Download Induction and Maintenance Therapy

Section 7-a
Induction and Maintenance Therapy
Palmina Petruzzo
Introduction
The optimal immunosuppressive regimen for
initial, maintenance and rejection therapy after
hand transplantation has not yet been identified.
Composite tissue allograft (CTA), such as hand
transplantation, has been performed only experimentally for many years because of the skin’s
high degree of immunogenicity. Indeed, it was
assumed that the dosage of immunosuppressive
drugs required to prevent rejection were too
high to be used safely in the clinical setting.
Advances in immunopharmacology and the
encouraging results achieved in animal models
[1–3] in this last decade allowed the realization
of different human CTAs, including larynx, knee,
hand and part of a face. These positive outcomes
have been made possible through the use of the
latest induction and maintenance regimens.
Induction Therapy
At present, all successful treatments of human
disease by transplantation (other than between
monozygotic siblings) require the use of general
immunosuppressive agents [4]. Induction therapy consists of administration of a brief course of
high-dose immunosuppression in the early posttransplant period, and it precedes and overlaps
with less intense long-term maintenance
immunosuppression. The primary objective of
induction therapy is to decrease the incidence of
acute cellular rejection as well as delay the onset
of the first episode and, when possible, delay the
introduction of calcineurin inhibitors. Induction
therapy generally refers to the use of polyclonal
or monoclonal antibodies.
Polyclonal Antibodies
Polyclonal antibodies are directed against lymphocyte antigens, but instead of the single specificity of the monoclonal antibodies, these antilymphocyte antibodies are directed against multiple epitopes. Antithymocyte globulin [5] is a
polyclonal antibody derived from either horses
(Atgam) or rabbits (Thymoglobulin). The agents
contain antibodies specific for many common Tcell antigens, including CD2, CD3, CD4, CD8,
CD11a and CD18. The antithymocyte globulin
binds lymphocytes that display the surface antigens previously listed. This effectively depletes
T-cell concentration in the body through complement-dependent cytolysis and cell-mediated
opsonization followed by T-cell clearance from
circulation by the reticuloendothelial system [6].
Monoclonal Antibodies
Monoclonal antibodies are antigen-specific
immunosuppressants that reduce immune
response to alloantigens of the graft while preserving the response to alloantigens to unrelated
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antigens. These agents are specific to the blocking of T-cell activation, resulting in rapid depletion of T cells from circulation by binding antibody-coated T cells to Fc receptors on phagocytic cells. Muromonab-CD3 is the first type of
murine monoclonal antibody directed against
the epsilon chain of the CD3 molecule (an integral part of the T cell receptor complex). It modulates the receptor and inactivates T-cell function, blocking both naïve T cells and cytotoxic T
lymphocytes (CTLs). This results in rapid depletion of T cells from circulation and cytokine
release [7]. Basiliximab (Simulect) is a chimeric
(70% human, 30% murine) monoclonal antibody
utilized in the prevention of acute organ rejection. This monoclonal antibody has a specificity
and high affinity for the “a subunit” of the interleukin (IL)-2 receptor (IL-2Ra, also known as
CD25 or Tac), preventing IL-2 from binding to
the receptor on the surface of activated T cells.
By acting as an IL-2Ra antagonist, basiliximab
inhibits IL-2-mediated activation and proliferation of T cells, the critical step in the cascade of
cellular immune response of allograft rejection.
Daclizumab [8] is a similar agent to basiliximab
but is a more humanized IgG monoclonal antibody (90% human, 10% murine). It also binds to
and inhibits the “a subunit” of IL-2 receptor.
Maintenance Therapy
Maintenance immunosuppression refers to the
classic combination therapy to which transplant
recipients usually adhere for the rest of their
lives. The combination includes a corticosteroid,
a calcineurin inhibitor and an antiproliferative.
Concurrent administration of these three drugs
has distinct combined effects on each individual.
The balance of dosages can be altered to enhance
efficacy of immunosuppression, but the most
effective combination of prescriptions is unique
for each individual. As with inductive therapy,
the goal of maintenance immunotherapy is to
find a balance between “underimmunosuppression” (which results in graft rejection) and “overimmunosuppression” (which exposes the patient
to high risks of infection and other potentially
fatal side-effects). The various side-effects of
each drug must be considered, as well as potential interactions between drugs, especially those
that cumulatively present significant risk factors
to certain patients.
Corticosteroids
Corticosteroids are an important part of maintenance therapy because of their anti-inflammatory and immunosuppressive effects [9]. They
inhibit cytokine production, circulation of lymphocytes, acid metabolites and microvascular
permeability. They also block T-cell activation
and proliferation and thus the clonal response.
The major elements blocked are IL-1 and IL-6.
Secondary effects of corticosteroids include the
blocking of IL-2, IFN-γ, and TNF-α. Prednisone
and methylprednisolone are two of the most
commonly prescribed corticosteroids for organ
transplant recipients. These drugs are nonspecific and suppress the immune system in a global
manner.
Calcineurin Inhibitors
In order to combat activated T cells (which play
a pivotal role in graft rejection), immunologists
employ calcineurin inhibitors, which have come
to be the integral cornerstone of triple therapy
for transplant recipients. Calcineurin inhibitors
block clonal expansion of T cells and therefore
significantly reduce acute rejection and improve
graft survival. This inhibition ultimately inhibits
the production and secretion of IL-2. The interaction between IL-2 and the IL-2 receptor is crucial in the activation and differentiation of B and
T cells. Cyclosporine (CSA) and tacrolimus are
the two most prominent drugs in this category;
they have comparable immunosuppressive efficacy and nephrotoxicity, which is their most
common serious side effect. CSA [10, 11] is a
fungal metabolite extracted from Tolypocladium
inflatum Gams, which works by binding a protein – cyclophilin – found in the cytosol, and this
complex inhibits calcineurin. Tacrolimus is a
metabolite of an actinomycete [12, 13],
Streptomyces tsukubaensis, which works in a
mechanism similar to that of CSA, bonding the
Induction and Maintenance Therapy
cytosolic protein FKPB-121. This complex
inhibits calcineurin in a manner parallel to CSA.
Antiproliferatives
The final part of triple therapy is antiproliferatives, such as mycophenolate mofetil (MMF),
azathioprine and sirolimus. These antimitotic
drugs inhibit DNA synthesis and thus the division of T cells. Before the advent of calcineurin
inhibitors, antiproliferatives were the primary
form of maintenance immunotherapy.
MMF is absorbed and rapidly hydrolyzed in the
blood to its active form, MPA, which inhibits the key
enzyme in the de novo pathway of purine biosynthesis, IMPDH1. Rapidly dividing cells, such as activated lymphocytes, depend on the de novo pathway for production of purines necessary for RNA
and DNA synthesis. In this way, activated lymphocytes are selectively inhibited since they are not allowed to proliferate once activated [14–16].
Sirolimus [16, 17] is a macrocyclic lactone
produced by S. hygroscopicus and resembles
tacrolimus and binds to the same intracellular
binding protein or immunophilin known as
FKBP-12. However, sirolimus has a novel mechanism of action: it inhibits activation and proliferation of T lymphocyte in response to stimulation by antigens and cytokines (IL-2, IL-4 and
IL-15). This inhibition is believed to be mediated
by a mechanism distinct from that of tacrolimus,
CSA or other immunosuppressants. It binds to
the immunophilin FK binding protein-12
(FKBP-12). The sirolimus FKBP-12 complex,
which has no effect on calcineurin activity, binds
to and inhibits activation of the mammalian target of rapamycin (mTOR), a key regulatory
kinase. This inhibition suppresses cytokinedriven T-cell proliferation, inhibiting cell-cycle
progression from the G1 to the S phase.
Induction and Maintenance
Therapy in Hand Transplantation
Induction and maintenance regimens used in
hand transplantation were similar to those
employed in solid organ transplantation.
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Clinical experience of CTA showed that it does
not need a particular immunosuppressive strategy. The majority of teams involved in hand
transplantation performed induction therapy
using antithymocyte globulins (ATG) while the
others used basiliximab [18]. The results in
terms of efficacy for basiliximab are on par with
ATG in recipients with low risk of acute rejection, but it has less success with higher-risk
patients. However, it elicits less adverse events
than ATG. Since the question of the effectiveness
of monoclonal or polyclonal antibody therapy
remains highly controversial in organ transplantation, ischemia-reperfusion injury determined
by a long cold ischemia time has to be considered in hand transplantation. It is likely that in
limb transplantation this injury may be greater
than in whole-organ transplantation because of
operation length and because of the mass of different transplanted tissues. Recent studies
showed that ATG might contribute to decrease
graft cellular infiltration during acute rejection
and possibly after postischemic reperfusion
[19]. Moreover, there is an advantage to using
polyclonal antithymocyte globulins, as they are a
mixture of antibodies against lymphocyte receptors and adhesion molecules with consequent
lymphocyte depletion but also significant downregulation or binding of other receptors and new
mechanisms of immunosuppression, such as
apoptosis of activated lymphocytes, which could
be important in tolerance induction [20].
Maintenance therapy used in hand transplantation by the large majority of teams has been a
combination regimen including glucocorticoids,
tacrolimus and MMF. The overall effect of combining several drugs that act by different mechanism is to achieve a powerful immunosuppressive effect with low doses of each drug, reducing
drug-related toxicity. Glucocorticoids were used
in all CTAs, and we have learned that it would be
better to use high doses only in the initial period
posttransplantation and decrease them slowly at
a level of 5 mg. Although chronic use of glucocorticoids does not seem to have particular
implications in CTA, as no alteration of wound
nor bone healing were reported, the toxicity of
chronic use of steroids is well known [21, 22],
and it has been confirmed by a case of hip necrosis in a hand-grafted patient.
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In solid organ transplantation, a number of
studies have demonstrated that acute rejection is
the primary determinant for the later development of chronic rejection, and treatment of this
occurrence increases risks and costs of transplantation. For this reason, in kidney transplantation,
the combination of prednisone, tacrolimus and
MMF was used to provide an effective immunosuppression resulting in less rejection [23]. The
same regimen was used in hand transplantation
showing its efficacy and safety in experimental
and clinical studies. Use of these three drugs allowed a decrease in dosage of glucocorticoids and
tacrolimus, thus influencing the incidence of sideeffects such as diabetes mellitus and nephrotoxicity. In addition, tacrolimus not only is known to
decrease the number of acute rejection episodes
compared with cyclosporine in renal allograft recipients, but it seems to accelerate axonal regeneration, increasing the synthesis of axotomy-induced growth-associated protein (GAP-43) [24]
and enhance osteoblastic differentiations induced
by bone morphogenic protein-4 [25]. It is very in-
teresting to note that the association of glucocorticoids, tacrolimus and MMF has no adverse effect
on vascular ingrowth; in fact, early callus formation and revascularization are normal compared
with forearm replantation as well as the next phase
of bone maturation to chondral and ossified callus [25].
Although sirolimus was used only in two handgrafted patients, it may be used as rescue therapy
for refractory allograft rejection or when calcineurin inhibitors determined major adverse effects. It is a powerful immunosuppressive drug
with antiproliferative effect and may have a potentially important role on prevention of chronic allograft rejection in the future of CTA.
Although immunosuppressive treatments
used by various hand transplantation teams
achieved results that were previously considered
a “miracle”, careful management of the recipient
is still indispensable and requires drug combination to strengthen rejection prophylaxis and
reduce doses of individual drugs in order to
avoid toxic effects.
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