OVERVIEW

Induction Immunosuppression
Allan D. Kirk
Induction immunosuppression is intense, prophylactic therapy used at the time of transplantation based on the empiric
observationthat more powerful immunosuppressionis requiredtoprevent acute rejectionearly. Inthe past decade, there has
been a growing trend towards the use of specialized agents such as antibody therapies for induction. In general, these agents
have been shown to reduce the rate of acute rejection. However, their use has not been clearly shown to improve long-term
transplant outcomes. This overviewwill reviewthe biological basis for induction immunosuppression and the mechanisms
of actionof those specializedinductionagents currently inclinical use. Clinical trials investigating inductionregimens will be
evaluated, and an individualized approach to the use of induction immunosuppressants will be presented.
(Transplantation 2006;82: 593602)
I
mmunosuppressive regimens used for organ transplanta-
tion can be generally characterized as induction, mainte-
nance, or rescue therapies. Induction immunosuppression is
relatively intense prophylactic therapy used at the time of
transplantation based on the empiric observation that more
powerful immunosuppressionis requiredtoprevent acuterejec-
tion early. It is typically of such potency that its prolonged use is
prohibitivelytoxic. Withtime, the needfor immunosuppression
wanes considerably and induction gives way to maintenance
therapy. Maintenance immunosuppression is of lesser potency,
but is tolerable for chronic use (albeit with side effects). Rescue
therapy is like inductioninthat it is intense, effective, andchron-
ically intolerable, but differs in that it is applied as in response to
a rejection episode. Most immunosuppressive medications can
conceivably fall into any or all of these categories based on the
dose, route and schedule used. Induction therapy can also in-
clude immunomodulatory maneuvers such as donor specific
transfusion or irradiation.
Essentially all transplant programs employ induction
regimens of some sort. Their strategies may include high dose
therapy with maintenance drugs (e.g., bolus glucocorticoste-
roids or intravenous cyclosporine [CsA]), or include special-
ized induction agents (e.g., antibodies or fusion proteins).
Nevertheless, the concept that more immunosuppression is
required early after transplantation is well established. Ac-
cordingly, the use of specialized induction agents is growing
in all organ categories in the United States and approximates
or exceeds 50%of patients for all organs except liver (Table 1)
(1, 2). Despite this general trend, however, it has not been
established whether specialized induction agents are required
to meet this need nor is it clear whether their use optimizes
the risk/ benefit ratio. Furthermore, the lasting effects of in-
duction agents remain incompletely defined. This manu-
script will provide an overview of the factors necessitating
induction therapy and review the specialized induction
agents currently available for clinical use.
The Biological Basis for Induction Therapy
Two major factors contribute to the general require-
ment for inductionimmunosuppression, andtheir scrutiny is
useful for developing a rational clinical approach (Fig. 1). The
first factor is the nonphysiologically high donor-specific T
cell precursor frequency present inmost recipients. Generally,
ones direct allospecific T cell precursor frequency is log-fold
higher than their precursor frequency to any given nominal an-
tigen presented by self major histocompatability complex
(MHC) molecules (3, 4). The ability to reshape the T cell reper-
toire to accommodate alloantigens is also increasingly impaired
withthymic involution. Giventhat immune responses are expo-
nential in nature, even modest increases in the starting precur-
sory frequency can markedly alter the ultimate efficiency of an
immune response (5) (Fig. 2). Thus, the number of cells avail-
abletomount adirect immuneresponsetowards donor antigens
is much higher than that available to respond in a physiological
manner to, for example, a nominal viral antigen. This increases
the efficiency withwhicha clinically relevant alloresponse is gen-
erated and makes alloimmune regulation more difficult.
Although the effective precursor frequency varies
widely among recipients based on MHCmismatch, prior im-
mune history, and MHC sensitization, the responding popu-
lation can approximate 10% of all lymphocytes (3, 4). The
number of T cells that is sufficient for a clinically relevant
immune response can also vary considerably based on the T
cell activation threshold (68). This thresholdis clearly altered
by prior antigenic exposure or heterologous cross activation(9
13). Thus, a na ve T cell has more stringent activation require-
ments than does a primed cell making ones immune history a
relevant variable in an initial immune response.
Transplantation Branch, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Department of Health
and Human Services, Bethesda, MD.
Address correspondence to: Allan D. Kirk, M.D., Ph.D., Room 5-5752,
Building 10CRC, Center Drive, Bethesda, MD 20892.
E-mail: allank@intra.niddk.nih.gov
Received 12 September 2005. Revision requested 30 January 2006.
Accepted 31 January 2006.
Copyright 2006 by Lippincott Williams & Wilkins
ISSN 0041-1337/06/8205-593
DOI: 10.1097/01.tp.0000234905.56926.7f
Transplantation Volume 82, Number 5, September 15, 2006 593
The second prominent factor compelling induction
therapy is the association of transplantation with tissue in-
jury. Immunity is intimately associated with injury in that
injury typically precedes exposure to an environmental
pathogen and pathogens themselves ultimately cause tissue
destruction (14). Thus, many injurious aspects of transplan-
tation such as endothelial damage, complement activation,
ischemia and reperfusion, surgical wounding to the recip-
ient, and donor injury or brain death all impact the inten-
sity of an immune response (Fig. 1). These factors impel
immunity and increase the effective precursor frequency
by lowering the threshold of T cell activation, improving
the efficiency of antigen presentation, and increasing the
trafficking of cells to the organ and its draining lymph
nodes.
The T cell precursor frequency and response to injury
conspire at the time of transplantation to produce optimal
conditions for alloimmunity. For example, complement de-
posited within a reperfused organ has been shown to facilitate
na ve T cell activation (15). Costimulation molecule expres-
sionis increasedinresponse toischemia andreperfusionboth
increasing the efficiency of resident or migratory antigen pre-
senting cells (APCs) andimproving the response of engagedT
cells (16). The cytokine milieu immediately after reperfusion
strongly favors activation and differs markedly fromthat seen
months after engraftment (17).
Cell trafficking is also greatly altered at the time of
transplantation. Reperfusion injury initiates APC mobiliza-
tion to the lymph nodes and spleen (18), and chemokines
liberated from damaged endothelium and parenchyma at-
tracts effector cells to the organ (19). Both of these events
increase the likelihood of a specific T cell meeting its suitable
APC or target antigen thus creating a locally enhanced T cell
precursor frequency.
In addition to these general effector issues, it is impor-
tant to recognize that transplanted organs differ clinically
withregardto their susceptibility to injury. The heart needs to
function immediately and continuously, is dependent on the
electrical activity of a small volume of tissue (the conduction
system), and is susceptible to the negative inotropic effects of
local cytokines. Conversely, a kidney can fail for weeks and
still regenerate its tubules and function, and a liver can dra-
matically regenerate over half its mass even after marked in-
jury. Furthermore, the need to avoid an immune response is
greater in older organs with preexisting injury. Thus, a sur-
vivable alloimmune response varies not only from person to
person, but also from organ to organ, and donor to donor.
Consequently, the perioperative immunosuppression re-
quired to obtain a satisfactory outcome also varies.
Relating the above factors to a clinical setting is a com-
plex process and has yet to be achieved in a quantitative man-
ner. However, one can, in a very general sense, identify that
there are diverse considerations at play. For example, a mul-
tiparous (prior sensitizationraising the precursor frequency),
middle aged (relatively athymic) female who is cytomegalo-
virus (CMV)/Epstein-Barr virus (EBV) positive (increased
heterogenous immunity potential) in need of a repeat (sensi-
tization) heart transplant (high organ susceptibility) receiv-
ing a marginal (high organ susceptibility), MHCmismatched
(increased precursor frequency) donor heart on bypass
(complement activation lowering activation threshold) with
an extended ischemic time (local APC activation and cyto-
kine induced cell trafficking to the organ) is likely to have a
more critical need for control of the initial immune response
than is a CMV/EBV negative prepubescent child (potential
for thymic reeducation and low potential for heterogeny) re-
ceiving a live donor (low ischemic injury, less APC activation
and chemotaxis), haploidentical (lower precursor frequency)
liver transplant (low organ susceptibility). Similarly, the im-
mune response to a MHC-mismatched kidney from a 65-
year-old donor with 24 hr of ischemic time reperfused by a
hypotensive recipient with atherosclerosis differs consider-
ably from that seen in a MHC-dentical teenage sibling trans-
plant with 30 min of ischemia. Thus, induction should be
considered has a highly individualized practice, with its effi-
cacy determined as much by its appropriate application as its
immune effects.
Targeting Specific Elements of an Initial
Immune Response
The term immunosuppression has very broad meaning.
Indeed to say that a patient is immunosuppressed gives no spe-
cific information regarding their risk of rejection. Sim-ilarly,
stating that induction therapy is more immunosuppression
does little to indicate whether it will be effective. As each patient
comes to transplantation with a unique immune history and
eachgraft has its unique vulnerabilities, it is likely that induction
TABLE 1. Trends in induction therapy from 1994 to 2003 by organ and agent in the United States (1, 2) shown as the
percent of patients using each indicated specialized induction agent for those organ transplants listed
a
Organ
Any
Induction OKT3
ATGAM/
ATG-F Daclizumab Basiliximab ATG-R Alemtuzumab
Year 1994 2003 1994 2003 1994 2003 1994 2003 1994 2003 1994 2003 1994 2003
Kidney 25 70 24 1 1 1 0 13 0 22 06 34 0 4
Pancreas 30 79 30 0 0 2 0 10 0 8 0 35 0 35
Kidney-pancreas 48 79 48 1 2 2 1 8 1 16 0 49 0 7
Liver 13 20 9 1 5 1 0 6 0 7 0 6 0 1
Intestine 13 74 17 2 0 2 0 16 0 2 0 46 0 9
Heart 36 48 16 5 20 8 0 15 0 9 0 13 0 0
Lung 25 44 6 1 19 5 0 16 0 19 0 3 0 1
a
The general trend for all organs is an increased use of specialized induction immunosuppressants.
594 Transplantation Volume 82, Number 5, September 15, 2006
therapies should also vary in their required intensity, duration
and target. Thus, it is best to look at the variable factors that
warrant induction therapy and choose drugs to respond specif-
ically to those factors (Table 2). One will note that while many of
the elements of induction are effectively targeted by specialized
agents, several are alsoaffectedby maintenance drugs.
Precursor Frequency
Precursory frequency can be nonspecifically reduced by
depletional inductionagents. Amongthese are polyclonal anti-T
lymphocyte/ thymocytepreparations (thymoglobulin[ATG-R],
ATGAM, ATG-Fresenius [ATG-F]), and monoclonal prepara-
tions specific for common lymphocyte determinants such as
FIGURE 1. The factors influencing a need for induction immunosuppression. 1) Precursor Frequency. Thymic selection
occurs without regard for alloantigens absent in the native thymus. The na ve T cell pool thus has a relatively high allospe-
cific precursor frequency. MHCmatchinginfluences this as does theintroductionof donor antigenintotherecipient thymus.
2) Antigen Presentation. Alloantigen is presented via donor (direct, semi-direct; early) or self (indirect; late) APCs in the
secondary lymphoid tissues inducing na ve T cell activation. Costimulatory blockade (e.g. Belatacept) limits this step, as
does T cell depletion, IL2R blockade, and methylprednisolone. Drugs that alter the threshold of activation (CNIs and
mTORIs) or cell division (anti-metabolites) also affect this process. 3) Activation Threshold. In addition to cells activated in
the nodes (3.1), injured endothelium and ischemia/ reperfusion injury induces platelet and complement binding and
activation thus activating endothelial cells and donor APCs, initiating chemotactic signals, and providing signals to lower
the activation threshold of local effector cells (3.2). Limiting ischemic injury attenuates this step as may costimulatory
blockade and polyclonal antibodies (e.g. ATG-R). The local cytokine milieu reinforces local cell activation and can be
inhibited by IL2R-specific agents, methylprednisolone, CNIs and mTOR inhibitors. Allosensitized memory cells and cells
activated through heterologous immunity or homeostatic proliferation bypass the need for nodal presentation (3.3). Deple-
tion can both attenuate and augment this effect. 4) Cell Trafficking. Activated T cells and recipient APCs (e.g. monocytes)
are attracted to the graft site by chemokines and adhesion molecule expression. Reperfusion injury initiates donor derived
APCs to mobilize toward the nodes for direct presentation. Depletion, FTY720, polyclonal antibodies and methylpred-
nisolone limit chemotaxis and/or adhesion. 5) Effector response. CTLs encounter the graft in sufficient numbers to cause
clinical damage, and are reenforced by a milieu rich in T cell derived cytokines (e.g. IL2). Damage to the organ occurs
through contact dependent CTL activity andthrough the direct effect of cytolytic cytokines (e.g. TNF-). Depletion limits the
productiveness of this response and prevents the attainment of a milieu that is supportive of CTL activity. Cytokine seques-
trates also limit this step.
2006 Lippincott Williams & Wilkins 595 A.D. Kirk
CD3 (OKT3) andCD52 (alemtuzumab). It has recently become
apparent, however, that not all T cells are depleted equally. Spe-
cifically, Tcells with a memory phenotype are less susceptible to
antibody mediated depletion than are na ve cells (20). Further-
more, when the T cell population is greatly reduced, cells are
induced to undergo homeostatic repopulation (9). This
evokes a memory-like phenotype that lowers the threshold of
activation for each cell considerably. As such, remnant cells
following depletion are relatively more active following gen-
eral depletion than when present in bulk population. It is
likely that this varies considerably based on the heterologous
allospecific immune repertoire present at transplantation
(10). Thus, while there are many situations where wholesale T
cell depletion could reduce the likelihood of acute rejection,
there are also situations where the effects of depletion are
countered by the effects of repopulation and selective resis-
tance to depletion. Regardless, even in situations of profound
T cell depletion, other immunosuppressive agents are re-
quired to prevent rejection (21, 22).
Irradiation has been shown to be an effective means of
achieving general lymphocyte depletion similar in magnitude
and kinetics to that seen after polyclonal anti-lymphocyte
preparations (23). However, given the increasing availability
of potent T cell depleting agents, irradiation is now used only
in a research setting.
Attempts have been made to more specifically target
activated T cells and thus preserve the general homeostatic
properties of the general cellular repertoire. Agents designed
FIGURE 2. The effect of precursor frequency on clinically relevant immune responses. An inefficient or suppressed
immune response starting with a high precursor frequency (PF) can exceed the magnitude of an efficient unsuppressed
immune response with a low precursor frequency. In order for an adaptive immune response to occur, T cells must reach a
critical number or activity (Immune Threshold) without exceeding their physiological homeostatic parameters (homeo-
static control). An optimal immune response [perfect cell doubling (y0.5e
0.69
) black solid line] reaches this point
exponentially after a considerable number of cell divisions (in this case 20) and this anticipated rate of division is subject
to regulation to keep it within the homeostatic bounds. Thus, under physiological conditions, an immune response will
proceed at an anticipatable rate and can be controlled by means that cover an anticipatable cell density. To prevent an
immune response clinically, the efficiency of cell division need only be reduced to maintain a cell number below the
threshold for effective immunity [e.g. removing costimulation inducing reduced division efficiency, in this case 6% effi-
ciency (y0.03e
0.69
); dotted black line]. Even though immune activity has occurred it fails to reach a point where it
registers as an immune phenotype. When the precursor frequency is raised above that which is typical (e.g. from 1, solid
black line, to 100, solid gray line), an immune response proceeding at the same typical exponential rate reaches the
immune threshold faster than would be anticipated under physiological conditions (y50e
0.69
). This results in an immune
phenotype more quickly than would be anticipated by physiological regulation. More importantly, when means of attenu-
ating an immune response are applied to a nonphysiological precursor frequency [e.g. again removing costimulation
inducing a reduced 6% division efficiency (y3e
0.69
); dotted gray line] the resulting response still exceeds the rate and
progression of an optimal immune response under physiological conditions (***).
TABLE 2. Specific factors contributing to the need for induction therapy and specific therapeutic responses
Precursor frequency
Efficiency of antigen
presentation Activation threshold Cell trafficking
Biological
factors
MHC mismatch Ischemia/reperfusion,
APC activation
Sensitization, complement, heterogony,
homeostasis
Ischemia/reperfusion,
endothelial injury
Therapeutic
responses
OKT3, ATGs, Alemtuzumab,
TLI, ?IL2R, ?DST, ?mTOR
Methylprednisone,
DSG, Belatacept,
?ATGs
CNIs, mTOR, MMF, Methylprednisone,
IL2R, ?ATGs
Methylprednisone,
FTY720, ?ATGs
596 Transplantation Volume 82, Number 5, September 15, 2006
with this selective depletion strategy in mind (although their
dominant mechanisms of action are likely not depletion) in-
clude the IL2R(CD25)-specific monoclonals daclizumab and
basiliximab, and may perhaps include experimental mono-
clonal antibodies specific for CD154 (24).
The use of donor cells in the formof a blood or marrow
transfusionhas beenshowninseveral experimental models to
facilitate allospecific T cell depletion, particularly when com-
bined with agents that foster activation induced cell death
(AICD) (2528). Among these are the mTOR inhibitors
sirolimus and everolimus. While a systematic appraisal of
these mechanisms remains to be demonstrated in humans, it
is likely that appropriately dosed and timed donor antigen
facilitates precursory frequency reduction in an antigen spe-
cific manner.
Efficiency of Antigen Presentation
Na ve antigen presentation is generally initiated via ac-
tivated APCs. In transplantation, graft derived APCs likely
dominate this process early throughreperfusioninducedmo-
bilizationto the secondary lymphoidtissue anddirect presen-
tation (18). This gives way to recipient derived migratory
APCs later through indirect mechanisms (2931) and may
also be influenced by semi-direct presentationof intact donor
MHC by recipient cells (32). Good preservation techniques
and expedient implantation likely limit APC mobilization
and activation as oxidative stress has been shown to influence
APCactivationand function(33). Methylprednisolone is also
known to attenuate APC mobilization and is commonly em-
ployed during induction (34, 35). Deoxyspergualin has been
shown experimentally to limit APC activation but its appropri-
ate use in humans has not been clearly defined (36). Polyclonal
antibody preparations potentially limit APC function by inter-
rupting the immune synapse through their anti-adhesion and
MHC-specific antibodies (3740).
One of the most important properties of activated
APCs facilitating their function is the enhanced expression of
costimulatory molecules. Most prominent in this realm are
the B7 molecules CD80 and CD86. While costimulatory mol-
ecule expression is likely attenuated by glucocorticoids and
other immunosuppressive agents, this pathway has recently
been directly targeted by several biologic agents. Belatacept, a
new B7-specific fusion protein specific for the B7 molecules,
is currently in clinical trials to specifically target this aspect of
APC and T cell interaction (41).
Threshold of Activation
T cell activation occurs as an aggregate effect of many
spectral processes. Cells can reach an effective activation thresh-
old as a result of marked antigen affinity, excess antigen pres-
ence, or insituations whereantigens areweak(as aremanydirect
alloantigens), through optimal costimulation or an environ-
ment abundant in stimulatory cytokines (68, 4244).
Given that T cells have long been known to be impor-
tant in rejection, most commercially available immunosup-
pressants alter activation threshold of responding cells. These
include calcineurin inhibitors and anti-TCR antibodies (by
limiting the efficiency of TCR binding or signal transduc-
tion), mTOR inhibitor and IL2R antagonists (by limiting the
effect of activating cytokines), glucocorticoids (by, among
other things, changing the nuclear binding proteins available
to respond to the TCR), and costimulatory antagonists (by
preventing the threshold lowering effects of CD28 engage-
ment). Other environmental factors also come into play here
including complement deposited in response to alloantibody
or produced in response to ischemia (15). In general, the high
dose application of most commercially available immuno-
suppressants can be seen as addressing this and serve as in-
duction agents of sorts.
Cell Trafficking
Almost all of the mechanical processes of transplantation
evoke anincrease incell mobilityanddirect cells towardthe graft
through a combination of adhesion receptor upregulation, en-
dothelial retraction or damage, and chemotactic cytokine and
chemokine liberation. This aspect of alloimmune initiation is
being increasingly recognized as important and specifically tar-
geted therapeutically. Glucocorticoids limit adhesion molecule
expression, and the available polyclonal antilymphocyte prepa-
rations have antiadhesion molecule activity (3740).
Most recently, a new class of agent has specifically tar-
geted the chemokine pathways involved in cell homing.
FTY720 is an agonist for the sphingosine-1-phosphate recep-
tor, a molecule critical in the regulation of chemokine sensi-
tivity. Binding of FTY720 leads to internalization of this
receptor and thus inhibits physiological lymphocyte egress
from the secondary lymphoid tissues (45). Therapeutic doses
of FTY720 result in lymphocytes being sequestered in the
secondary lymph tissue thus making them unavailable in the
periphery for use as effectors. Since most primary immune
activation occurs in these sites, it remains unclear whether
sequestration prevents immunization through ignorance, or
whether the efficacy is limited to efferent mechanisms. Acrit-
ical unknown is whether chemokine inhibitors prevent or
perhaps enhance the mobilization of graft derived APCs to
the draining lymph nodes and spleen. Early trials with
FTY720 yielded promising preliminary result (46, 47), but its
development in transplantation remains uncertain at this
time.
Clinical Results with Specialized
Induction Agents
There are many specialized induction agents that are
now being used to target the components of immunity
heightened during transplantation. Many have been studied
in randomized trials and been proven efficacious when com-
bined with standard maintenance regimens and compared to
bolus methylprednisolone induction. There are few prospec-
tive studies comparing the prominent agents and no agent
has distinguished itself as clearly superior in all clinical cir-
cumstances. Most trials use the surrogate endpoint of acute
rejection, rather thanmore definitive outcome measures such
as patient or graft survival.
Specific induction agents considered as a whole have
been shown to reduce the incidence of acute rejection in the
first six months of transplantation in kidney recipients, par-
ticularly those who are sensitized, compared to the historical
standard of bolus methylprednisolone induction and main-
tenance with CsA, azathioprine and prednisone (48, 49). In-
duction in simultaneous kidney-pancreas transplantation
offers a modest trend toward reduction of rejection (50, 51)
and its efficacy in heart transplantation remains controversial
2006 Lippincott Williams & Wilkins 597 A.D. Kirk
(52). Inductionhas not beenshownto benefit liver transplan-
tation. Long-term analysis suggests that a measurable effect
on rejection in kidney transplantation disappears after five
years (49). This may indicate that the effects of maintenance
therapy or comorbidities are dominant over time.
The benefits of induction are seen without a demon-
strable change in technical complications (53) and appear to
include a reduced risk of graft thrombosis in children (54).
However, several induction strategies have been shown to
measurably increase the risk of posttransplant lymphoprolif-
erative disease (PTLD) and death from malignancy when
combined with conventional maintenance immunosuppres-
sion (55, 56). Specifically, the expected PTLD rate is 0.5% in
patients who do not receive specialized induction, or who
receive CD25-specific therapy. OKT3 induction carries a sig-
nificantly higher rate of 0.85% as does polyclonal depletion at
0.81%(56) particularlyinrecipients newlyexposedtotheEBVat
transplantation. Early complications including cardiovascular
and infectious deaths are correlated with induction use, but the
interpretation of this relationship is confounded by the prefer-
ential use of induction in high risk patients (55, 57). When con-
sidered individually, each agent class has a unique side effect
profile.
OKT3
The first monoclonal antibody approved for any ther-
apy was the mouse antihuman CD3 specific antibody OKT3
(58). OKT3 binds to CD3 causing internalization of the TCR
and simultaneous T cell activation and depletion. OKT3 was
shown to be efficacious as an induction agent in early kidney,
liver and heart transplantation (5961) when combined with
otherwise effective maintenance immunosuppression (21),
particularly in sensitized patients (62). With improvements
in technique and immunosuppression its role in liver trans-
plantation disappeared (63).
Inmore recent literature, OKT3has beenshowntoreduce
acute cellular rejection(ACR) comparedtoCsA, azathioprine or
mycophenolate (MMF), and steroids without changing patient
or graft survival (6466), but is equivalent to intravenous CsA
inductioninchildren(67). Despiteits earlyprominence, OKT3s
use as an induction agent has dramatically declined in recent
years, primarily due tois side-effect profile (1, 2). Its mechanism
of action induces a cytokine release syndrome that manifests as
fever, rigors, hypotension, and in severe cases hypotension and
pulmonary edema.
Recently anti-CD3 antibodies have been humanized and
engineered to eliminate their undesirable activating properties
(6870). Phase one studies have indicated that modified ver-
sions of a CD3-specific antibody can achieve T cell depletion
without the confounding problem of cytokine release. Clinical
trials are nowunderway investigating these antibodies as induc-
tion agents.
Polyclonal Antibody Preparations
Heterologous antibody preparations derived from im-
munized animals have been used in transplantation since the
1960s. They have been shown to mediate T cell depletion and
are used both as induction and rescue therapies. Given their
broad spectrum of specificity, they have frequently been sug-
gested to mediate their anti-rejection properties through
means other than depletion, including costimulation block-
ade, adhesionmolecule modulation, andBcell depletion(37
40). This broadspecificity has alsobeencitedas a liability with
some constituent antibodies causing thrombocytopenia and
leukopenia. Anti-endothelial antibodies in polyclonal anti-
bodies have recently been suggested to induce humoral rejec-
tion in some patients (71).
Three polyclonal preparations are currently used for
induction: two rabbit derived antibody preparations, ATG-R
and ATG-F, and one horse derived product (ATGAM). Of
these, ATG-R is used most commonly (1, 2), and appears to
be significantly better tolerated and more efficacious than
ATGAM when used in a quadruple regimen for renal
transplantation(72). BothATG-Rand ATG-F have beenpro-
spectively demonstrated to be superior to OKT3 in heart
transplantation with respect to reducing the rate and conse-
quences of acute rejection (73, 74). When compared to each
other their results have been equivalent in heart transplanta-
tion (75). Polyclonal induction agents have not been shown
to be of use in liver transplantation (76).
To date, most trials have been designed to evaluate
polyclonal antibodies added to an otherwise rigorous main-
tenance regimen (typically triple immunosuppressive ther-
apy). Not unexpectedly, this intense quadruple, sequential
regimen has reduced acute rejection rates, but been associ-
ated with a reciprocal increase in infectious morbidity (77,
78). Given that polyclonal antibodies likely target many of the
factors requiring induction and are thought to have lasting
effects both in terms of CD4 depletion and cell surface mole-
cule modulation, more recent trials have been designed to
reduce the need for maintenance therapy. Two pilot studies
have recently demonstrated that ATG-R induction facilitates
monotherapy maintenance immunosuppression in selected
patients with graft and patient survival comparable to the
current standard (79, 80). These studies have emphasized
prereperfusion administration and relatively high dose ther-
apy to specifically limit the effects of reperfusion and achieve
rapid and lasting T cell depletion. While these studies do not
indicate that this approachis preferable, they are important in
viewing effective induction as an alternative to maintenance
rather than an adjunct, specifically addressing the increas-
ingly evident adverse effects of prolonged maintenance
immunosuppression.
Alemtuzumab
Given their experience with depletion, clinicians have
searched for agents that have the benefits of monoclonal anti-
bodies (ease of administration, consistency) with the prolonged
and potent depletional capabilities seen in polyclonal prepara-
tions. The CD52-specific humanized monoclonal antibody
alemtuzumab has emerged as a promising candidate. Alemtu-
zumab rapidly depletes CD52 expressing lymphocytes (TB
cells) both centrally and peripherally (22). In preliminary un-
controlled studies it has been shown to facilitate reduced main-
tenance immunosuppressive requirements without anapparent
increase in infectious or malignant complications in kidney,
pancreas, liver, andlung transplantationwhencomparedto his-
torical controls (22, 8189). Although the efficacy of alemtu-
zumab as an induction agent has been encouraging to date, it is
just nowbeing prospectively comparedwithother regimens (90,
91). Additional experience and follow-up will be required to de-
termine this agents place in the induction armamentarium.
598 Transplantation Volume 82, Number 5, September 15, 2006
CD25-specific Antibodies
The high affinity alpha chain IL2 receptor (CD25) was
the first molecule to be successfully targeted with a human-
ized monoclonal antibody in solid organ transplantation
(92). Two CD25 (IL2R)-specific monoclonal antibodies, da-
clizumab and basiliximab, are currently available and widely
used as induction agents. These antibodies have been de-
signed with clear cognizance of the limits plaguing other
available therapies. They have been humanized (daclizumab)
or chimerized (basiliximab) to prevent drug clearance and
serum sickness associated with mouse, rabbit or horse, de-
rived proteins, and are monoclonal, free from the significant
variation associated with polyclonals. Importantly, they tar-
get a receptor unique to activated T cells, and were designed
with hopes that they would minimally alter general immuno-
competence. Their mechanism of action is thought to be pri-
marily related to their steric inhibition of IL-2 with CD25
(93). Additional effects continue to be elucidated and while
not depletional per se, these agents may facilitate an attrition
of activated cells (94).
Both anti-CD25 antibodies have been shown to reduce
the incidence of ACR compared to methylprednisolone in-
duction when used in triple or double immunosuppressive
regimens with exceptional patient tolerability in kidney, liver,
heart and islet transplantation (95101). Recent studies com-
paring basiliximab to conventionally dosed ATGAM(102) or
ATG-R(103, 104) in regimens using CsA, MMF, and steroids
have shown comparable outcomes. This induction approach
has also been successfully employed in steroid-free regimens
inkidney and liver transplantation(105, 106). The anti-CD25
approach has not been shown to facilitate monotherapy
maintenance or calcineurin avoidance to the extent seen with
depletional agents (107, 108).
Costimulation-Based Therapies
The past decade has seenexplosive interest inthe costimu-
lation pathways as targets for immune manipulation (109).
These agents reduce the efficiency of antigen presentation and
raise the threshold for activation of na ve T lymphocytes. Some
may also facilitate the elimination of cells selectively expressing
inducible costimulatory molecules (24). While most of the ex-
perimental work has been focused in tolerance induction (elim-
inationof aneedfor anymaintenance therapy), the clinical focus
has been on pairing costimulation-directed biologicals with
maintenance minimization strategies, particularly calcineurin
sparingapproaches. Agents interferingwithtwomajor pathways
have reached clinical trials. Two humanized monoclonal anti-
bodies specific for CD154, hu5c8 and IDEC-131, have been
shown in non-human primates to prevent acute rejection for
months to years without additional immunosuppression and
have also been paired with sirolimus monotherapy and donor
specifictransfusiontoleadtooperational toleranceinsomecases
(110113). Unfortunately, early human trials with hu5c8 were
hindered by unimpressive efficacy and concerns for thrombo-
embolic risk (114). As such, CD154-specific therapies have not
been studied clinically in recent years. Nevertheless, interest in
the lasting effects of costimulation blockade has remained
intense.
Two agents specific for the B7 molecules have reached
clinical trials in organ transplantation, a cocktail of humanized
antibodies specific for CD80 and CD86, and a high affinity B7-
specific fusion protein combining an engineered version of
CD152 (CTLA4) with the constant region of human IgG1, Be-
latacept. Both agents have been shown to facilitate prolonged
rejection-free survival in non-human primates with calcineurin
and steroid sparing maintenance immunosuppression (115,
116) and have been shown to be safe in Phase one trials.
Belatacept has been developed further and been shown to
facilitate calcineurin inhibitor avoidance when used as an in-
duction agent (41). Given its tolerability and apparent effi-
cacy, this agent is now entering Phase three trials with great
promise not only as a nondepletional, well-tolerated induc-
tion agent, but also as a potential maintenance agent.
CONCLUSIONS
Induction therapy has been demonstrated as an effec-
tive means of achieving low rates of acute rejection in most
allograft settings. However, the trials performed to date have
either shown that specialized induction agents have modest
benefits over regimens with non-specialized induction, or
have been associated with increased morbidity (56). This has
been a result of a rather general method of application com-
bined with a view that induction should be added to conven-
tional immunosuppression. With an increasing awareness
that induction may in fact facilitate reduced maintenance im-
munosuppression, trials are now being designed to trade in-
duction for maintenance. It is in these trials that the clinical
benefits of specialized induction agents will likely be realized
and effect lasting improvements in patient quality of life and
reductions in late morbidity and mortality.
The proper use of induction immunosuppression is still
being determined, but it is increasingly clear that the benefits
derived from specialized induction agents are determined by
their appropriate application. Modernimmunosuppressive reg-
imens should be individualized, specifically pairing induction
agents based on their mechanism of action to a specific clinical
need, and combining them with complementary maintenance
therapies.
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Pro-
gram of the National Institute of Diabetes and Digestive and
Kidney Diseases of the National Institutes of Health. The author
gratefully acknowledges Dr. Douglas A. Hale for his critical
reading of this manuscript.
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