanistically, it is likely that direct allor-
ecognition can proceed via both mechanisms discussed
above, the overall contribution of each being related to the
site and magnitude of the differences in MHC molecules
between responder and stimulator cells. Specifically, where
Figure 1 Direct,indirectandsemi-directpathwaysofallorecognition.(A)Directpathway.Recognitionofintactforeignmajorhistocompatibilitycomplex
(MHC) on donor antigen-presenting cell (APC) primes CD4 and CD81recipient T cells. CD41cells then provide T-cell help for the effector function of
CD81cells. (B) Indirect pathway. The indirect pathway involvespresentation of processed allogeneic MHC shed from foreign cells through cell necrosis
andapoptosis.RecipientAPCspresenttheprocessedpeptidesinthecontextofself-MHCclassIItoMHCclassIIrestrictedCD41Tcells.(C)Semi-direct
pathway.Cell-to-cellcontactbetweendonorandrecipientAPCmaytransferintactmembranecomponentsincludingintactallo-MHC(a).Likewise,donor
APC can release small vesicles, known as ‘endosomes’ containing intact MHC (b), which fuse with the membrane of recipient APCs (c). The recipient
APC,now chimaericforMHC, stimulatedirectpathwayCD4andCD8responsesthroughintactforeignMHCandindirectresponsesthroughprocessing
and presentation of peptides of foreign MHC acquired from necrotic and apoptotic cell material. Given that the same APC stimulates both CD4 and CD8
cells, linked help can occur.
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
547
B. Afzali et al.
Allorecognition and the alloresponse

Page 4

the allogeneic MHC is structurally very disparate from
responder MHC, the alloresponse may be directed against
residues on the MHC itself (high determinant density
pattern of recognition), whereas where self and foreign
MHC are closely matched, the focus of the alloreactivity
may be directed towards epitopes of endogenous peptides
thataredisplayedbystimulatorbutnotbyresponderMHC
molecules (multiple binary complex pattern) (17).
Indirect allorecognition
The indirect pathway refers to the recognition of processed
peptides of allogeneic histocompatibility antigen presented
by self-MHC (7) and therefore differs from the direct
pathway by the requirement for antigen processing (Fig-
ure 1B). There is considerable evidence for the involvement
of this pathway in graft rejection (18) including studies of
human recipients of heart, kidney and liver allografts with
in vitro detection of indirect response showing a strong
correlation with episodes of clinical rejection (19).
Alloantigens shed from a graft are, in general, processed
as exogenous antigens and therefore presented by APCs in
association with self-MHC class II. Therefore, the response
to alloantigen presented by the indirect pathway is domi-
nated by CD41T cells. While there is considerable ampli-
fication of the rejection response through the generation of
multiple epitopes via processing of alloantigens, the natural
corollary is that responses to the indirect pathway are
comparatively slower compared with those to the direct
pathway. It is also likely that the indirect response is re-
sponsible for long-term responses to engrafted tissues once
passenger (donor) APC, and by inference direct responses,
are exhausted.
The importance of the indirect pathway is suggested by
demonstrationsthatimmunizationofanimalswithpeptides
of allogeneic MHC (by definition able to elicit only indirect
rather than direct responses) results in vigorous allograft
rejection (20), whereas intrathymic injection of similar
peptides down-modulates the indirect response sufficiently
to prolonged survival of subsequent allografts of the same
MHC type (21). Similarly, in the antibody response to
transplanted tissues, B-cell function is dependent on T-cell
help from CD41T cells stimulated through the indirect,
rather than the direct response (22).
Semi-direct allorecognition
Recently, a number of publications have shown that intact
cell surface molecules, including MHC, can be transferred
betweencellsoftheimmunesystemandthatMHC-recipient
cells becomeabletostimulate T-cellresponsesasaresult (8)
(Figure 1C). Although the mechanism of this transfer is
likely to involve cell-to-cell contact (23), other mechanisms
such asreleaseanduptakeofsmallvesicles (exosomes)have
also been implicated (24).
Traditional descriptions of cross-talk between the direct
and indirect pathways (e.g. that indirect pathway CD41
TcellscanbothamplifyanddiminishdirectpathwayCD81
T-cellresponses)(25,26)havereliedonafour-cell,unlinked
model, whereby CD81T cells are stimulated through the
direct pathway by donor cells, while helper or regulatory
CD41T cells are recruited through interaction with recipi-
ent DC presenting allogeneic MHC through the indirect
pathway.
The description of MHC transfer helps to resolve the
paradox that the four-cell hypothesis is non-compliant
withthedogmathatCD4andCD8Tcellsarerecruited(and
linked) by the same APC by proposing an alternative
method of alloantigen presentation. This ‘semi-direct’
pathway of allorecognition (27), whereby recipient APCs
acquire allogeneic MHC:peptide complex through MHC
transfer (and stimulate CD81T cells through the direct
pathway) as well as peptides of allogeneic histocom-
patibility antigens (which are processed and recruit CD41
T cells through the indirect pathway) links direct and
indirect allorecognition through a single APC and also
provides a mechanism for the observed cross-talk between
them.
It is also a possibility that molecular transfer of MHC
in comparison with antigen processing may lead to a more
faithful delivery of allogeneic antigens to lymph node
resident T cells. Although there is no direct evidence in
supportofthis,CD41TcellsacquiringMHCbymembrane
transfer are capable of both stimulating and inhibiting
autologous CD4 cells responses in the same manner as
‘professional’ APCs (28). Therefore. the semi-direct path-
way of allorecognition may have implications for the regu-
lation of responses to allogeneic tissues.
Relative contribution of the direct, indirect and
semi-direct pathways to allorecognition
The presence of passenger APC in donor tissues at the time
of transplantation dictates that the direct anti-donor allo-
response is vigorous in the early period post-engraftment
and diminishes with the death and removal of these APCs
over time. The indirect alloresponse, on the contrary,
requiring antigen capture and processing, is less rapid than
the direct pathway but continues for the life of the graft as
graft-derived antigens are continuously acquired and
processed.Asaratioofalloresponsiveness, therefore,direct
allorecognition predominates in the early post-transplant
period,whiletheindirectpathwaybecomesmoreprominent
with time. Of clinical relevance is the observation that
rejectionoftransplantedtissuesismorecommonlyobserved
in the early post-engraftment period (usually the first 6
months), while tolerance to grafts develop at a later time
point. This correlates with demonstrations that regulatory
CD41CD25hiT cells that can mediate transplant tolerance
548
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
Allorecognition and the alloresponse
B. Afzali et al.

Page 5

have indirect rather than direct pathway alloreactivity (29).
The relative contribution of the semi-direct pathway to
clinical rejection is as yet unknown.
Histocompatibility antigens
MHC protein products
The protein products of MHC molecules, expressed on the
surfaceofallnucleatedcells,areresponsiblefortheimmune
response to allogeneic tissues. Of all the genes included
in this region, two highly variable groups are central in
allorecognition. These are the class I and class II molecules.
Class I molecules are known as human leukocyte antigens
(HLA)-A, -B and -C in humans and H2-K, -D, -L in mice
and are constitutively expressed on most nucleated cells.
Class II molecules are known as HLA-DR, -DP and -DQ in
humans and H2-A and -E in mice and are constitutively
expressed only by bone marrow-derived APCs, such as
macrophages, DC, B lymphocytes and by thymic epithelial
cells. The convention is to identify the genes in Roman
letters (e.g. HLA-DRB or H2-D) and the encoded proteins
in corresponding Greek symbols (e.g. HLA-DR bor H2-
Ab) (Figure 2).
The MHC contains the most variable functional genes
described in vertebrates. At three of the more variable
human MHC loci, HLA-A, HLA-B and HLA-DRB1, 243,
499 and 321 alleles have been resolved worldwide, re-
spectively, and nucleotide diversity in the human MHC is
up to two orders of magnitude higher than the genomic
average (30). This polymorphism underlies the extreme
difficulty in finding perfectly matched organs or unrelated
bone marrow donors that will not induce a strong anti-
MHC alloresponse. MHC genes are inherited from the
parents as a whole set or haplotype, and because each
individual has two sets of chromosomes, one haplotype
will come from the mother and the other from the
father.
Thesemoleculesplayacritical roleinthenormalimmune
system, namely the presentation of peptides in a form that
can be recognized by T cells. In particular, CD81T cells
recognizepeptidespresentedbyclassImoleculesandCD41
T cells recognize those presented by class II molecules and
this is valid both for the self-MHC molecules as well as
the allo-MHC molecules. From the crystal structures of
the extracellular portions of human class I and class II
molecules, it is now clear that the MHC molecules form
a ‘groove’ where the peptide to be presented is bound (31).
The peptides presented are the result of the natural
processing of cellular and serum proteins. The peptide-
binding groove of the MHC molecules on each cell is thus
occupiedbyaverydiverse(severalhundreds)setofdifferent
peptides. Class I molecules are mainly occupied by peptides
originating from intracellular proteins, whereas those pre-
sented by class II molecules have mainly an extracellular
origin (32); although cross-presentation of peptides of ex-
tracellular origin has been widely demonstrated in class I
molecules (33). It has been confirmed that the TCR re-
cognizes a complex of two MHC helixes and a bound
peptide. In the allorecognition setting in a direct pathway
response, these MHC–peptide complexes recognized are
from the allogeneic tissue. Recently, it has been shown that
complementarity-determining region (CDR) 3a could
undergo rearrangements to adapt to structurally different
peptideresidues.ThisCDR3loopflexibilityhelpstoexplain
TCR binding cross-reactivity and thus supports the
conundrum of T cells responding to MHC molecules that
they have not been selected to recognize (34).
The MHC class I-related chain (MIC) system
In 1994, two new polymorphic families of MHC class I-
related genes, termed MHC class I-related chain A (MICA)
and B (MICB), were described (35). These genes are located
near the HLA-B locus on chromosome 6 and encode cell
surface glycoproteins that do not associate with b-2 micro-
globulin. These molecules function as restriction elements
for intestinal g/dT cells and they behave as cell stress
molecules. MICA is expressed in endothelial cells, kerati-
nocytes and monocytes, but not in CD41, CD81or CD191
lymphocytes (36). It is, therefore, likely that the poly-
morphic MICA molecule may be a target for specific
antibodiesandTcellsinsolidorgangraftsoringraftvshost
disease (GvHD) (37). The anti-MICA antibodies induce
a prothrombotic state, characterized by a loss of surface
heparan sulphate and thrombomodulin from cultivated
endothelial cells (38). In fact, in kidney transplants, two
prospective trials, after 1 and 4 years, have provided strong
evidence that HLA and MICA antibodies are associated
with graft failure (39).
Figure 2 The major histocompatibility complex (MHC) in mice and
humans. MHC genes are encoded on chromosomes 6 and 17 in humans
in humans and mice, respectively.
Adapted from http://pathmicro.med.sc.edu/ghaffar/mhc2000.htm
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
549
B. Afzali et al.
Allorecognition and the alloresponse

Page 6

Minor histocompatibility antigens
A different set of polymorphic non-MHC proteins have
been identified that are important in provoking transplant
rejection, they were defined by Snell and colleagues as
mHAg, as the rejection reactions they induced in mice were
slower (40). In principle, any protein that has polymor-
phisms within a species can become mHAg. Peptides from
these proteins are presented to T cells in an MHC class I or
class II restricted manner (41). The number of possible
mHAgs in transplants performed between genetically
unrelated, MHC-matched individuals, is very large. How-
ever, the reactions seem to be restricted to a few epitopes,
thus dubbed immunodominant (41). The molecular basis
for this phenomenon is incompletely understood, although
it has recently been shown that both the duration of
individual mHAg presentation and the avidity of T-cell
antigenrecognitioninfluencethemagnitudeofthecytotoxic
response that ensues (42).
The frequency of T cells responding to these antigens in
non-transplanted individuals is very small and can only be
measured in vitro after in vivo immunization or repeated
stimulations,asopposedtodirectpathwayresponses.When
alloresponses of mHAgs have been measured, the cells that
respond to these antigens are generally CD81T cells,
implyingthatmostmHAgsarepeptidesboundtoself-MHC
class I molecules. However, peptides bound to self-MHC
class II molecules can also participate in the response to
MHC-identical grafts (43). The in vivo correlate of an
immune response to an mHAg is transplant rejection, or
inMHC-matchedindividuals,GvHD(44).GvHDisaseries
of manifestations and symptoms that appear after bone
marrow transplantation (BMT) and results from an im-
mune response of the immunocompetent cells of the donor
against the tissues of the recipient. The effector immune
responses are specifically described later on. Notably, even
though mHAgs are named minor, and the frequency of
responders to these antigens is very low, after transplanta-
tion, a single immunodominant mHAg can induce GvHD.
Apart from gene polymorphisms, homozygous gene dele-
tions can also serve as mHAgs as it has recently been
described for an autosomal gene in the UDP-glycosyltrans-
ferase 2 family (45).
Minor HLA antigens important in transplantation have
been described from different cellular origins.
(a) Encoded by sex chromosomes: The most thoroughly
studied are a set of proteins encoded on the male-specific Y
chromosome that are known collectively as H-Y antigens.
The absence of Y-chromosome-specific gene products in
females induces responses to male antigens. In fact, these
responses are very frequent (37–50%) in women with
previous male pregnancies (46), whereas male anti-female
responses are not seen (because both males and females
express X-chromosome-derived genes). To date, the number
of H-Y epitopes described in humans that are important in
transplantationis10(47).Thesearerestrictedbyeitherclass
IorclassIImoleculesandoriginateinsixdifferentlociofthe
Y chromosome (DFFRY, SMCY, TMSB4Y, UTY, DBY
and RPS4Y1).
(b) Encoded by autosomes: Non-Y-linked mHAgs have
also been shown by T cells from patients with GvHD after
BMT between HLA identical individuals. The first example
identified in humans was named ‘HA’ (48) after the patient.
Recognition of this peptide was restricted by class I
molecules. In the interim, other antigens have been
identified for humans (HA-1, -2, -3, -8, HB-1, ACC-1,
etc.); their cellular origin is varied: Mysoin 1G, LBC
oncogen, BCL2A1, and some not yet identified genes (47)
are examples.
(c)Encoded bymitochondrial DNA (mtDNA): Tracking
of an mHAg to the small mitochondrial genome from the
studies of a maternally transmitted transplantation antigen
informed that such peptides could become histocompati-
bility antigens (49). Cytotoxic T lymphocytes (CTL) were
used to test candidate peptides derived from polymorphic
regions of the enzyme mt-ND1. A simple amino acid dif-
ference in the peptide was found to account for immuno-
genicity. Subsequently, additional mitochondrial genes in
mouseandrat havebeenfoundtoencodemH peptides, and
severalarepresentedtoTcellsbynon-classical,MHCclassI
molecules (50). In the humans, however, no effect was
observed on cumulative disease-free survival or incidence
rate of GvHD when the clinical effect of mtDNA
mismatches was studied in a Japanese cohort (51).
Natural killer-cell-mediated allorecognition
Recent genetic studies have established that the killer cell
immunoglobulin-like receptor (KIR) genomic region dis-
plays extensive diversity through variation in gene content
and allelic polymorphism within individual KIR genes. It is
shown by family segregation analysis, genomic sequencing
and gene order determination that genomic diversity by
gene content alone gives rise to more than 20 different KIR
haplotypes and at least 40–50 KIR genotypes (52). The
importance of this recognition stems from the fact that in
the clinical setting of mismatched hematopoietic stem cell
transplantation, donor vs recipient natural killer (NK) cell
alloreactivity has been associated with better outcome (53).
This alloreactivity derives from a mismatch between
inhibitory receptors for self-MHC class I molecules on
donor NK clones and the MHC class I ligands on recipient
cells. NK-cell function is regulated by clonally distributed
inhibitory receptors that are specific for self-MHC class I
molecules. Lack of engagement of these receptors results in
target cell lysis (missing self-recognition), which has the
potential to eliminate the remaining malignant recipient-
originated cells (54). The role of NK-cell alloreactivity in
550
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
Allorecognition and the alloresponse
B. Afzali et al.

Page 7

solid organ transplantation is less known. Results in animal
models show that NK cells are neither necessary nor suf-
ficient for acute immune rejection – which does not exclude
an NK-cell contribution to the rejection process (55).
The alloresponse
When an alloantigen that is both antigenic and immuno-
genic is recognized by any of the pathways mentioned
above, the resulting effector arm of the immune system is
termed the alloresponse. In such a response, the innate and
adaptive immune systems function synergistically to reject
the allograft through non-exclusive pathways: including
contact-dependent T-cell cytotoxicity, granulocyte activa-
tion by either T helper 1 (Th1)- or Th2-derived cytokines,
NK-cell activation, alloantibody production and comple-
ment activation.
Grafted tissue destruction is achieved through different
mechanisms: (i) direct cytotoxicity exerted by CD41or
CD81T cells that are recognizing donor MHC molecules
through the direct pathway, (ii) macrophage-mediated
delayed type hypersensitivity stimulated by CD41and
CD81T cells that have been activated through the direct or
the indirect pathway and (iii) complement activation or
antibody-dependent cytotoxicity of grafted cells opsonized
by allogeneic antibodies (56). The important role of these
alloantibodies in mediating rejection has been emphasized
by Terasaki (57). Of note, the presence of anti-donor
antibodiesimpliesthatB-celltoT-cellcross-talkinresponse
to alloantigens has occurred; this by definition should have
occurred via the indirect pathway. Namely, B cells re-
cognizing antigen via their B-cell receptor have internalized
it, processed it to peptides that have then been presented in
thecontextof self-MHCtoTcells,whichhaveprovidedhelp
for B-cell effector function and antibody class switching.
In terms of T-cell polarized effector responses, both Th1
and Th2 responses can result in rejection responses, par-
ticularlyinthehumansetting(56).Theroleofinterleukin17
(IL-17) and transplant rejection is yet to be elucidated (58).
This combined cellular and molecular response is
reflected in vivo by different manifestations. The following
descriptions have been extensively studied for kidney grafts
because of availability of biopsy material from engrafted
tissue, but the features apply to all solid organ transplants.
Hyperacute rejection
This is the term applied to very early graft loss, usually
within the first 48 h. It occurs when preformed antibodies
are present in the recipient’s serum, specific for donor
antigens expressed on graft vascular endothelial cells. Such
antibodies fall into two main categories: low affinity
immunoglobulin M (IgM) antibodies, which are specific
for ABO blood group antigens and high affinity IgG
antibodies directed against HLA antigens. The binding of
these antibodies to their targets triggers activation of
clotting, complement and kinin cascades leading to intra-
vascular thrombosis, ischaemia and subsequent necrosis.
Previously, ABO blood matching in solid organ trans-
plantation was mandatory between donor and recipient.
However, recently, protocols to overcome the humoral
response have been developed (including pretransplanta-
tion plasmaphoresis) and experience in transplanting into
presensitized recipients is being obtained (59). Natural
antibodies exist in humans against the Galactose-a-1-3-
galactose epitope present in all other mammals and
constitute one of the major impediments to successful
xenotransplantation (60). The generation of Gal-deficient
pigs has overcome hyperacute anti-Gal-mediated xenograft
rejection in nonhuman primates. However, non-Gal anti-
porcine natural antibodies still represent a potentially rele-
vant immunological hurdle in a subgroup of individuals by
inducing endothelial damage in xenografts (61). The second
group of antibodies consists of high affinity IgG antibodies
directed against donor HLA antigens. As already men-
tioned, the existence of anti-MHC alloantibodies indicates
indirectpathwayT-cellsensitization.Theseusuallyoccuras
a result of previous immunization, by blood transfusions,
pregnancies or failed allografts. They also occur in 1% of
the population for no obvious reason (62). A full immu-
nological evaluation withABO blood group determination,
HLA typing, screening for antibody to HLA phenotypes
and cross-matching need to be gathered before trans-
plantationtoavoidantibody-mediatedhyperacuterejection
or to proceed with specific protocols in highly sensitized or
in positive T-cell cross-match patients (63).
Acute rejection
In the absence of any preformed antibodies, solid organ
grafts can still be rejected after a few days. In the clinical
setting, with the presence of pharmacological immunosup-
pression, this form of rejection usually occurs between
5 days and 3 months after transplantation. Histological
findings in acute rejection (AR) generally show a diffuse
interstitial cellular infiltrate composed of both CD41and
CD81T cells, where the picture is dominated by CD81T
cells with an activated or memory, CD45RO1, phenotype
(64). Whereas, for other forms of AR, such as vascular re-
jection, the infiltrating cells found in the intimal arteritis
lesions of the biopsies are predominantly macrophages and
T cells are in the minority (65). Recently, the specific
transcriptional activity of the infiltrating cells has been
associated with clinically significant acute cellular rejection
to differentiate it from other forms of lymphocytic in-
filtrates (66). In some animal models, it is notable that both
CD41T-cell and CD81T-cell populations can reject solid
organallograftsindependently,whileinothersthereissome
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
551
B. Afzali et al.
Allorecognition and the alloresponse

Page 8

evidence that CD41cells are an absolute requirement (67).
In the clinical setting, it is likely that both cell subtypes are
involved in the rejection process. In summary, it appears
that the AR process is a complex event composed of many
effector cells including CD41T cells, CD81T cells and
macrophages.
Chronic rejection
This term was used in the initial years to describe slow late
deterioration of graft function. Recently, the term is limited
to mean late graft loss caused by a host-anti-graft immune
response(68).Severalfactorscontributetothepathogenesis
of late graft loss. To better understand the mechanisms
involved in this process, the terminology is being redefined.
The array of changes found in biopsies of grafts with
progressive dysfunction is referred to as chronic allograft
nephropathy. This is characterized by chronic interstitial
fibrosis, tubular atrophy, vascular occlusive changes and
glomerulopathy (69).
Despite limiting the term chronic rejection (CR) to
describe the immune-mediated chronic changes present in
late graft dysfunction, there are disagreements about the
histological changes that constitute CR. The Banff criteria
include extension of interstitial fibrosis, tubular atrophy,
mesangial matrix increase, chronic glomerular changes
(presence of ‘double contours’ in capillary loops thought
to be secondary to basement membrane duplication) and
chronic vascular changes. Several authors agree that the
vascular features of CR are disruption of the elastic lamina,
the presence of inflammatory cells in the intima (endothe-
lialitis) and fibrous intimal thickening because of pro-
liferation of myofibroblasts (70). Other authors claim that
thespecificchangesrelatedtoimmune-relatedresponsesare
endothelialitis, tubulitis and complement (C4d) deposition
inperitubularcapillaries(68).Othersarguethatthevascular
changes are the primary immunological insult and the
parenchymal fibrosis changes are secondary to the ischae-
mia(71).ThereiscommonconsentthatthedetectionofC4d
deposits in the presence of donor-specific alloantibodies in
thecirculation implyaB-cell involvementin CR(68). These
andotherfindingssuggestthatantibody-mediatedrejection
is important in graft failure (57). In fact, in recipients of
renal, cardiac and lung allografts, the development of anti-
HLA antibodies is linked to the development of CR (72).
Although common consent has not yet been reached
concerning the histology of CR, it is clear that there are
risk factors linking chronic transplant dysfunction and the
anti-donor immune response.
The damage sustained to an allograft is therefore the
result of a complex process; it usually does not represent
asingleentitybutthesummatedeffectsoftissueinjuryfrom
several pathogenic insults and the graft’s healing response,
modified by alloimmunity and immunosuppression. A
mixed histological picture is thus common with several
drivers of tissue damage and fibrosis often operating
simultaneously (73). Additionally, the processes underlying
CR can develop very early, in fact in kidney transplants it
has been described to appear as early as 3 months post-
transplantation (70).
Special considerations
There are several circumstances that pose specific problems
for alloresponsiveness. Pregnancy, for instance, carries a
significant alloantigenchallenge as50% offoetal histocom-
patibilityantigensarepaternallyderived(theyareantigenic)
and should elicit a rejection response. Nevertheless, in con-
trast to partially matched transplanted allografts, tolerance
rather than rejection develops to the foetal tissues (i.e. these
tissues are not fully immunogenic) (74). Foetal attempts to
evade the maternal immune response [by diversion of
expression of histocompatibility antigens from classical
forms(e.g.HLA-AandHLA-B)towardsnon-classicalforms
(such as HLA-E, HLA-F and HLA-G) on cells of the
trophoblast (75)] are only partially successful as T cells
alloreactive to paternal antigens persist throughout preg-
nancy (74). The relative immunological privilege that is
affordedtothedevelopingfoetusinspiteofthisistheresultof
cooperation between the maternal and foetal immune
systems and are characterized by a number of mechanisms
which are reviewed in Hunt (76). Briefly, production of inhi-
bitory factors, either soluble [e.g. IL-10 (77), transforming
growth factor-b (TGF-b) (78) and indoleamine 2,3-dioxy-
genase (IDO) (79)] or cell-bound [e.g. programmed death
ligand-1 (PDL-1) (80) and FasL (81)] as well as a significant
increase in the proportion of CD41CD251Tregs, both
locally (uterine) and systemically (spleen and lymph node)
(82), enhance tolerance towards paternally derived alloanti-
gens during pregnancy. Indeed, the role of Tregs cannot be
underestimated as Treg deficiency leads to termination of
pregnancy between genetically disparate but not genetically
identical parents (82). In fact, the cumulative effects of these
mechanism may underlie and explain the frequent ameliora-
tion of human (maternal) autoimmune diseases during preg-
nancy (83) and the detectable persistence of foetal cells in the
maternal circulation many years following parturition (84).
Another situation that requires special consideration is
GvHD. The mechanism of allorecognition during GvHD is
similar to host recognition of donor antigens but in reverse,
that is to say that donor T cells recognize alloantigens on
host APC (direct allorecognition) (85) and on syngeneic
(donor) APC (indirect allorecognition) although it is
probably the contribution of the host APC, which is of
critical importance in GvHD (85). Although a full descrip-
tionoftheseprocessesisbeyondthescopeofthisreview[the
reader is directed towards reference (86)], allorecognition
(by donor T cells of recipient ‘alloantigens’) clearly plays
552
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
Allorecognition and the alloresponse
B. Afzali et al.

Page 9

a central role as donor TCR Va and Vb usage appear
restricted and skewed in both murine (87) and human (88)
GvHD and often show specificity for distinct immunodo-
minant antigens, usually of the mHAg family (87). This
latterisofimportanceasGvHDdevelopsevenifthedonor–
recipient pair are matched for HLA antigens (89). Not
surprisingly, perhaps, the risk of GvHD is higher in the
settingofgendermismatching,especiallyifthefemaledonor
is multiparous or has had previous blood transfusions
(presumablythrough sensitization totheH-Y antigen) (90).
Although most frequent following allogeneic BMT (91),
GvHD does also occur in association with solid organ
transplants including liver (92), intestine (93), lung (94),
pancreas (95) and kidney (96). The relative risk of
developing GvHD (higher in BMT than in solid organ
transplants) is thought to be related to the number of donor
lymphocytes which are transferred along with the allo-
graftedtissueespeciallybecausemurinemodelsshowadose–
response relationship between GvHD severity and T-cell
infusate number and depletion of donor T cells reduces the
risk and severity of the disease. The pathophysiology of
this condition consists of a three-step process (86), namely
(i) tissue damage incited by the conditioning regime leading
to upregulation of inflammatory mediators such as IL-1,
tumour necrosis factor alpha (TNF-a), adhesion molecules
and increased expression of MHC and co-stimulatory
molecules on recipient APCs, (ii) migration of donor T cells
to lymphoid tissues, activation and differentiation through
interaction with host (and donor) APC followed by
migration to target tissues of GvHD (including mucosal
surfaces and skin) and (iii) an effector phase characterized
by tissue injury mediated by reactive oxygen species and
cytolytic mechanisms including TNF-a, perforin, granzyme
and Fas–FasL interactions.
The role of regulatory cells, including Natural Killer T
(NKT)cellsandCD41CD251TregsinGvHDisunclearat
present although they are capable of suppressing GvHD
(97, 98). The latter may operate through mechanisms
including IL-10 production and can be expanded in vitro
for this purpose (99).
The translational relevance of the basic science
The studyofallorecognition andalloresponses ismore than
merely the study of immunology in the context of an
artificial model. The very real immunological emphasis on
maintenance of self-integrity through the exclusion of
tissues belonging to genetically disparate members of the
same species while permitting tolerance to semi-allogeneic
foetal tissues argues in favour of the existence of a dynamic
structure, which lends itself to modification and which may
be manipulated through appropriate interventions. The
identification of different pathways of allorecognition and
different patterns of clinical alloresponses emphasizes the
concept that a number of different targets may exist for
monitoring or manipulation to engender clinical tolerance
to engrafted transplants without the need for high dose
broad-spectrum immunosuppression that currently carries
with it the risk of life-threatening infections and malig-
nancy.
Inparticular,therearetwoongoinginternationalstudies,
the Immune Tolerance Network and the European Union
study, which aim to identify indices of tolerance that may
distinguishthosekidneytransplantrecipientswhoareaptto
develop tolerance to a transplant from those that are not;
and effector mechanisms whose alteration/modification
may be critical in engendering tolerance.
With regard to immune manipulation, the most promis-
ing cellular therapies that are being tested to inhibit the
response in solid organ transplantation are the adoptive
transfer of ex vivo T cells with regulatory function and DC
with specific tolerogenic potential. This illustrates the
conceptofantigenicityandimmnogenicitywherebytherapy
aims to alter the response to an alloantigen, which is
antigenicsoastorenderitnon-immunogenic.Inthecontext
of allogeneic stem cell transplantation, the focus is on the
ability to control relapses of the original leukaemic disease.
In this area, in vitro cultured leukaemia-reactive CTL lines
selected on their ability to inhibit the proliferation of
leukaemic progenitor cells in vitro have been successfully
applied to treat accelerated phase Chronic Myeloid
Leukaemia (CML) (100).
Concluding remarks
In summary, allorecognition and the alloresponse are key
components of the immune response that may actually
predatethedevelopmentofimmunity.Theyare,inaddition,
dynamic entities, which may manifest as either acceptance
or rejection of foreign tissues. An understanding of the
mechanisms underlying allorecognition and the alloresponse
as well as pathways of tolerance development will be
essential in the design of clinically viable immunotherapy
aimed at preservation of functional allografts without
immunosuppression or development of GvHD.
References
1. Nyholm SV, Passegue E, Ludington WB et al. fester, A
candidateallorecognitionreceptorfromaprimitivechordate.
Immunity 2006: 25: 163–73.
2. Rinkevich B. Primitive immune systems: are your ways my
ways? Immunol Rev 2004: 198: 25–35.
3. Whitelegg AM, Oosten LE, Jordan S et al. Investigation
of peptide involvement in T cell allorecognition using
recombinant HLA class I multimers. J Immunol 2005: 175:
1706–14.
4. Ford D, Burger D. Precursor frequency of antigen-specific
T cells: effects of sensitization in vivo and in vitro. Cell
Immunol 1983: 79: 334–44.
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
553
B. Afzali et al.
Allorecognition and the alloresponse

Page 10

5. Lombardi G, Sidhu S, Batchelor JR, Lechler RI.
Allorecognition of DR1 by T cells from a DR4/DRw13
responder mimics self-restricted recognition of endogenous
peptides. Proc Natl Acad Sci USA 1989: 86: 4190–4.
6. Warrens AN, Lombardi G, Lechler RI. Presentation and
recognition of major and minor histocompatibility antigens.
Transpl Immunol 1994: 2: 103–7.
7. Lechler RI, Batchelor JR. Restoration of immunogenicity to
passenger cell-depleted kidney allografts by the addition of
donor strain dendritic cells. J Exp Med 1982: 155: 31–41.
8. Herrera OB, Golshayan D, Tibbott R et al. A novel pathway
ofalloantigenpresentationbydendriticcells.JImmunol2004:
173: 4828–37.
9. Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry
AN, Lechler RI. The role of the allograft in the induction of
donor-specific T cell hyporesponsiveness. Transplantation
2001: 72: 480–5.
10. SchneckJ,MunitzT,ColiganJE,MaloyWL,MarguliesDH,
Singer A. Inhibition of allorecognition by an H-2Kb-derived
peptide is evidence for a T-cell binding region on a major
histocompatibility complex molecule. Proc Natl Acad Sci
USA 1989: 86: 8516–20.
11. Villadangos JA, Galocha B., Lopez de Castro JA. Unusual
topology of an HLA-B27 allospecific T cell epitope lacking
peptide specificity. J Immunol 1994: 152: 2317–23.
12. Lombardi G, Barber L, Sidhu S, Batchelor JR, Lechler RI.
The specificity of alloreactive T cells is determined by MHC
polymorphisms which contact the T cell receptor and which
influence peptide binding. Int Immunol 1991: 3: 769–75.
13. Smith PA, Brunmark A, Jackson MR, Potter TA.
Peptide-independent recognition by alloreactive cytotoxic T
lymphocytes (CTL). J Exp Med 1997: 185: 1023–33.
14. Sherman LA, Chattopadhyay S. The molecular basis of
allorecognition. Annu Rev Immunol 1993: 11: 385–402.
15. Weber DA, Terrell NK, Zhang Y et al. Requirement for
peptide in alloreactive CD41 T cell recognition of class II
MHC molecules. J Immunol 1995: 154: 5153–64.
16. Eckels DD, Gorski J, Rothbard J, Lamb JR.
Peptide-mediated modulation of T-cell allorecognition. Proc
Natl Acad Sci USA 1988: 85: 8191–5.
17. Lechler RI, Lombardi G, Batchelor JR, Reinsmoen N, Bach
FH. The molecular basis of alloreactivity. Immunol Today
1990: 11: 83–8.
18. Dalchau R, Fangmann J, Fabre JW. Allorecognition of
isolated, denatured chains of class I and class II major
histocompatibility complex molecules. Evidence for an
importantroleforindirectallorecognitionintransplantation.
Eur J Immunol 1992: 22: 669–77.
19. Vella JP, Spadafora-Ferreira M, Murphy B et al. Indirect
allorecognition of major histocompatibility complex
allopeptides in human renal transplant recipients with
chronicgraftdysfunction.Transplantation 1997:64:795–800.
20. Fangmann J, Dalchau R, Fabre JW. Rejection of skin
allografts by indirect allorecognition of donor class I major
histocompatibility complex peptides. J Exp Med 1992: 175:
1521–9.
21. Sayegh MH, Perico N, Imberti O, Hancock WW, Carpenter
CB, Remuzzi G. Thymic recognition of class II major
histocompatibility complex allopeptides induces
donor-specific unresponsiveness to renal allografts.
Transplantation 1993: 56: 461–5.
22. Steele DJ, Laufer TM, Smiley ST et al. Two levels of help for
B cell alloantibody production. J Exp Med 1996: 183:
699–703.
23. Game DS, Rogers NJ, Lechler RI. Acquisition of HLA-DR
and costimulatory molecules by T cells from allogeneic
antigen presenting cells. Am J Transplant 2005: 5: 1614–25.
24. Morelli AE, Larregina AT, Shufesky WJ et al. Endocytosis,
intracellular sorting, andprocessingofexosomes bydendritic
cells. Blood 2004: 104: 3257–66.
25. Lee RS, Grusby MJ, Glimcher LH, Winn HJ, Auchincloss H
Jr. Indirect recognition by helper cells can induce
donor-specific cytotoxic T lymphocytes in vivo. J Exp Med
1994: 179: 865–72.
26. Wise MP, Bemelman F, Cobbold SP, Waldmann H. Linked
suppression of skin graft rejection can operate through
indirect recognition. J Immunol 1998: 161: 5813–6.
27. Smyth LA, Herrera OB, Golshayan D, Lombardi G, Lechler
RI.Anovelpathwayofantigenpresentationbydendriticand
endothelial cells: Implications for allorecognition and
infectious diseases. Transplantation 2006: 82(Suppl):
S15–S18.
28. Tsang JY, Chai JG, Lechler R. Acquisition of MHC:peptide
complexes by mouse CD41 T cells may play a role in
T-cell-mediated immunoregulation. Transplant Proc 2002:
34: 2849–50.
29. Hara M, Kingsley CI, Niimi M et al. IL-10 is required for
regulatoryTcellstomediatetolerancetoalloantigensinvivo.
J Immunol 2001: 166: 3789–96.
30. Marsh SG, Albert ED, Bodmer WF et al. Nomenclature for
factors of the HLA system, 2004. Tissue Antigens 2005: 65:
301–69.
31. Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind
MHCs, peptides, and coreceptors. Annu Rev Immunol 2006:
24: 419–66.
32. Abbas AK, Lichtman AH. The Major Histocompatibility
Complex. Cellular and Molecular Immunology, 5th edn,
updated edn. Philadelphia: Elsevier Saunders, 2005.
33. Bozzacco L, Trumpfheller C, Siegal FP et al. DEC-205
receptor on dendritic cells mediates presentation of HIV gag
protein to CD81 T cells in a spectrum of human MHC I
haplotypes. Proc Natl Acad Sci USA 2007: 104: 1289–94.
34. Borg NA, Ely LK, Beddoe T et al. The CDR3 regions of
an immunodominant T cell receptor dictate the ‘energetic
landscape’ of peptide-MHC recognition. Nat Immunol 2005:
6: 171–80.
35. Bahram S, Bresnahan M, Geraghty DE, Spies T. A second
lineage of mammalian major histocompatibility complex
class I genes. Proc Natl Acad Sci USA 1994: 91: 6259–63.
36. Zwirner NW, Dole K, Stastny P. Differential surface
expression of MICA by endothelial cells, fibroblasts,
keratinocytes, and monocytes. Hum Immunol 1999: 60:
323–30.
37. Zhang Y, Stastny P. MICA antigens stimulate T cell
proliferation and cell-mediated cytotoxicity. Hum Immunol
2006: 67: 215–22.
554
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
Allorecognition and the alloresponse
B. Afzali et al.

Page 11

38. Glotz D, Lucchiari N, Pegaz-Fiornet B, Suberbielle-Boissel
C. Endothelial cells as targets of allograft rejection.
Transplantation 2006: 82(Suppl): S19–S21.
39. Terasaki PI, Ozawa M, Castro R. Four-year follow-up of
a prospective trial of HLA and MICA antibodies on kidney
graft survival. Am J Transplant 2007: 7: 408–15.
40. Barth R, Counce S, Smith P, Snell GD. Strong and weak
histocompatibilityfinedifferencesinmiceandtheirroleinthe
rejection of homografts of tumors and skin. Ann Surg 1956:
144: 198–204.
41. Simpson E, Scott D, James E et al. Minor H antigens: genes
and peptides. Transpl Immunol 2002: 10: 115–23.
42. Yoshimura Y, Yadav R, Christianson GJ, Ajayi WU,
Roopenian DC, Joyce S. Duration of alloantigen
presentation and avidity of T cell antigen recognition
correlate with immunodominance of CTL response to minor
histocompatibility antigens. J Immunol 2004: 172: 6666–74.
43. SimpsonE,RoopenianD,GoulmyE.Muchadoaboutminor
histocompatibility antigens. Immunol Today 1998: 19:
108–12.
44. Simpson E. Minor transplantation antigens: animal models
for human host-versus-graft, graft-versus-host, and
graft-versus-leukemia reactions. Transplantation 1998: 65:
611–6.
45. Murata M, Warren EH, Riddell SR. A human minor
histocompatibility antigen resulting from differential
expression due to a gene deletion. J Exp Med 2003: 197:
1279–89.
46. Piper KP, McLarnon A, Arrazi J et al. Functional
HY-specific CD81 T cells are found in a high proportion of
women following pregnancy with a male fetus. Biol Reprod
2007: 76: 96–101.
47. Goulmy E. Minor histocompatibility antigens: from
transplantationproblemstotherapyofcancer.HumImmunol
2006: 67: 433–8.
48. Goulmy E, Gratama JW, Blokland E, Zwaan FE, van Rood
JJ. A minor transplantation antigen detected by
MHC-restricted cytotoxic T lymphocytes during
graft-versus-host disease. Nature 1983: 302: 159–61.
49. LovelandB,WangCR,YonekawaH,HermelE,LindahlKF.
Maternally transmitted histocompatibility antigen of mice:
a hydrophobic peptide of a mitochondrially encoded protein.
Cell 1990: 60: 971–80.
50. Bhuyan PK, Young LL, Lindahl KF, Butcher GW.
Identification of the rat maternally transmitted minor
histocompatibility antigen. J Immunol 1997: 158:
3753–60.
51. Ishikawa Y, Kashiwase K, Okai M et al. Polymorphisms in
the coding region of mtDNA and effects on clinical outcome
of unrelated bone marrow transplantation. Bone Marrow
Transplant 2001: 28: 603–7.
52. Hsu KC, Chida S, Geraghty DE, Dupont B. The killer cell
immunoglobulin-like receptor (KIR) genomic region:
gene-order, haplotypes and allelic polymorphism. Immunol
Rev 2002: 190: 40–52.
53. RuggeriL,CapanniM,UrbaniEetal.Effectivenessofdonor
natural killer cell alloreactivity in mismatched hematopoietic
transplants. Science 2002: 295: 2097–100.
54. Ruggeri L, Aversa F, Martelli MF, Velardi A. Allogeneic
hematopoietic transplantation and natural killer cell
recognition of missing self. Immunol Rev 2006: 214: 202–18.
55. VilchesC,ParhamP.DoNK-cellreceptorsandalloreactivity
affectsolidorgantransplantation?TransplImmunol2006:17:
27–30.
56. Le MA, Goldman M, Abramowicz D. Multiple pathways to
allograft rejection. Transplantation 2002: 73: 1373–81.
57. Terasaki PI. Humoral theory of transplantation. Am J
Transplant 2003: 3: 665–73.
58. Afzali B, Lombardi G, Lechler RI, Lord GM. The role of
T helper 17 and regulatory T cells in human disease. Clin
Exp Immunol 2007: [Epub ahead of print].
59. Magee CC. Transplantation across previously incompatible
immunological barriers. Transpl Int 2006: 19: 87–97.
60. Parker W, Bruno D, Holzknecht ZE, Platt JL.
Characterization and affinity isolation of xenoreactive
human natural antibodies. J Immunol 1994: 153: 3791–803.
61. Baumann BC, Stussi G, Huggel K, Rieben R, Seebach JD.
Reactivity of human natural antibodies to endothelial cells
from Galalpha(1, 3)Gal-deficient pigs. Transplantation 2007:
83: 193–201.
62. Scornik JC, Salomon DR, Howard RJ, Pfaff WW.
Evaluation of antibody synthesis in broadly sensitized
patients. Transplantation 1988: 451: 95–100.
63. Gallon LG, Leventhal JR, Kaufman DB. Pretransplant
evaluation of renal transplant candidates. Semin Nephrol
2002: 22: 515–25.
64. Ibrahim S, Dawson DV, Sanfilippo F. Predominant
infiltration of rejecting human renal allografts with T cells
expressing CD8 and CD45RO. Transplantation 1995: 59:
724–8.
65. Matheson PJ, Dittmer ID, Beaumont BW, Merrilees MJ,
Pilmore HL. The macrophage is the predominant
inflammatory cell in renal allograft intimal arteritis.
Transplantation 2005: 79: 1658–62.
66. Hoffmann SC, Hale DA, Kleiner DE et al. Functionally
significant renal allograft rejection is defined by
transcriptional criteria. Am J Transplant 2005: 5: 573–81.
67. Krieger NR, Ito H, Fathman CG. Rat pancreatic islet and
skin xenograft survival in CD4 and CD8 knockout mice.
J Autoimmun 1997: 10: 309–15.
68. Colvin RB. Chronic allograft nephropathy. N Engl J Med
2003: 349: 2288–90.
69. Racusen LC, Solez K, Colvin RB et al. The Banff 97 working
classification of renal allograft pathology. Kidney Int 1999:
55: 713–23.
70. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen
RD, Chapman JR. The natural history of chronic allograft
nephropathy. N Engl J Med 2003: 349: 2326–33.
71. Libby P, Pober JS. Chronic rejection. Immunity 2001: 14:
387–97.
72. Terasaki PI, Ozawa M. Predicting kidney graft failure by
HLAantibodies: aprospective trial.AmJTransplant2004: 4:
438–43.
73. Nankivell BJ, Chapman JR. Chronic allograft nephropathy:
current concepts and future directions. Transplantation 2006:
81: 643–54.
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
555
B. Afzali et al.
Allorecognition and the alloresponse

Page 12

74. Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. T
cell awareness of paternal alloantigens during pregnancy.
Science 1995: 270: 630–3.
75. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and
immune tolerance in pregnancy. FASEB J 2005: 19: 681–93.
76. Hunt JS. Stranger in a strange land. Immunol Rev 2006: 213:
36–47.
77. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ,
Fisher SJ. Human placental cytotrophoblasts produce the
immunosuppressivecytokineinterleukin10.JExpMed1996:
184: 539–48.
78. JonesRL,StoikosC,FindlayJK,SalamonsenLA.TGF-beta
superfamily expression and actions in the endometrium and
placenta. Reproduction 2006: 132: 217–32.
79. Munn DH, Zhou M, Attwood JT et al. Prevention of
allogeneic fetal rejection by tryptophan catabolism. Science
1998: 281: 1191–3.
80. Guleria I, Khosroshahi A, Ansari MJ et al. A critical role for
the programmed death ligand 1 in fetomaternal tolerance.
J Exp Med 2005: 202: 231–7.
81. Makrigiannakis A, Zoumakis E, Kalantaridou S et al.
Corticotropin-releasing hormone promotes blastocyst
implantation and early maternal tolerance. Nat Immunol
2001: 2: 1018–24.
82. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells
mediatematernaltolerancetothefetus.NatImmunol2004:5:
266–71.
83. Nelson JL, Ostensen M. Pregnancy and rheumatoidarthritis.
Rheum Dis Clin North Am 1997: 23: 195–212.
84. Bianchi DW. Fetomaternal cell trafficking: a new cause of
disease? Am J Med Genet 2000: 91: 22–8.
85. Shlomchik WD, Couzens MS, Tang CB et al. Prevention of
graft versus host disease by inactivation of host
antigen-presenting cells. Science 1999: 285: 412–5.
86. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host
disease: pathobiology and management. Exp Hematol 2001:
29: 259–77.
87. Friedman TM, Jones SC, Statton D, Murphy GF, Korngold
R. Evolution of responding CD41 and CD81 T-cell
repertoires during the development of graft-versus-host
disease directed to minor histocompatibility antigens. Biol
Blood Marrow Transplant 2004: 10: 224–35.
88. Hirokawa M, Matsutani T, Saitoh H et al. Distinct TCRAV
and TCRBV repertoire and CDR3 sequence of T
lymphocytes clonally expanded in blood and GVHD lesions
after human allogeneic bone marrow transplantation. Bone
Marrow Transplant 2002: 30: 915–23.
89. Goulmy E, Schipper R, Pool J et al. Mismatches of minor
histocompatibility antigens between HLA-identical donors
and recipients and the development of graft-versus-host
disease after bone marrow transplantation. N Engl J Med
1996: 334: 281–5.
90. GaleRP,BortinMM,vanBekkumDWetal.Riskfactorsfor
acute graft-versus-host disease. Br J Haematol 1987: 67:
397–406.
91. Schmitz N, Eapen M, Horowitz MM et al. Long-term
outcome of patients given transplants of mobilized blood or
bone marrow: a report from the International Bone Marrow
Transplant Registry and the European Group for Blood and
Marrow Transplantation. Blood 2006: 108: 4288–90.
92. Smith DM, Agura E, Netto G et al. Liver
transplant-associated graft-versus-host disease.
Transplantation 2003: 75: 118–26.
93. Mazariegos GV, bu-Elmagd K, Jaffe R et al. Graft versus
host disease in intestinal transplantation. Am J Transplant
2004: 4: 1459–65.
94. Smith DM, Agura ED, Ausloos K, Ring WS, Domiati-Saad
R, Klintmalm GB. Graft-vs-host disease as a complication of
lung transplantation. J Heart Lung Transplant 2006: 25:
1175–7.
95. WeinsteinA,DexterD,KuKurugaDL,PhilosopheB,HessJ,
Klassen D. Acute graft-versus-host disease in pancreas
transplantation: a comparison of two case presentations and
a review of the literature. Transplantation 2006: 82: 127–31.
96. Smith DM, Agura ED, Levy MF, Melton LB, Domiati-Saad
R, Klintmalm G. Graft vs host disease following kidney
transplantationusingan‘0HLAantigenmismatched’donor.
Nephrol Dial Transplant 2006: 21: 2656–9.
97. HoffmannP,ErmannJ,EdingerM,FathmanCG,StroberS.
Donor-type CD4(1)CD25(1) regulatory T cells suppress
lethal acute graft-versus-host disease after allogeneic bone
marrow transplantation. J Exp Med 2002: 196: 389–99.
98. Zeng D, Lewis D, Dejbakhsh-Jones S, Lan F, Garcia-Ojeda
M, Sibley R, Strober S. Bone marrow NK1.1(2) and
NK1.1(1)Tcellsreciprocallyregulateacutegraftversushost
disease. J Exp Med 1999: 189: 1073–81.
99. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL.
CD4(1)CD25(1) immunoregulatory T cells: new
therapeutics for graft-versus-host disease. J Exp Med 2002:
196: 401–6.
100. Falkenburg JH, Wafelman AR, Joosten P et al. Complete
remission of accelerated phase chronic myeloid leukemia by
treatment with leukemia-reactive cytotoxic T lymphocytes.
Blood 1999: 94: 1201–8.
556
ª 2007 The Authors
Journal compilation ª 2007 Blackwell Munksgaard ? Tissue Antigens 69, 545–556
Allorecognition and the alloresponse
B. Afzali et al.