Transplantation

Trans p lantation is the process of taking cells, tissues,

or organs, called a ,graft, from one individual and
placing them into a (;sually) different individual. The
~ctivitionof ~lloreactiieT Cells and Rejectio individual who provides the graft is called the donor,
of Allografts 375 and the individual who receives the graft is called either
Effector Mechanisms of the recipient or the host. If the grgft is placed into its
Hyperacute Rejection normal anatomic location, the procedure is called
Acute Rejection 380 orthotopic transplantation; if the graft is placed in a
Chronic Rejection 381 different site, the procedure is called heterotopic
transplantation. Transfusion is the transplantation of
, Prevention and Treatment of Allog circulating blood cells or plasma from one individual to
Reiection 381 another. In clinical practice, transplantation is used to
Immunosuppression to Prevent or to Treat overcome a functional or anatomic deficit in the recip-
: Allograft Rejection 381 ient. This approach to treatment of human diseases has
Methods to Reduce the lmmunogenicity of increased steadily during the past 40 years, and trans-
Allografts 383 plantation of kidneys, hearts, lungs, livers, pancreas,
Methods to Induce Donor-Specific Tolerance and bone marrow is widely used today. More than
Suppression 385 30,000 kidney, heart, lung, liver, and pancreas trans-
Xenogeneic Transplanta plants are currently performed in the United States
each year. In addition, transplantation of many other
Blood Transfusion 386 organs or cells is now being attempted.
Bone Marrow Tran A major limitation in the success of transplanta-
Craft-Versus-Host tion is the immune response of the recipient to the
lmmunodeficienc donor tissue. This problem was first appreciated when
attempts to replace damaged skin on burn patients with
skin from unrelated donors were found to be uniformly
unsuccessful. During a matter of 1 to 2 weeks, the trans-
planted skin would undergo necrosis and fall off. The
failure of the grafts led Peter Medawar and many other
investigators to study skin transplantation in animal
models. These experiments established that the failure
of skin grafting was caused by an inflammatory reaction
called rejection. Several lines of experimental evidence
indicated that rejection is caused by an adaptive
immune response (Fig. 16-1).

@ A skin graft transplanted between genetically unre-

lated individuals, for example, from a strain A mouse
to a strain B mouse, is rejected by a naive recipient in
7 to 10 days. This process is called first-set rejection and
is due to a primary immune response to the graft. A
subsequent skin graft transplanted from the same
 Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology
Ea
Grafts may fail because of abnormalities other than 0 Cells or organs transplanted between individuals of
rejection. In clinical practice, it is important to dis- different inbred strains of a species are almost always
tinguish between rejection, which is immunologically rejected.
mediated, and other causes of graft failure. Our dis- 0 The offspring of a mating between two different
cussion focuses on the immunologic basis of rejection. inbred strains will typically not reject grafts from either
Transplant immunologists have developed a special parent. In other words, an (A x B)F1 animal will not
vocabulary to describe the kinds of cells and tissues reject grafts from an A or B strain animal. (This rule
encountered in the transplant setting. A graft trans- is violated by bone marrow transplantation, which we
planted from one individual to the same individual is will discuss later in the chapter.)
called an autologous graft (shortened to autograft). A
Recipient
(Strain B) A
$ graft transplanted between two genetically identical or
syngeneic individuals is called a syngeneic graft. A graft
0 A graft derived from the offspring of a mating between
two different inbred strains will almost always be re-
jected by either parent. In other words, a graft from an
transplanted between two genetically different individ-
(A x B)FI animal will be rejected by either an A or a B
uals of the same species is called an allogeneic graft
strain animal.
(or allograft). A graft transplanted between individuals
of different species is called a xenogeneic graft (or Such experimental results suggested that polymor-
Recipient (strain B injected with xenograft). The molecules that are recognized as phic, codominantly expressed molecules in the grafts
by previous graft from strai lymphocytes from strain A animal foreign on allografts are called alloantigens, and those were responsible for eliciting rejection. Polymorphism
hat has rejected a strain B graft) on xenografts are called xenoantigens. The lympho- refers to the fact that these graft antigens differed
cytes and antibodies that react with alloantigens or among individuals of a species or between different
xenoantigens are described as being alloreactive or inbred strains of animals, for example, between strain
xenoreactive, respectively. A and strain B mice. Codominant expression means
The immunology of transplantation is important for that an (A x B) F1 animal expresses both A strain and B
two reasons. First, the immunologic rejection response strain alleles. (A x B) Fl animals see both A and B tissues
is still one of the major barriers to transplantation as self, and A or B animals see (A x B) F1 tissues as partly

/-- Yes
Yes I
today. Second, although an encounter with alloantigens
is unlikely in the normal life of an organism, the
immune response to allogeneic molecules is strong
foreign. This is why an (Ax B)F1animal does not reject
either A or B strain grafts and why both A and B strain
recipients reject an (A x B)F1graft.
and has therefore been a useful model for studying Major histocompatibility complex (MHC) mole-
the mechanisms of lymphocyte activation. Most of this cules are responsible for almost all strong (rapid)
chapter focuses on allogeneic transplantation because rejection reactions. George Snell and colleagues used
it is far more commonly practiced and better under- congenic strains of inbred mice to identify the MHC
stood than xenogeneic transplantation, which is dis- complex as the locus of polymorphic genes that encode
cussed briefly at the end of the chapter. We consider the molecular targets of allograft rejection (see Chapter
Yes - both the basic immunology and some aspects of the 4, Fig. 4-2). Because MHC molecules, the targets of
clinical practice of transplantation. We conclude the allograft rejection, are widely expressed, many different
First-se-. - :tion I chapter with a discussion of allogeneic bone marrow
transplantation, which raises special issues not usually
kinds of tissues evoke responses from alloreactive T
cells. As discussed in Chapters 4 and 5 , MHC molecules
encountered in solid organ transplants. play a critical role in normal immune responses to
Figure 16-1 First- and second-set allograft rejection.
Results of the experiments shown indicate that graft rejection displays the features of adaptive
foreign antigens, namely, the presentation of peptides
immune responses, namely, memory and mediation by lymphocytes. A strain B mouse will reject a derived from protein antigens in a form that can be
graft from a strain A mouse with first-set kinetics (left panel). A strain B mouse sensitized by a previ- The Immunology of Allogeneic recognized by T cells. The role of MHC molecules as
ous graft from a strain A mouse will reject a second graft from a strain A mouse with second-set kinet- Transplantation alloantigens is incidental, as discussed later.
ics (middle panel), demonstrating memory. A strain B mouse injected with lymphocytes from another Allogeneic MHC molecules are presented for recog-
strain B mouse that has rejected a graft from a strain A mouse will reject a graft from a strain A mouse Alloantigens elicit both cell-mediated and humoral
with second-set kinetics (right panel), demonstrating the role of lymphocytes in mediating rejection nition by the T cells of a graft recipient in two funda-
and memory. A strain B mouse sensitized by a previous graft from a strain A mouse will reject a graft immune responses. In this section of the chapter, we mentally different ways (Fig. 16-3). The first way, called
from a third unrelated strain with first-set kinetics, thus demonstrating another feature of adaptive discuss the molecular and cellular mechanisms of direct presentation, involves recognition of an intact
immunity, specificity (not shown). Syngeneic grafts are never rejected (not shown). allorecognition, with an emphasis on the nature of graft MHC molecule displayed by donor antigen-presenting
antigens that stimulate allogeneic responses and the cells (APCs) in the graft and is a consequence of the
donor to the same recipient is rejected more rapidly, new graft elicits only a first-set rejection. Thus, the phe-
features of the responding lymphocytes. similarity in structure of an intact foreign (allogeneic)
in only 2 or 3 days. This accelerated response, called nomenon of second-set rejection shows specificity, an- MHC molecule and self MHC molecules. Therefore,
second-set rejection, is due to a secondary immune other cardinal feature of adaptive immune responses. Recognition of Alloantigens direct presentation is unique to foreign MHC mole-
response. Thus, grafts that are genetically disparate cules. The second way, called indirect presentation,
0 The ability to mount second-set rejection against a Recognition of transplanted cells as self or foreign is involves processing of donor MHC molecules by recip-
from the recipients induce immunologic memory, one determined by polymorphic genes that are inherited
of the cardinal features of adaptive immune responses. graft from strain A mice can be adoptively transferred ient APCs and presentation of peptides derived from
to a naive strain B recipient by immunocompetent from both parents and are expressed codominantly. the allogeneic MHC molecules in association with self
Second-set rejection ensues if the first and second skin lymphocytes taken from a strain B animal previously This conclusion is based on the results of experimental MHC molecules. In this case, the foreign MHC mole-
grafts are derived from the same donor or from genet- exposed to a graft from strain A mice. This experiment transplantation between inbred strains of mice. The cule is handled as though it were any foreign protein
ically identical donors, for example, strain A mice. demonstrated that second-set rejection is mediated by basic rules of transplantation immunology are derived antigen, and the mechanisms of indirect antigen pres-
However, if the second graft is derived from an indi- sensitized lymphocytes and provided the definitive evi- from such animal experiments (Fig. 16-2). entation are indistinguishable from the mechanisms of
vidual unrelated to the donor of the first graft, for dence that rejection is the result of an adaptive presentation of a microbial protein antigen. Alloanti-
0 Cells or organs transplanted between individuals of the
example, strain C, no second-set rejection occurs; the immune response. gens in a graft other than MHC molecules can also
same inbred strain of a species are never rejected.
 , Section V - The Immune System in Disease

9Direct allorecognition
Chapter 16 - Transplantation Immunology
I
Alloaeneic MHC
T cell recognizes
unprocessed
lloreactive atlogeneic
cell MHC molecule
on graft APC
ISkin graft 1 ,
Recipient
MHCa)
1

$. Recipient
(Strain A x B,
MHCalb)
f Recipient
(Strain A,
Dlndirect alloantigen presentation

MHC APC in recipient Alloreactive

MHca!A I
I- - I- -
I
Presentation of
processed peptide
of aliogeneic
IC molecule bound
..
I 1 to self MHC molecule I
Uptake and processing of ~ k p t i d ederived
allogeneic MHC molecules from allogeneic
by recipient APC MHC molecule

Graft
reiection I
I No Yes Yes
centrated in the regions that bind to the TCR, each
Fully ailogeneic Graft from F1hybrid different residue may contribute to a distinct deter-
graft is not graft is parental strain is not is rejected by inbred minant recognized by a different clone of self
rejected rejected by F1hybrid parental strain MHC-restricted T cells. Thus, each allogeneic MHC
molecule can be recognized by multiple T cell clones.
Figure 1f5-2 The genetics of graft rejection.
In this case, the cross-reactive T cell allorecognition is
In the illustration, the two different mouse colors represent different MHC haplotypes, Inherited entirely attributable to differences in amino acid
MHC alleles from both parents are codominantly expressed in the skin of an A x B offspring, and sequences between self MHC and allogeneic MHC
therefore these mice are represented by both colors. Syngeneic grafts are not rejected (A). Allografts molecules, and bound peptide serves only to ensure
are always rejected (B). Grafts from a parent of an A x B mating will not be rejected by the offspring stable expression of the allogeneic MHC molecule.
(C), but grafts from the offspring will be rejected by either parent (D). These phenomena are due to
the fact that MHC gene products are responsible for graft rejection; grafts are rejected only if they 1 Many different peptides may combine with one allo-
express an MHC type (represented by a color) that is not expressed by the recipient mouse.
geneic MHC gene product to produce determinants
that are recognized by different cross-reactive T cells.
The surface of each allogeneic cell has 1@or more
be presknted to host T cells by the indirect pathway. We copies of each allogeneic MHC molecule, and each
discuss the molecular basis of direct and indirect pres- MHC molecule can form a complex with a different
entation separately. peptide. Thus, any cell in an allograft may express
many distinct peptide-MHC complexes composed of
Direct Presentation of Alloantigens different peptides bound to one or a few alleles of the
foreign MHC molecules. Because only a few hundred
Direct recognition of foreign MHC molecules is a peptide-MHC complexes are needed to activate a
cross-reaction of a normal T cell receptor (TCR), which particular T cell clone, many different clones may be
was selected to recognize a self MHC molecule plus activated by the same allogeneic cell.
foreign peptide, with an allogeneic MHC molecule plus
peptide. On face value, it seems puzzling that T cells that All of the MHC molecules on an allogeneic APC are
are normally selected to be self MHC-restricted are foreign to a recipient and can therefore be recognized
capable of recognizing foreign MHC molecules. The by T cells. In contrast, on self APCs, most of the self
explanation for this apparent paradox came from MHC molecules are displaying self peptides, and any
studies with monoclonal T cell populations, which foreign peptide probably occupies 1% or less of the
showed that the same TCR may recognize self MHC- total MHC molecules expressed. As a result, the
foreign peptide complexes and allogeneic MHC density of allogeneic determinants on allogeneic
molecules. APCs is much higher than the density of foreign
peptide-self MHC complexes on self APCs. The abun-
0 A T cell clone that expresses a TCR specific for self dance of recognizable allogeneic MHC molecules may
MHC plus a foreign peptide may also recognize one or allow activation of T cells with low affinities for the
more allogeneic MHC molecules in the absence of that determinant, thereby increasing the numbers of T
foreign peptide. cells that can respond.
rr Section V - The Immune System in Disease
Figure 1fj-4 Molecular basis of molecules. Some antigens of phagocytosed graft cells reactive CD4+helper T cells differentiate into cytokine-
) Normal direct recognition of allogeneic appear to enter the class I MHC pathway of antigen producing effector cells that damage grafts by reactions
MHC molecules. presentation and are indirectly recognized by CD8+T
Direct recognition of allogeneic that resemble delayed-type hypersensitivity (DTH).
MHC molecules may be thought of as cells. Because MHC molecules are the most poly- Alloreactive CD8+T cells activated by the direct pathway
a cross-reaction in which a T cell spe- morphic proteins in the genome, each allogeneic MHC differentiate into CTLs that kill nucleated cells in the
cific for a self MHC molecule-foreign molecule may give rise to multiple foreign peptides, graft, which express the allogeneic class I MHC mole-
peptide complex (A) also recognizes each recognized by different T cells. cules. The CD8' CTLs that are generated by the indi-
an allogeneic MHC molecule (B, C).
Nonpolymorphic donor peptides, rect pathway are self MHC-restricted, and therefore
@ One of the first indications that T cell responses to
Self MHC molecule mav not con-
labeled "self ~e~tide." they cannot directly kill the foreign cells in the graft.
presents foreign peptide tribute to allogeneic MHC molecules can occur by indirect
Therefore, when alloreactive T cells are stimulated by
to T cell selected to may (C). presentation was the demonstration of cross-priming
the indirect pathway, the principal mechanism of rejec-
recognize self of alloreactive CD8+cytolytic T lymphocytes (CTLs) by
tion is probably DTH mediated by CD4+effector T cells
MHC-foreign self APCs that had been exposed to allogeneic cells.
that infiltrate the graft and recognize donor alloanti-
peptide complexes Evidence that indirect presentation of allogeneic MHC gens being displayed by host APCs that have also
molecules occurs in graft rejection was obtained from entered the graft. The relative importance of the direct
studies with knockout mice lacking class I1 MHC and indirect pathways in graft rejection is still unclear.
expression. For example, skin grafts from donor mice It has been suggested that CD8' CTLs induced by direct
lacking class I1 MHC are able to induce recipient CD4+ recognition of alloantigens are most important for
(i.e., class 11-restricted) T cell responses to the donor acute rejection of allografts, whereas CD4+ effector T
alloantigens, including peptides derived from donor cells stimulated by the indirect pathway play a greater
class I MHC molecules. This result implies that the role in chronic rejection.
The self MHC- restricted donor class I MHC molecules are processed and pre- The importance of MHC molecules in the rejection
T cell recognizes the sented by class I1 molecules on the recipient's APCs of tissue allografts has been established by studies with
allogeneic MHC and stimulate the recipient's helper T cells. inbred animals showing that rapid rejection usually
molecule whose Qb More recently, evidence has been obtained from requires class I or class I1 MHC differences between the
self
peptide
J structure resembles the human transplant recipients that indirect antigen pres- graft donor and the recipient. In clinical transplanta-
tion, minimizing MHC differences between the donor
self MHC-foreign entation may contribute to late rejection of allografts.
peptide complex For example, CD4+T cells from heart and liver allo- and the recipient improves graft survival, as we shall
graft recipients can be activated in uitro by peptides discuss later.
derived from donor MHC and presented by host APCs. The response of alloreactive T cells to foreign MHC
molecules has also been analyzed in an in uitro reaction
There may be polymorphic antigens other than called the mixed lymphocyte reaction (MLR). The MLR
MHC molecules that differ between the donor and the is a model of direct T cell recognition of allogeneic
recipient. These antigens induce weak or slower (more MHC molecules and is used as a predictive test of T
gradual) rejection reactions than do MHC molecules cell-mediated graft rejection. Studies of the MLR were
and are called minor histocompatibility antigens. Most among the first to establish the role of class I and class
minor histocompatibility antigens are proteins that are I1 MHC molecules in activating distinct populations of
processed and presented to host T cells in association T cells (CD8' and CD4+,respectively).
T cell recognizes a with self MHC molecules on host APCs (i.e., by the indi- %Q The MLR is induced by culturing mononuclear
Self
I structure formed by rect pathway). leukocytes (which include T cells, B cells, NK cells,
both the allogeneic mononuclear phagocytes, and dendritic cells) from
peptide' ,
All( -
-
neic MHC
MHC molecule and
the bound peptide
Activation of Alloreactive T Cells and
Rejection of Allografts
The activation of alloreactive T cells in vivo requires
one individual with mononuclear leukocytes derived
from another individual. In humans, these cells are
typically isolated from peripheral blood; in the mouse
or rat, mononuclear leukocytes are usually purified
presentation of alloantigens by donor-derived APCs
in the graft (direct presentation of alloantigens) or by from the spleen or lymph nodes. If the two individuals
Many of the alloreactive T cells that respond to the processed MHC molecules are recognized by T cells have differences in the alleles of the MHC genes, a
first exposure to an allogeneic MHC molecule are like conventional foreign protein antigens (see Fig. host APCs that pick up and present graft alloantigens
(indirect presentation). Most organs contain resident large proportion of the mononuclear cells will prolif-
memory T cells that were generated during previous 16- 3). Because allogeneic MHC molecules differ struc- erate during a period of 4 to 7 days. This proliferative
exposure to other foreign (e.g., microbial) antigens. turally from those of the host, they can be processed APCs such as dendritic cells. Transplantation of these
organs into an allogeneic recipient provides APCs that response is called the allogeneic MLR (Fig. 16-5).
Thus, in contrast to the initial naive T cell response and presented in the same way that any foreign protein In this experiment, the cells from each donor react
to microbial antigens, the initial response to alloanti- antigen is, generating foreign peptides associated with express donor MHC molecules as well as costimulators.
Presumably, these donor APCs migrate to regional and proliferate against the other, thus resulting in a
gens is mediated in part by already expanded clones self MHC molecules on the surface of host APCs. This two-way MLR. To simplify the analysis, one of the two
of memory T cells. phenomenon is an example of cross-presentation or lymph nodes and are recognized by the recipient's T
cells that circulate through the peripheral lymphoid leukocyte populations can be rendered incapable of
cross-priming (see Chapter 5, Fig. 5-7), in which pro- proliferation before culture, either by y-irradiation or
Because of the high frequency of alloreactive T cells, organs (the direct pathway). Dendritic cells from the
fessional APCs, usually dendritic cells, present antigens by treatment with the antimitotic drug mitomycin C.
primary responses to alloantigens are the only primary recipient may also migrate into the graft, or graft
of another cell, from the graft, to activate, or "prime,"
responses that can readily be detected i n vitro. alloantigens may traffic into lymph nodes, where they In this one-way MLR, the treated cells serve exclusively
T lymphocytes. Indirect presentation may result in as stimulators and the untreated cells, still capable of
allorecognition by CD4' T cells because alloantigen is are captured and presented by recipient APCs (the
Indirect Presentation of Alloantigens indirect pathway). Alloreactive T cells in the recipient proliferation, serve as the responders.
acquired by host APCs primarily through the endoso-
Allogeneic MHC molecules may be processed and pre- ma1 vesicular pathway (i.e., as a consequence of phago- may be activated by both pathways, and these T cells @ Among the T cells that have responded in an MLR,
sented by recipient APCs that enter grafts, and the cytosis) and is therefore presented by class I1 MHC migrate into the grafts and cause graft rejection. Allo- any one cell is specific for only one allogeneic MHC
- Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology
I
0
Allografts survive for longer periods when they are lated by mechanisms similar to those involved in the
Mitotically transplanted into knockout mice lacking B7-1 (CD80) stimulation of B cells reactive with other foreign proteins.
inactivate
h
and B7-2 (CD86) compared with transplants into Many of the issues that arise in discussions of
normal recipients. However, even in B7 knockout alloreactivity and graft rejection are also relevant to
recipients, allografts show histologic evidence of rejec- maternal-fetal interactions. The fetus expresses pater-
Mix blood
mononuclear cells tion and eventually fail because of chronic rejection. nal MHC molecules and is therefore semiallogeneic
to the mother. Nevertheless, the fetus is not rejected
from two donors Donor X Donor Y In contrast to T cell alloreactivity, much less is known by the maternal immune system. Many possible mech-
in tissue culture
about the mechanisms that lead to the production anisms have been proposed to account for this lack of
of alloantibodies against foreign MHC molecules. rejection, and it is not yet clear which of these mecha-
Presumably, B cells specific for alloantigens are stimu- nisms is the most significant (Box 16-1).

I Class I Class II I
Donor X CD8+ The mammalian fet~.-,-.xcept in instances which the 1 fetal alloantigens are not known. Even if trophoblast
T lymphocyte mother and father are syngeneic, will express paternally cells do express classical MHC molecules, they may
(Responder cell inherited antigens that are allogeneic to the mother. In lack costimulator molecules and fail to act as antigen-
essence, the fetus is a naturally occurring allograft. Never- presenting cells.
J theless, fetuses are not normally rejected by the mother. It A second explanation for lack of rejection is that the
is clear that the mother is exposed to fetal antigens during uterine decidua may be an immunologicalIyprivilegedsite.
Donor Y APC pregnancy since maternal antibodies against paternal These anatomic sites are tissues where immune responses
(Stimulator cell) MHC molecules are easily detectable. An understanding of generally fail to occur and include brain, eye, and testis.
how the fetus escapes the maternal immune system may be Several factors may contribute to immune privilege. For
relevant for transplantation. Protection of the fetus against example, the brain vasculature limits lymphocyte access
the maternal immune system probably involves several to the brain tissue, and the anterior chamber of the eye
mechanisms including special molecular and barrier fea- may contain high concentrations of immunosuppressive
tures of the placenta and local immunosuppression. cytokines such as transforming growth factor$ (TGF-P).In
Several experimental observations indicate that the support of the idea that the decidua is an immune privi-
anatomic location of the fetus is a critical factor in the leged site is the observation that mouse decidua is highly
DonorY absence of rejection. For example, pregnant animals are susceptible to infection by Listeria monoqtogents and cannot
i",class I MHC+ able to recognize and reject allografts syngeneic to the support a delayed-type hypersensitivity response. The basis
target cell ~&n'brY fetus placed at extrauterine sites without compromising of immunologic privilege is clearly not a simple anatomic
class II MHC+ fetal survival. Wholly allogeneic fetal blastocysts that lack barrier because maternal blood is in extensive contact with
stimulator cell maternal genes can successfully develop in a pregnant or trophoblast. Rather, the barrier is likely to be created by
pseudopregnant mother. Thus, neither specific maternal functional inhibition. Cultured decidual cells directly
nor paternal genes are necessary for survival of the fetus. inhibit macrophage and T cell functions, perhaps by pro-
Hyperimmunization of the mother with cells bearing ducing inhibitory cytokines, such as TGF-p. Some of these
paternal antigens does not compromise placental and fetal inhibitory decidual cells may be resident regulatory T cells,
Figure 16-5 The mixed leukocyte reaction (MLR). growth. although the evidence for this proposal is limited. Some
In a one-way primary MLR, stimulator cells (from donor Y) activate and cause the expansion of The failure to reject the fetus has focused attention on experiments have led to the suggestion that TH2cytokines
two types of responder T cells (from donor X). CD4' T cells from donor X react to donor Y class I I the region of physical contact between the mother and are produced at the maternal-fetal interface and are
molecules, and CD8' T lymphocytes from donor X react to donor Y class I MHC molecules. The CD4' fetus. The fetal tissues of the placenta that most intimately responsible for local suppression of TH1 responses to
T cells differentiate into cytokine-secreting helper T cells, and the CD8'T cells differentiate into cytolytic fetal antigens. However, this idea is not supported by
T lymphocytes (CTLs). APC, antigen-presenting cell. contact the mother are composed of either vascular tro-
phoblast, which is exposed to maternal blood for purposes the data that IL4 and ILlO knockout mice have normal
of mediating nutrient exchange, or implantation site tro- pregnancies.
molecule, and the entire population of activated T stimulators.Such experiments demonstrate that allore-
phoblast, which diffusely infiltrates the uterine lining There is evidence that immune respwses to the fetus
lymphocytes contains cells that recognize all the MHC active T cells are specific for allogeneic MHC mole- (decidua) for purposes of anchoring the placenta to the may be regulated by local tryptophan concentrations in
differences between stimulators and responders. CD8+ cules, and activation of alloreactive T cells in the MLR mother. the decidua. The enzyme indolamine 2,3-dioxygenase
CTLs are generated only if the class I MHC alleles of occurs mainly by the direct pathway. One simple explanation for fetal survival is that tro- (IDO) catabolizes tryptophan, and the IDO-inhibiting
the stimulators and responders are different. Similarly, phoblast cells fail to express paternal MHC molecules. So drug 1-methyl-tryptophan induces abortions in mice in a
In addition to recognition of alloantigen, costimula-
CD4' effector T cells are generated only if the class I1 far, class I1 molecules have not been detected on tro- T cell-dependent manner. These observations have led to
tion of T cells by B7 molecules on APCs is important phoblast. In mice, cells of implantation trophoblast, but the hypothesis that T cell responses to the fetus are
molecules are different.
for activating alloreactive T cells. not of vascular trophoblast, do express paternal class I mol- blocked because decidual tryptophan levels are normally
@ Stimulator cells lacking MHC molecules cannot acti- ecules. In humans, the situation may be more complex in maintained below the level required for T cell activation.
vate responder cells in an MLR. Transfection of MHC
0 Rejection of allografts, and stimulation of alloreactive
T cells in an MLR, can be inhibited by agents that bind that trophoblast cells express only a nonpolymorphic class Trophoblast and decidua may also be relatively resist-
genes into the stimulators makes these cells capable of IB molecule called HLA-G. This molecule may be involved ant to complement-mediated damage because they express
to and block B7 molecules. Most studies indicate that
inducing an MLR. in protecting trophoblast cells from maternal NK cell- high levels of a C3 and C4 inhibitor called Crry. Crry-
B7 antagonists are more effective at blocking acute deficient embryos die before birth and show evidence of
mediated lysis. A specialized subset of NK cells called
1 CD8' CTLs generated in an MLR will kill cells from rejection of allografts and activation of alloreactive T uterine NK cells are the major type of lymphocyte present complement activation on trophoblast cells. Thus, this
other donors only if these cells share some class I cells by the direct pathway. In contrast, chronic rejec- at implantation sites, and IFN-y production by these cells inhibitor may block maternal alloantibody-mediated
alleles with the original stimulators. Similarly, CD4' T tion and activation of alloreactive T cells by the indi- is essential for decidual development. The way uterine NK damage &:%ugh the classical pathway of complement
cells generated in an MLR recognize APCs from other rect pathway are often insensitive to such agents, for cells are stimulated and their role in maternal responses activatiodes5:;$a
rap .
donors only if these APCs share class I1 alleles with the unknown reasons.
 Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology
Yljl YY
Effector Mechanisms of forms of von Willebrand factor that mediate platelet
adhesion and aggregation. Both endothelial cells and ) Hyperacute rejection
Allograft Rejection platelets undergo membrane vesiculation leading to
shedding of lipid particles that promote coagulation.
Thus far, we have described the molecular basis of
Endothelial cells lose the cell surface heparan sulfate
alloantigen recognition and the cells involved in the Complement
proteoglycans that normally interact with antithrombin
recognition of and responses to allografts. We now turn activation,
I11 to inhibit coagulation. These processes contribute to
to a consideration of the effector mechanisms used by endothelial
thrombosis and vascular occlusion, and the grafted
the immune system to reject allografts. In different damage,
experimental models in animals and in clinical trans- organ suffers irreversible ischemic damage.
In the early days of transplantation, hyperacute
inflammation
plantation, alloreactive CD4+or CD8' T cells or alloan- and thrombosis
rejection was often mediated by preexisting IgM allo-
tibodies are capable of mediating allograft rejection.
antibodies, which are present at high titer before
These different immune effectors cause graft rejection
transplantation. Such "natural antibodies" are believed Alloantiaen
by different mechanisms. (e.g., bl6od Circulating alloantigen-
For historical reasons, graft rejection is classified on to arise in response to carbohydrate antigens expressed
by bacteria that normally colonize the intestine. The group antigen) specific antibody
the basis of histopathologic features or the time course
best known examples of such alloantibodies are those
of rejection after transplantation rather than immune ) Acute rejection
directed against the ABO blood group antigens
effector mechanisms. Based on the experience of renal
transplantation, the histopathologic patterns are called expressed on red blood cells (Box 16-2). ABO antigens
hyperacute, acute, and chronic (Fig. 16-6). are also expressed on vascular endothelial cells. Today,
hyperacute rejection by anti-ABO antibodies is not a Parenchymal
clinical problem because all donors and recipients are cell damage,
selectedAsothat they have the same ABO type.^~owever, interstitial
Hyperacute Rejection inflammation
as we shall discuss later in the chapter, hyperacute rejec-
~arenbhymalcells
Hyperacute rejection is characterized by thrombotic tion caused by natural antibodies is the major barrier
occlusion of the graft vasculature that begins within to xenotransplantation and limits the use of animal
minutes to hours after host blood uessels are anasto- organs for h;man transplantation.
mosed to graft uessels and is mediated by preexisting Currently, hyperacute rejection of allografts, when it
antibodies in the host circulation that bind to donor occurs, is usually mediated by IgG antibodies directed
endothelial antigens (Fig. 16-7). Binding of antibody against protein alloantigens, such as foreign MHC
to endothelium activates complement, and antibody molecules, or against less well defined alloantigens
and complement induce a number of changes in the expressed on vascular endothelial cells. Such anti-
graft endothelium that promote intravascular throm- bodies generally arise as a result of previous exposure
bosis. Complement activation leads to endothelial cell to alloantigens through blood transfusion, previous
injury and exposure of subendothelial basement mem- transplantation, or multiple pregnancies. If the titer of
brane proteins that activate platelets. The endothelial these alloreactive antibodies is low, hyperacute rejec- -
J

cells are stimulated to secrete high molecular weight tion may develop slowly, during several days. In this ) Chronic rejection

Figure 16-6 Histopathology of different forms of graft rejection.

A. Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin Figure 16-7 Immune mechanisms of graft rejection.
thrombi, and early neutrophil infiltration in a glomerulus. A. In hyperacute rejection, preformed antibodies reactive with vascular endothelium activate
B. Acute rejection of a kidney with inflammatory cells in the interstitium and between epithelial complement and trigger rapid intravascular thrombosis and necrosis of the vessel wall.
cells of the tubules. B. In acute rejection, CD8+ T lymphocytes reactive with alloantigens on endothelial cells and
C. Acute rejection of a kidney allograft with destructive inflammatory reaction destroying the parenchymal cells mediate damage to these cell types. Alloreactive antibodies formed after engraft-
endothelial layer of an artery. ment may also contribute to vascular injury.
D. Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced C. In chronic rejection with graft arteriosclerosis, injury to the vessel wall leads to intimal smooth
by an accumulation of smooth muscle cells and connective tissue in the vessel intima. (Courtesy of muscle cell proliferation and luminal occlusion. This lesion may be caused by a chronic delayed-type
Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital and Harvard Medical hypersensitivity (DTH) reaction to alloantigens in the vessel wall.
School, Boston.)
 Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology
Cli(il CLiY
one allogeneic to the host. When these skin grafts are consistent with the hypothesis that DTH is involved in
transplanted, the allogeneic cells are killed without lesion formation. Other studies with knockout mice
injury to the "bystander" syngeneic cells. indicate that CD4+T cells and B lymphocytes are more
important for the development of graft arteriosclero-
CD4+ T cells may be important in mediating acute sis than are CD8+T cells.
graft rejection by secreting cytokines and inducing
DTH-like reactions in grafts, and some evidence indi- Chronic rejection of different transplanted organs is
cates that CD4+T cells are sufficient to mediate acute associated with distinct pathologic changes. Lung trans-
rejection. plants undergoing chronic rejection show thickened
small airways (bronchiolitis obliterans), and liver trans-
e Acute rejection of allografts does occur in knockout plants show fibrotic and nonfunctional bile ducts (the
mice lacking CD8' T cells or perforin, suggesting that vanishing bile duct syndrome).
other effector mechanisms also contribute.
0 Adoptive transfer of alloreactive CD4+T cells into a
mouse can cause rejection of an allograft. Prevention and Treatment of
Antibodies can also mediate acute rejection if a graft
Allograft Rejection
recipient mounts a humoral immune response to vessel
If the recipient of an allograft has a fully functional
wall antigens and the antibodies that are produced
immune system, transplantation almost invariably
bind to the vessel wall and activate complement. The
results in some form of rejection. The strategies used
histologic pattern of this form of acute rejection is one
in clinical practice and in experimental models to avoid
of transmural necrosis of graft vessel walls with acute
or delay rejection are general immunosuppression and
inflammation, which is different from the thrombotic
minimizing the strength of the specific allogeneic reac-
occlusion without vessel wall necrosis seen in hyper-
tion. An important goal in transplantation is to induce
acute rejection.
donor-specific tolerance, which would allow grafts to
survive without pharmacologic immunosuppression.
Chronic Rejection
Chronic rejection is characterized by Jibrosis and lmmunosuppression to Prevent or to
vascular abnormalities with loss of graft function Treat Allograft Rejection
occurring during a prolonged period. As therapy for
controlling acute rejection has improved, chronic rejec- Immunosuppression is the major approach for the
tion has emerged as the major cause of allograft loss. prevention and management of transplant rejection.
The pathogenesis of chronic rejection is less well under- Several methods of im&mosuppressio~are commonly
stood than that of acute rejection. The fibrosis of used (Table 16-1).
chronic rejection may result from immune reactions Immunosuppressive drugs that inhibit or kill T
case, it is sometimes referred to as accelerated allograft medium-sized arteries also occurs at an early stage of and the production of cytokines that stimulate fibro- lymfihocy tes -ire the princGa1 treatment regimen for
rejection because the onset is still earlier than that acute rejection and is indicative of severe rejection, blasts, o; it may represent wound healing after the graft rejection. The most important immunosuppres-
typical for acute rejection. As we will discuss later in the which, left untreated, will likely result in acute graft parenchymal cellular necrosis of acute rejection. sive agent in current clinical use is cyclosporine.
chapter, patients in need of allografts are routinely failure. Perhaps the major cause of chronic rejection of vascu- Cyclosporine is a cyclic peptide made by a species of
screened before grafting for the presence of antibodies Both CD4' T cells and CDBf T cells may contribute larized organ grafts is arterial occlusion as a result of fungus. The major action of cyclosporine on T cells
that bind to cells of a potential organ donor to avoid to acute rejection. Several lines of evidence suggest the woliferation of intimal smooth muscle cells. This is to inhibit the transcription of certain genes, most
hyperacute rejection. that recognition and killing of graft cells by alloreactive process is called accelerated (or graft) arteriosclerosis notably those encoding cytokines such as interleukin
CD8' CTLs is an important mechanism of acute (see Fig. 16-6). Graft arteriosclerosis is frequently seen (1L)-2. Cyclosporine binds with high affinity to a
rejection. in failed cardiac and renal allografts and can develop ubiquitous cellular protein called cy~lophilin. 'AS dis-
Acute Rejection
in any vascularized organ transplant within 6 months to cussed in Chapter 8, the complex of cyclosporine and
Acute rejection is a process of vascular and parenchy- The cellular infiltrates present in grafts undergoing cyclophilin binds to and inhibits the enzymatic activity
acute cellular rejection are markedly enriched for a year after transplantation. The lesion appears to occur
mal injury mediated by T cells and antibodies that without evidence of overt vascular injury, and no cor- of the calcium/calmodulin-activated protein phos-
usually begins after the j r s t week of transplantation. CD8+CTLs specific for graft alloantigens. rshatase calcineurin. Because calciu~/calmodulin-
relation has clearly been established between the devel-
Effector T cells and antibodies that mediate acute reiec-
8.
@ The presence of CTLs in renal graft biopsy specimens, opment of graft arteriosclerosis and infection, episodes activated calcineurin function is required to activate the
tion develop during a few days or weeks in response to as indicated by sensitive reverse transcriptase-polym- of previous acute rejection, or lipid abnormalities. The transcription factor NFAT (nuclear factor of activated
the graft, accounting for the time at onset of acute erase chain reaction assays for RNAs encoding CTL smooth muscle cell proliferation in the vascular intima T cells), cyclosporine blocks NFAT activation and the
rejection. specific genes (e.g., perforin and granzyme B), is a may represent a specialized form of chronic DTH reac- transcription of IL-2 and other cytokine genes. The net
T lymphocytes play a central role in acute rejection specific and sensitive indicator of clinical acute tion of the organ parenchyma in which lymphocytes result is that cyclosporine blocks the IL-2-dependent
by responding to alloantigens, including MHC mole- rejection. activated by alloantigens in the graft vessel wall induce growth and differentiation of T cells.
cules, present on vascular endothelial and parenchymal macrophages to secrete smooth muscle cell growth The introduction of cyclosporine into clinical prac-
@ Alloreactive CD8' CTLs can be used to adoptively tice ushered in the modern era of transwlantation.
cells (see Fig. 16-7). The activated T cells cause direct factors (see Fig. 16-7).
transfer acute cellular graft rejection.
lysis of graf<cells or produce cytokines that recruit and Before the use of cyclosporine, the majority of trans-
activate inflammatory cells, which injure the graft. In Q1) The destruction of allogeneic cells in a graft is highly Knockout mice lacking different components of the planted hearts and livers were rejected. Now the major-
vascularized grafts such as kidney grafts, endothelial specific, a hallmark of CTL killing. The best evidence adaptive immune system have been used as graft re- ity of these allografts survive for more than 5 years
cells are the earliest targets of acute rejection. Microvas- for this specificity has come from mouse skin graft cipients and show varying resistance to graft arterio- (Fig. 16-8). evei it he less, cyclosporine is not a
cular endothelitis is a freauent early finding. " in acute experiments using chimeric grafts that contain two dis- sclerosis. For instance, graft arteriosclerosis does not for transplantation. Drug levels needed for optimal
rejection episodes. Endothelitis or intimal arteritis in tinct cell populations, one syngeneic to the host and develop in interferon-y (EN-y)-deficient recipients, immunosuppression cause kidney damage, and some
 Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology
.l
ir
Table 16-1. Methods of Immunosuppression in Clinical Use the ability to bind calcineurin and inhibit its activity. Antibodies that react with T cell surface structures promises to improve early survival of grafts even more.
FK-506 has been used most frequently in liver and deplete or inhibit T cells are used to treat acute Heart transplantation, for which HLA matching (dis-
I Mechanism of action I transplant recipients and in cases of kidney allograft rejection episodes. The most widely used antibody is cussed later) is not practical, has significantly improved
rejection that are not adequately controlled by a mouse monoclonal antibodv called 0KT3 that is with the use of cyclosporine and now has a similar 90%
cyclosporine. specific for human CD3. It may seem surprising that 1-year survival rate. Experience with other organs is
An immunosuppressive agent with a different one would use a potential polyclonal activator such as more limited, but survival rates for liver and lung trans-
mechanism of action is the antibiotic rapamycin, anti-CD3 antibody to reduce T cell reactivity. In vivo, plants have also benefited from modern immunosup-
Blocks proliferation of whose principal effect is to inhibit T cell proliferation. however, 0KT3 either acts as a lytic antibody by acti- pressive therapy.
lymphocyte precursors
Like FK-506, rapamycin also binds to FKBP, but the vating the complement system to eliminate T cells or Acute rejection, when it occurs, is managed by
Blocks lymphocyte pro life ratio&^^,&^ rapamycin-FKBP complex does not inhibit calcineurin. opsonizes T cells for phagocytosis. T cells that escape rapidly intensifying immunosuppressive therapy. In
by inhibiting guanine nucleotidq':y~:~,: Instead, this complex binds to another cellular protein probably do so by capping and endocytosing ("modu- modern transplantation, chronic rejection has become
Tk)dkqpi+jp(n:?,~~qp@4@s
$fiar3 I r called the mammalian target of rapamycin (MTOR). lating") CD3 off their surface, but such cells may be ren- a more common cause of allograft failure, especially
Blocks lymphocyte proliferation The mechanism by which rapamycin inhibits T cell dered transiently nonfunctional. Another antibody now in cardiac transplantation. Chronic rejection is more
by inhibiting IL-2 signaling growth is not known. Rapamycin-treated T cells display in clinical use is specific for CD25, the a-subunit of the insidious than acute rejection, and it is much less
abnormalities in the levels of certain cyclin/cyclin- IL-2 receptor. This reagent, which is administered at the reversible by immunosuppression. It is likely that pre-
Reduce inflammation by inhibit[gLq
macrophage cytokine secretion ,?:ie ' : dependent kinase complexes, suggesting that MTOR
may be a regulator of a protein kinase that participates
time of transplantation, may prevent T cell activation by
blocking IL-2 binding to activated T cells, or it may
vention rather than treatment will be the best approach
to this problem, but successful intervention will require
Depletes T cells by binding to CD3 in cell cycle control. Combinations of cyclosporine deplete CD25-expressing activated T cells by mecha- a better understanding of its pathogenesis.
and promoting phagocytosis or (which blocks IL2 synthesis) and rapamycin (which nisms similar to those described for OKT3. The major Sustained immunosuppression required for pro-
complement-mediatedlysis
(used to treat acute rejection) blocks IL2-driven proliferation) are potent inhibitors limitation on the use of mouse monoclonal antibodies longed graft survival leads to increased susceptibility
of T cell responses. is that humans given these agents produce anti-mouse to viral infections and virus-associated malignant
Anii-k-2 Inhibits T cell proliferation by Cj:,! ;, Metabolic toxins that kill proliferating T cells are immunoglobulin (Ig) antibodies that eliminate the tumors. The major thrust of transplant-related immuno-
-P- Q$j9hiFp.$~-$ii~,iq,g
* -
>< + ,pt,$ $%
:+;is. also used to treat graft rejection. These agents inhibit injected mouse Ig. For this reason, human-mouse suppression is to reduce the generation and function of
ant
7

I .- I d ,I,~;..,?,: ..,*I. the maturation of lymphocytes from immature precur- chimeric ("humanized") antibodies to CD3 and CD25 helper T cells and CTLs, which mediate acute cellular
sors and also kill proliferating mature T cells that have that may be less immunogenic have been developed. rejection. It is therefore not surprising that defense
CTeft&@ Inhibits T cell activation by blocking
been stimulated by alloantigens. The first such drug to
B7 costimulator binding to Acute rejection mediated by antibodies can be against viruses, the physiologic function of CTLs, is
T cell CD28; used to induce be developed for prevention and treatment of rejection treated with drugs that inhibit antibody production. also undermined in immunosuppressed transplant
tolerance [experimental) was azathioprine. This drug is still used, but it is toxic Several new immunosuppressive agents, including recipients. Reactivation of latent cytomegalovirus, a her-
to precursors of leukocytes in the bone marrow and rapamycin and brequinar, inhibit antibody synthesis pesvirus, is particularly common in immunosuppressed
enterocytes in the gut. The newest and most widely used and are therefore potentially useful in preventing acute patients. For this reason, transplant recipients are now
drug in this class is mycophenolate mofetil (MMF). vascular rejection. given prophylactic antiviral therapy for cytomegalovirus
MMF is metabolized to mycophenolic acid, which ~nti-inflammatoryagents are also routinely used infections. Two malignant tumors commonly seen in
blocks a lymphocyte-specific isoform of inosine mono- for the prevention and treatment of graft rejection. allograft patients are B cell lymphomas and squamous
phosphate dehydroxygenase, an enzyme required for de The most potent anti-inflammatory agents available are cell carcinoma of the skin. The B cell lymphomas
rejection episodes are refractory to cyclosporine treat- novo synthesis of guanine nucleotides. Because MMF corticosteroids. The proposed mechanism of action for are thought to be sequelae of unchecked infection by
ment. Another immunosuppressive fungal metabolite selectively inhibits the lymphocyte-specific isoform of these natural hormonesand their synthetic analogues Epstein-Barr virus, another herpesvirus (see Chapter 17,
in clinical use is called FK-506, and it functions like this enzyme, it has relatively few toxic effects. MMF is is to block the synthesis and secretion of cytokines, Box 17-2).The squamous cell carcinomas of the skin are
cyclosporine. FK-506 and its binding protein (called now routinely used in combination with cyclosporine to including tumor necrosis factor (TNF) and IL-1, by associated with human papillomavirus.
FKBP) share with the cyclosporine-cyclophilin complex prevent acute allograft rejection. macrophages. Lack of TNF and IL-1 synthesis reduces
graft endothelial cell activation and recruitment of
Methods to Reduce the lmmunogenicity
inflammatory leukocytes (see Chapters 12 and 13).
of Allografts
Corticosteroids may also block other effector mecha-
Cyclosporine nisms of macrophages, such as the generation of In human transplantation, the major strategy to
.. ,introduced prostaglandins, reactive oxygen intermediates, and reduce graft immunogenicity has been to minimize
nitric oxide. Very high doses of corticosteroids may alloantigenic differences between the donor and recip-
inhibit T cell secretion of cytokines or even kill T cells, ient by donor selection. To avoid hyperacute rejection,
but it is unlikely that the levels of corticosteroids the ABO blood group antigens of the graft donor are
achieved in vivo act in this way. Newer anti-inflamma- selected to be identical to those of the recipient.
tory agents are in clinical trials, including soluble Patients in need of allografts are also tested for the pres-
cytokine receptors, anticytokine antibodies, and anti- ence of preformed antibodies against donor cells. This
bodies that block leukocyte-endothelial adhesion type of testing is called crossmatching and involves
(e.g., anti-intercellular adhesion molecule-1 [anti- mixing recipient serum with leukocytes from potential
ICAM-11).
-, donors. Complement is added to promote classical
Current immunosuppressive protocols have dra- pathway-mediated lysis of donor cells. If preformed
matically improved graft survival. Before the use of antibodies, usually against donor MHC molecules, are
Figure 1- Influence of cyclosporine on graft cyclosporine, the 1-year survival rate of unrelated present in the recipient's serum, the donor cells are
survival. cadaveric kidney grafts was between 50% and 60%, lysed (a positive crossmatch), and such lysis indicates
Five-year survival rates for patients receiving cardiac allo- with a 90% rate for grafts from living related donors that the donor is not suitable for that recipient. For
grafts are seen to have increased significantly beginning when (which are better matched with the recipients). Since kidney transplantation from living related donors,
cyclosporine was introduced in 1983. (Data from Transplant
Patient Datasource, United Network for Organ Sharing, cyclosporine and MMF have been introduced, the attempts are made to minimize both class I and class I1
, I I E Year of transplant '' Richmond, Va. Retrieved February 16, 2000, from the World survival rate of unrelated cadaveric kidney grafts has MHC allelic differences between the donor and recipi-
, . *,c
7-
- Wide Web: http://207.239.150.13/tpd/.) approached about 90% at 1 year. The use of rapamycin ent. All potential kidney donors and recipients are
I Section V - The Immune System in Disease Chapter 16 - Transplantation Immunology

Several experimental approaches and clinical ob-

YiY

servations have suggested that it should be possible to

achieve tolerance to allografts.
@ In experiments with skin grafts in mice, Medawar and
Several clinical laboratory tests are routinely perform4 ping cannot a1 s resolv colleagues showed that if neonatal mice of one strain
reduce the risk of immunologic rejection in transplant; .esent. (the recipient) are given spleen cells of another strain
tion. These include ABO blood typing; the determinatio,, The poly,nerase chain reaction (PCI., has L cent^ (the donor), the recipients will subsequently accept
of HLA alleles expressed on donor and recipient cells, been used to permit more complete typing of the class I1
grafts from the donor. Such tolerance is alloantigen
called tissue typing; the detection of preformed antibodies loci, replacing serologic methods. The polymorphic
in the recipient that recognize HLA and other antigens residues of class I1 MHC molecules are largely encodea specific because the recipients will reject grafts from
representative of the donor population; and the detection within exon 2 of both the a and P chains (i.e., within th mouse strains that express MHC alleles that differ from
of preformed antibodies in the recipient that bind to a1 and P l polypeptide regions). This entire region of th the donor's (see Chapter 10, Fig. 10-2).
antigens of an identified donor's leukocytes, called cross gene can be amplified by PCR methods with use of prime] Renal transplant patients who have received blood
matching. Not all of these tests are done in all types c that bind to conserved sequences within the 5' and :
transfusions containing allogeneic leukocytes have
msplantation. ends of these exons. The amplified segment of DNA ca
ABO BLOOD TYPIP 4 This test is uniformly used i._ then readily be sequenced. Thus, the actual nucleotid- a lower incidence of acute rejection episodes than do
all transplantation because no type of graft will survive if sequence, and therefore the predicted amino acid those who have not been transfused. The postulated
there are ABO incompatibilities between the donor an
'
sequence, can be directly determined for the HLA-DT explanation for this effect is that the introduction of
Number of mismatched HLA alleles
recipient. Natural IgM antibodies specific for allogenei -DQ and -DP alleles of any cell, providing precise mole1 allogeneic leukocytes by transfusion produces toler-
ABO blood group antigens (see Box 16-2) will cause ular tissue typing. Figure 1&9 Influence of MHC matching on graft survival. ance to alloantigens. Indeed, pretreatment of potential
hyperacute rejection. Blood typing is performed by mixing SCREENING FOR THE PRESENCE OF PRE~uKMEI Matching of MHC alleles between the donor and recipient sig- recipients with blood transfusions is now widely used as
a patient's red blood cells with standardized sera contain- ANTIBODIES Patients waiting for organ transplants ar nificantly improved living donor renal allograft survival. HLA match- prophylactic therapy to reduce rejection.
ing anti-A or anti-B antibodies. If the patient expresses sc ned for the presence of preformed antibodies ing has more of an impact on survival of renal allografts from
either blood group antigen, the serum specific for thz- tive with allogeneic HLA molecules. These antiboa~e cadaver donors than from living donors, and some MHC alleles are @ Animals given bone marrow transplants who subse-
antigen will agglutinate the red cells. which may be produced as a result of previous pregnal more important than others in determining outcome. (Data from quently contain both donor and recipient cells in the
TISSUE TYPING: HLA MATCHING For living related cies, transfusions, or transplantation, can identify risk ( Organ Procurement and Transplantation Network/Scientific Registry circulation (called mixed chimerism) are tolerant to
kidney transplantation, attempts are made to reduce the hyperacute or acute vascular rejection. Small amour - -
s report, 1999.) organ allografts derived from the same donor as the
number of differences in HLA alleles expressed on donor the patient's serum are mixed, in separate wells, with bone marrow graft. Human allogeneic bone marrow
and recipient cells, which will have a modest ct i from a panel of 40-60 different donors representative transplantation to establish mixed chimerism has been
reducing the chance of rejection. In bone marruw trans- the organ donor population. Binding of the patient's an tried in a small number of patients before solid organ
plantation, HLA matching is essential to reduce the risk of bodies to cells of each donor of the panel is determin before transplantation until a well-matched recipient transplantation, but this approach may be limited by the
GVHD. Routine HLA typing focuses only on HLA-A, HLA- by complement-mediated lysis, as described be can be identified and because patients needing a kidney
B, and HLA-DR because these are the only loci that appea- fl9w cytometry with use of fluorescent-labeled problem of graft-versus-host disease, which is discussed
hllograft can be maintained with dialysis until a well- later in this chapter. More benign methods to establish
to predict the likelihood of rejection or GVHD. Unt tib bodies to human IgG. The results are repor matched ornan is available. In the case of heart and
recently, most HLA haplotype determinations were pel (percent reactive antibody), which is the per " mixed chimerism in humans are under investigation.
liver transplantation, organ preservation is more diffi-
formed by serologic testing. This procedure relies 0.. the donor cell pool with which the patient's serum reac Experimentally, graft rejection is reduced or delayed
cult, and potential recipients are often in critical con-
standardized collections of sera from multiple donors pre- The PRA is determined on multiple occasions while
dition. For these reasons, HLA typing is simply not by blocking costimulatory signals, such as with a
viously sensitized to different HLA molecules by pregnancy d e n t waits for an organ allograft. This is because t
or transfusions. Each of these sera is mixed with a person's --ZA can vary, since each panel is chosen at ran ; considered in pairing of potential donors and recipi- soluble form of CTLA-4 that prevents the B7 molecules
lymphocytes in separate wells of a tissue culture plate. , and the patient's serum antibody titers may change ents, and the choice of donor and recipient is based on APCs from interacting with T cell CD28 or with an
source of complement is added to the wells, as is a L ,, time. only on ABO blood group matching and anatomic antibody that binds to T cell CD40 ligand and prevents
rescent dye that will enter only dead cells. After an i n c ~
bation time, the wells are examined under a fluoresce^
microscope for the presence of dead cells. B lymphocytes
are used as target cells because they normally express both
CROSSMATCHING If a potential donor is identifie
the crossmatching test will determine whether the patie
has antibodies that react specifically with the donor cel
Iacompatibility.

bethods to induce Donor-Specific Tolerance

its interactions with CD40 on APCs (see Chapters 6
and 8). In some experimental protocols, simultaneous
blockade of both B7 and CD40 appears to be more
The test is performed in a way similar to the antibo effective than either alone in promoting graft survival.
class I and class I1 MHC molecules. On the basis of which screening assays, but in this case, the recipient's serum or Suppression Antibody to CD40 ligand also delays the rejection of
antisera cause lysis, the HLA haplotype of the individual tested for reactivity against only the particular dor ' ;c Allograft rejection may be prevented by making the kidney and pancreatic islet allografts in primates. It is
can be determined. Since the typing sera may not be (typically lymphocytes). Cytotoxic and flow c le
host tolerant to the alloantigens of the graft. Toler- not established whether these treatments inhibit the
absolutely specific r a single allelic product, serologic assays can be u
ance in this setting means that the host does not injure activation of alloreactive T cells or actually induce
the graft despite the absence or withdrawal of immuno- long-lived tolerance in these cells. Clinical trials of co-
suppressive and anti-inflammatory agents. It is pre- stimulator blockade in transplantation are ongoing,
sumed that tolerance to an allograft will involve the but the initial results are not encouraging.
I
"tissue-typed" to determine the identity of the HLA linkage disequilibrium, so matching at the DR locus same mechanisms that are involved in tolerance to self @ The potentially important role of indirect presentation
molecules that are expressed (Box 16-3). often also matches at the DQ locus. DP typing is not in antigens (see Chapter l o ) , namely, central deletion of of allogeneic MHC antigens in graft rejection raises the
In kidney transplantation, the larger the number of common use, and its importance is unknown.) Because alloreactive T cells, peripheral anergy or deletion of possibility of another approach for inducing tolerance,
MHC alleles that are matched between the donor and two codominantly expressed alleles are inherited for alloreactive T cells, and active suppression of alloreac- namely, the use of peptides derived from donor
recipient, the better the graft survival, especially in each of these MHC genes, it is possible to have zero tive T cells. Tolerance is desirable in transplantation MHC molecules as tolerogens. In this approach,
the Jirst year after transplantation (Fig. 16-9). MHC to six MHC antigen mismatches between the donor because it is alloantigen specific and will therefore immunodominant peptides derived from donor MHC
matching had a more profound influence on graft and recipient. Zero-antigen mismatches predict the avoid the major problem associated with nonspecific molecules would be administered to future recipients
survival before modern immunosuppressive drugs were best living donor graft survival, and one-antigen- immunosuppression, namely, increased susceptibility
routinely used. Clinical experience has shown that of matched grafts do slightly worse. The survival of grafts to infection and to virus-induced tumors. In addition, ., in a manner that would favor tolerance induc-
of a graft
tion, such as high-dose intravenous injection (see
all the class I and class I1 loci, matching only HLA-A, with two to six MHC mismatches all are significantly achieving graft tolerance may reduce chronic rejection, Chapter 10).
HLA-B, and HLA-DR is important for predicting worse than zero- or one-antigen mismatches. which has to date been unaffected by the commonly
outcome. (HLA-C is not as polymorphic as HLA-A HLA matching in renal transplantation is possible used immunosuppressive agents that prevent and Although the best approaches for inducing tolerance
or HLA-B, and HLA-DR and HLA-DQ are in strong because donor kidneys can be stored in organ banks reverse acute rejection episodes. need to be established in clinical trials, it is hoped that
- Section V - The Immune System in Disease

tolerance induction will become a standard part of

transplantation therapy in the near future.
intravascular thrombosis and fibrinoid necrosis of vessel
walls. The mechanisms of delayed xenograft rejection
are incompletely understood,. but it is likely to be
Chapter 16 - Transplantation Immunology

bodies to the mother within 72 hours of birth of the

YiY

first Rh-positive baby. The treatment kills the baby's Rh-

positive red blood cells that entered the mother's cir-
Xenogeneic Transplantation caused by natural antibodies to various endothelial anti- culation and prevents sensitization and production of
gens and by T cell activation and cytokine-mediated anti-Rh antibodies in the mother.
The use of solid organ transplantation as a clinical endothelial damage.
therapy is greatly limited by the lack of availability of Xenografts can also be rejected by T cell-mediated
donor organs. For this reason, the possibility of trans- immune responses to xenoantigens. The mechanisms Bone Marrow Transplantation
plantation of organs from other mammals, such as pigs, of cell-mediated rejection of xenografts are believed to
into human recipients has kindled great interest. be similar to those that we have described for allograft Bone marrow transplantation is the transplantation of
A major immunologic barrier to xenogeneic trans- rejection, and T cell responses to xenoantigens can be pluripotent hematopoietic stem cells, most commonly
plantation is the presence of natural antibodies that as strong as or even stronger than responses to alloanti- in an inoculum of bone marrow cells collected by aspi-
cause hyperacute rejection. More than 95% of primates gens. Human T cell recognition of pig MHC molecules ration. Hematopoietic stem cells can also be purified
have natural IgM antibodies that are reactive with the may involve both direct and indirect pathways. Fur- from the blood of donors, especially after treatment
carbohydrate determinants expressed by the cells of thermore, several intercellular molecular interactions with colony-stimulating factors, which mobilize stem
members of species that are evolutionarily distant, required for T cell responses, such as CD4/class I1 cells from the bone marrow. After transplantation, stem
such as the pig. The vast majority of human anti-pig MHC, CD8/class I MHC, CD2/LFA-3, CD28/B7, cells repopulate the recipient's bone marrow with their
natural antibodies are directed at one particular car- CD40L/CD40, and VLA-4/vascular cell adhesion differentiating progeny. We consider bone marrow
bohydrate determinant formed by the action of a pig molecule-1 (VCAM-1). , . are functional even when one transplantation separately in this chapter because
a-galactosyltransferase enzyme. This enzyme places an member of these pairs is from a pig and the other from several unique features of this type of grafting are not
a-linked galactose moiety on the same substrate that in a human. encountered with solid organ transplantation.
human and other primate cells is fucosylated to form Cell-mediated responses to xenografts may be too Bone marrow transplantation may be used clinically
the blood group H antigen (see Box 16-2). Species strong to be adequately controlled-by the immuno- to remedy acquired defects in the hematopoietic system
combinations that give rise to natural antibodies against suppressive protocols used for allograft rejection, and or in the immune system because blood cells and lym-
each other are said to be discordant. Natural antibodies research is therefore focused on inducing specific tol- phocytes develop from a common stem cell. It has
are rarely produced against carbohydrate determinants erance to xenografts. The methods of tolerance induc- also been proposed as a means of correcting inherited
of closely related, concordant species, such as human tion that are being" considered include those we have deficiencies or abnormalities of enzymes or other pro-
and chimpanzee. Thus, chimpanzees or other higher discussed for allografts, such as blocking costimulation teins (e.g., abnormal hemoglobin) by providing a self-
primates technically can and have been used as organ when the recipient is first exposed to the donor tissue, renewing source of normal stem cells. In addition,
donors to humans. However, both ethical and logistic administration of peptides from xenogeneic MHC allogeneic bone marrow transplantation may be used as
concerns have limited such procedures. For reasons of molecules, and establishment of xenogeneic" mixed part of the treatment of bone marrow malignant disease
anatomic compatibility, pigs are the preferred xeno- lymphohematopoietic chimerism. (i.e., leukemias) and disseminated solid tumors. In this
geneic species for organ donation to humans. case, the chemotherapeutic agents needed to destroy
Natural antibodies against xenografts induce hyper- cancer cells also destroy normal marrow elements, and
acute rejection by the same mechanisms as those seen Blood Transfusion bone marrow transplantation is used to "rescue" the
in hyperacute allograft rejection. These mechanisms patient from the side effects of chemotherapy. In addi-
include the generation of endothelial cell procoagu- Blood transfusion is a form of transplantation in which tion, in some forms of leukemia, the grafted cells can
lants and platelet aggregating substances, coupled with whole blood or blood cells from one or more individu- be effective in destroying residual leukemia cells by a
the loss of endothelial anticoagulant mechanisms. als are transferred intravenously into the circulation of process analogous to the graft-versus-host responses dis-
However, the consequences of activating human com- a host. Blood transfusions are performed to replace cussed later. For other malignant tumors, when the
plement on pig cells are typically more severe than the blood lost by hemorrhage or to correct defects caused marrow is not involved by tumor or when it can be
consequences of activation of complement by natural by inadequate production of blood cells, which may purged of tumor cells, the patient's own bone marrow
antibodies on human allogeneic cells, possibly because occur in a variety of diseases. The major barrier to suc- may be harvested and reinfused after chemotherapy.
some of the complement regulatory proteins made by cessful blood transfusions is the immune response to This procedure, called autologous bone marrow trans-
pig cells, such as decay accelerating factor, are not able cell surface molecules that differ between individuals. plantation, does not elicit the immune responses asso-
to interact with human complement proteins and thus The most important alloantigen system in blood trans- ciated with allogeneic bone marrow transplantation
cannot limit the extent of complement-induced injury fusion is the ABO system (see Box 16-2). ABO antigens and will not be discussed further.
(see Chapter 14). A strategy under exploration for are expressed on all cells, including red blood cells. Before bone marrow is transplanted, recipients must
reducing hyperacute rejection in xenotransplantation Individuals lacking a particular blood group antigen often be "prepared" with radiation and chemotherapy
is to construct and breed transgenic pigs expressing may produce natural IgM antibodies against that anti- to deplete their own marrow cells and vacate these sites
human proteins that inhibit complement activation or gen, probably as a result of responses to cross-reactive to allow the transplanted stem cells to "home" to the
fail to express enzymes that synthesize pig antigens. antigens expressed on bacteria that colonize the gut. marrow and establish themselves in the appropriate
Such pigs could, for example, overexpress human H If such individuals are given blood cells expressing environment. Allogeneic stem cells are readily rejected
group fucosyltransferase and overexpress human com- the missing antigen, the preexisting antibodies bind by even a minimally immunocompetent host, and
plement regulatory proteins such as decay accelerating to the transfused cells, activate complement, and lyse therefore the donor and recipient must be carefully
factor. the transfused cells. Lysis of the foreign red blood matched at all polymorphic MHC loci. In addition,
Even when hyperacute rejection is prevented, cells results in transfusion reactions, which can be life- it is often necessary to greatly suppress the recipient's
xenografts are often damaged by a form of acute vas- threatening. Transfusion across an ABO barrier may immune system to permit successful bone marrow
cular rejection that occurs within 2 to 3 days of trans- trigger an immediate hemolytic reaction, resulting in transplantation. Such suppression is accomplished by
plantation. This form of rejection has been called both intravascular lysis of red blood cells, probably radiation and chemotherapy. The mechanisms of rejec-
delayed xenograft rejection, accelerated acute rejec- mediated by the complement system, and extensive tion of bone marrow cells are not completely known,
tion, or acute vascular rejection and is characterized by phagocytosis of antibody- and complement-coated but in addition to adaptive immune mechanisms,
4 Section V - The Immune System in Disease

hematopoietic stem cells may also be rejected by NK Cyclosporine and the metabolic toxin methotrexate are
Chapter 16 - Transplantation Immunology

bodies cause hyperacute rejection characterized by

cells. The role of NK cells in bone marrow rejection has Apoptotic cells also used for prophylaxis against GVHD. thrombosis of graft vessels. Alloreactive T cells and
been studied in experimental animals. antibodies produced in response to the graft cause
Immunodeficiency After Bone blood vessel wall damage and parenchymal cell
@ Irradiated F, hybrid mice reject bone marrow donated Marrow Transplantation death, called acute rejection. Chronic rejection is
by either inbred parent. This phenomenon, called characterized by fibrosis and vascular abnormalities
hybrid resistance, is in distinction to the classical laws Bone marrow transplantation is often accompanied (accelerated arteriosclerosis), which may represent a
of solid tissue transplantation (see Fig. 16-2). Hybrid by clinical immunodeficiency. Several factors may con-
chronic DTH reaction in the walls of arteries.
resistance is seen in T cell-deficient mice, and deple- tribute to defective immune responses in recipients.
tion of recipient NK cells with anti-NK cell antibodies Bone marrow transplant recipients may be unable to Rejection may be prevented or treated by immuno-
prevents the rejection of parental bone marrow. regenerate a complete new lymphocyte repertoire. The suppression of the host, by minimizing the immuno-
Hybrid resistance is probably due to host NK cells transplanted bone marrow may not contain a sufficient genicity of the graft (e.g., by limiting MHC allelic
reacting against bone marrow precursors that lack class number and variety of self-renewing lymphoid progen- differences), or by induction of tolerance. Most
I MHC molecules expressed by the host. itors, and the thymus gland of the recipient may have immunosuppression is directed at T cell responses
involuted so that T cell maturation does not occur. and entails the use of cytotoxic drugs, specific
Even after successful engraftment, two additional Studies in mice suggest that irradiation may unmask a immunosuppressive agents, or anti-T cell antibodies.
problems are frequently associated with bone marrow population of "natural suppressor" cells that inhibit The most widely used immunosuppressive agent is
transplantation, namely, graft-versus-host disease and Figure 16-10 Histopathology of acute graft-versus-host immune responses. cyclosporine, which blocks T cell cytokine synthesis.
immunodeficiency. These complications are discussed disease in the skin. The consequence of immunodeficiency is that bone Immunosuppression is often combined with anti-
in the following. A sparse lymphocytic infiltrate can be seen at the derrnal- marrow transplant recipients are susceptible to viral inflammatory drugs such as corticosteroids that
epidermal junction, and damage to the epithelial layer is evident as infections, especially cytomegalovirus infection, and to inhibit cytokine synthesis by macrophages.
vacuolization at the dermal-epidermal junction, cells with abnormal
Graft-Versus-Host Disease keratin staining (dyskeratosis), and disorganization of maturation of many bacterial infections. They are also susceptible to Patients receiving solid organ transplants may
keratinocytes from the basal layer to the surface. (Courtesy of Dr. Epstein-Barr virus-provoked B cell lymphomas. The become immunodeficient because of their therapy
Graft-versus-host disease (GVHD) is caused by the
Scott Grantor, Department of Pathology, Brigham and Women's immunodeficiencies of bone marrow transplant recipi- and are susceptible to viral infections and virus-
reaction of- -grafted
- mature T cells in the marrow inocu- Hospital and Harvard Medical School, Boston.) ents can be more severe than those of conventionally related malignant tumors.
lum with alloantigens of the host. It occurs when the
immunosuppressed patients. Therefore, bone marrow
host is immunocompromised and therefore unable to Xenogeneic transplantation of solid organs is limited
transplant recipients commonly receive prophylactic
reject the allogeneic cells in the graft. In most cases, the engraftment. Elimination of T cells from the donor by the presence of natural antibodies to carbohydrate
antibiotics and anticytomegalovirus therapy and are
reaction is directed against minor histocompatibility marrow also decreases the graft-versus-leukemia effect antigens on the cells of discordant species that cause
often actively immunized against capsular bacteria such
antigens of the host because bone marrow transplant& that is often critical in treating leukemias by bone hyperacute rejection, antibody-mediated acute vas-
as pneumococcus.
tion is not commonly performed when the donor and marrow transplantation. cular rejection, and a strong T cell-mediated im-
recipient have differences in MHC molecules. GVHD Although GVHD is initiated by grafted T cells rec- mune response to xenogeneic MHC molecules.
may also develop when solid organs that contain sig- ognizing host alloantigens, the effector cells that cause Summary
nificant numbers of T cells are traisulanted, such as the epithelial cell injury are less well defined. On histologic Bone marrow transplants are susceptible to rejection,
small bowel, lung, or liver. examination, NK cells are often attached to the dying Transplantation of tissues from one individual to a and recipients require intense preparatory immuno-
GVHD is the principal limitation to the success of epithelial cells, suggesting that NK cells are important genetically nonidentical recipient leads to a specific suppression. In addition, T lymphocytes in the bone
bone marrow transplantation. As in solid organ trans- effector cells of acute GVHD. CD8+CTLs and cytokines immune response called rejection that can destroy marrow graft may respond to alloantigens of the host
plantation, GVHD may be classified on the basis of his- also appear to be involved in tissue injury in acute the graft. The major molecular targets in transplant and produce GVHD. Acute GVHD is characterized
tologic patterns into acute and chronic forms. GVHD. rejection are allogeneic class I and class I1 MHC by epithelial cell death in the skin, intestinal tract,
Acute GVHD is characterized by epithelial cell death The relationship of chronic GVHD to acute GVHD molecules. and liver; it may be fatal. Chronic GVHD is charac-
in the skin, liver (biliary epithelium), and gastrointesti- is not known and raises issues similar to those of relat- terized by fibrosis and atrophy of one or more of
Many different, normally present T cell clones spe- these same target organs as well as the lungs and may
" 16-10). Acute GVHD is manifested clini-
nal tract (Fig. ing chronic allograft rejection to acute allograft rejec-
,
cally by rash, jaundice, diarrhea, and gastrointestinal tion. For example, chronic GVHD may represent the cific for different foreign peptides plus self MHC also be fatal. Bone marrow transplant recipients also
hemorrhage. When the epithelial cell death is extensive, fibrosis of wound healing secondary to loss of epithe- molecules may cross-react with an individual allo- often develop severe immunodeficiency, rendering
the skin or lining of the gut may simply slough off. In lial cells. However, chronic GVHD can arise without evi- geneic MHC molecule. This high frequency of them susceptible to infections.
this circumstance, acute GVHD may be fatal. dence of prior acute GVHD. An alternative explanation T cells capable of directly recognizing allogeneic
Chronic GVHD is characterized by fibrosis and is that chronic GVHD represents a response to ischemia MHC molecules explains why the response to
atrophy of one or more of the same organs, without caused by vascular injury. alloantigens is much stronger than the response to
evidence of acute cell death. Chronic GVHD may also Both acute and chronic GVHD are commonly treated conventional foreign antigens.
Selected Readings
involve the lungs and produce obliteration of small with intense immunosuppression. It is not clear that Allogeneic MHC molecules may be presented on
airways. When it is severe, chronic GVHD leads to com- either condition responds very well. A possible explana- donor APCs to recipient T cells (the direct pathway), The April 2001 issue of Immunity (14:345-446, 2001) has a
plete dysfunction of the affected organ and may be fatal. tion for this therapeutic failure is that conventional or the alloantigens may be picked up by host APCs collection of review articles on immunological issues in
In animal models, acute GVHD is initiated by mature immunosuppression is targeted against T lymphocytes, that enter the graft or reside in draining lymphoid transplantation; these are not included in this list.
T cells present in the bone marrow inoculum, and especially CTLs, but is less efficacious for NK cell- organs and be processed and presented to T cells as Cascalho M, and JL Platt. Xenotransplantation and other
elimination of mature donor T cells from the graft can mediated responses. Agents that suppress cytokine peptides associated with self MHC molecules (the means of organ replacement. Nature Reviews Immunology
prevent the development of GVHD. Efforts to eliminate production, such as the drug thalidomide, or that indirect pathway). 1:154-160, 2001.
T cells from the marrow inoculum have reduced the antagonize cytokine action have been effective in treat- Erlebacher A. Why isn't the fetus rejected? Current Opinion
Graft rejection is mediated by T cells, including CTLs in Immunology 13:590-593, 2001.
incidence of GVHD but also appear to reduce the effi- ing GVHD in clinical trials. Much effort has focused on
that kill graft cells and helper T cells that cause DTH Gould DS, and H Auchincloss Jr. Direct and indirect re-
ciency of engraftment, probably because mature T cells prevention of GVHD, and HLA typing is important in cognition: the role of MHC antigens in graft rejection.
reactions, and by antibodies.
produce colony-stimulating factors that aid in stem this regard. Indeed, most human bone marrow trans- Immunology Today 20:77-82, 1999.
cell repopulation. A current approach is to combine plants are performed between siblings who are com- Several effector mechanisms cause rejection of solid Mellor AL, and DH Munn. Immunology at the maternal-fetal
removal of T cells with supplemental granulocyte- pletely identical at all HLA loci, and clinical GVHD is organ grafts, and each mechanism may lead to a his- interface: lessons for T cell tolerance and suppression.
macrophage colony-stimulating factor to promote due to differences at minor histocompatibility loci. tologically characteristic reaction. Preexisting anti- Annual Review of Immunology 18:367-392, 2000.