Immunosuppression

allowed for lower doses of all drugs, which mini-

mizes the potential side effects and toxicities of

The underlying premise of organ transplanta-

these

powerful

antirejection

medications.

Overall, there are no absolute rules in determin-

tion is to promote acceptance of a foreign organ

ing which and how much of each antirejection

while attempting to prevent rejection and main-

drug to utilize. There is significant bias from one

tain the immune system’s integrity. This is a

transplant center to another, and pharmaceuti-

delicate balance to strike. Complicating the issue

cal companies compete actively.

is individualizing patients’sensitivities to immu-

Modern immunosuppressive therapy may be

nosuppressive medications as well as specific

broken down into three distinct types. The initial

physiologic states that may affect their levels of

exposure to immunotherapy is induction ther-

tolerance or rejection.

apy. This entails the use of antibody preparations

The first

successful renal

transplant with

within the first week posttransplant to reduce

long-term function was performed by Joseph

exposure to calcineurin inhibitor toxicity or to

Murray between twin males in 1954. During this

decrease the incidence of rejection within the

time, they realized that foreign

organs were

first 6 months. Maintenance therapy is the life-

rejected at

alarming rates. This

necessitated

long use of immunosuppression to prevent rejec-

matching between twin siblings during this era

tion. This therapy is frequently fine-tuned over

of transplantation. The progression of immuno-

the lifetime of the allograft. Often, the therapy is

suppression began with the institution of total

weaned to lower levels as some level of tolerance

body irradiation, thoracic duct drainage, and

is achieved. Furthermore, the incidence of rejec-

splenectomy. During the late 1950s and early

tion is highest during the first 6 months of trans-

1960s, pharmacologic methods of immune sup-

plantation. Finally, rejection is observed when

pression became prevalent.Corticosteroids were

the innate immune system recognizes the foreign

employed in 1956 and azathioprine was intro-

organ and begins to mount a response. This

duced in 1962. Polyclonal antibodies were devel-

occurs secondary to many causes including drug

oped in the mid-1960s. These advances were

noncompliance,malabsorption of drug,etc.Most

brought from the basic science laboratories to

often,

use of high-dose steroids

or antibody

the clinical bedside and permitted for the pre-

preparations are employed to reverse rejection.

vention of rejection and long-term maintenance

of the functioning allograft.

Major advances in the field of transplantation

mirrored such advancements in immunosup-

Induction Therapy

pression. With the discoveries of cyclosporine

and tacrolimus, the field of transplantation was

The goal of induction therapy is to provide potent

transformed. It became commonplace to expect

immunosuppressive activity during the initial

and achieve long-term graft survival with more

7–14 days following transplantation. This allows

easily treatable and less frequent allograft rejec-

for coverage of the patient while introducing and

tions. The mechanism of action of cyclosporine

titratingmaintenanceimmunosuppressivedrugs.

and tacrolimus is the inhibition of calcineurin.

Induction has been demonstrated to be extremely

This prevents the transcription of IL-2, and its

effective in decreasing rates of rejection. Its use

subsequent actions on T-cells as described

has increased as has its effectiveness. Polyclonal

above.

antibody preparations include Atgam and

The pharmacologic principles of immuno-

Thymoglobulin, while monoclonal preparations

suppression have evolved since their inception.

include OKT3, Basiliximab, Alemtuzumab, and

The goal is to titrate the immune response to

Daclizumab. Standard for induction therapy has

prevent rejection while attempting not to over-

been the use of high-dose steroids and, in some

immunosuppress and elicit infection. Immu-

cases, an antilymphocyte antibody preparation.

nosuppression is usually initiated before or

Unfortunately, it is an expensive endeavor, cost-

during surgery. Furthermore, other drugs have

ing $1,000–$1,500 per day of treatment.

been developed such as mycophenolate mofetil,

Thymoglobulin

induces dose-dependent

an inosine

monophosphate

dehydrogenase

T-cell depletion in both the blood and periph-

inhibitor, to assist as antirejection therapies. The

eral lymphoid tissues. This depletion is thought

concomitant use of all of these therapies has

to involve complement-dependent lysis and

activation-associated apoptosis. Thymoglobulin

period, while other centers administer the doses

also modulates several functional molecules

split over several days. Of course, many centers

that mediate the interaction between leukocytes

fall in between these two extremes. Others advo-

and the endothelium. As a result, there is decre-

cate the use of induction in only select cases.

ased leukocyte adhesion and translocation into

What is clear is that highly sensitized patients

sites of inflammation (Figs. 14.2 and 14.3)8-11).

benefit from the use of a combined steroid and

The monoclonal antibody preparations have

antilymphocyte regimen as induction. These

gained some acceptance as well. The original

highly sensitized patients include those with

monoclonal antibody, OKT3, is T-cell directed. It

previous exposure to blood transfusions, previ-

binds CD3 and was historically used for induc-

ous transplantation, and African-Americans.

tion as well as treatment of rejection. Unfor-

Induction therapy occasionally prolongs hos-

tunately, it may cause a cytokine release

pitalization.As a result,some centers have begun

syndrome initiating a life-threatening anaphy-

to alter the administration schedule as outlined

lactoid reaction resulting in hypotension and

above. Antilymphocyte antibody preparations

pulmonary edema. Newer monoclonal prepara-

are often given as a single dose initiated periop-

tions include Daclizumab and Basiliximab. They

eratively and continued until the final and goal

are monoclonal antibodies directed at the IL-2

dose is achieved. Many agree that a full dose

receptor. They are primarily utilized for induc-

constitutes 6 mg/kg. Significant side effects can

tion and have few, if any, side effects.

be observed secondary to induction therapy.

There are as many derivations of induction

Many cytokines are released as a consequence

therapy as there are transplant centers. There is

of induction. Potential opportunistic infections

obviously no clear and correct manner to

occur at an increased rate and pose a significant

administer induction therapy. Some centers will

threat to the patient as well as the allograft via-

administer the entire induction at once during

bility. Rarely, a patient may also develop anti-

the operative and immediate postoperative

bodies to the antilymphocyte antibody.

Thymoglobulin®

Thymoglobulin®

Thymoglobulin®

Human

iC3b

Complement

(C1q...)

T cell

T cell

T cell

FcR

CR3

CD14

Macrophage

Complement

CD36

anb3

cascade

PS-R

Macrophage

ABC-1

Opsonization

etc.

Membrane attack

Apoptosis

complex

Lysis

Phagocytosis

Phagocytosis

Demonstrated

Demonstrated

Hypothetical

Target Of Rapamycin (mTOR), a key regulatory

gain, ulcers, and nausea. They cause hyperglyce-

kinase. This inhibition suppresses cytokine-

mia and promote diabetes mellitus. Acne, hir-

driven T-cell proliferation, inhibiting the pro-

sutism, skin atrophy, and easy bruising are

gression from the G1 to the S phase of the cell

frequent side effects. Muscle weakness and

cycle. Its main side effect is the inhibition of the

osteoporosis often ensue. Many patients experi-

healing process; however, it may also cause

ence edema, hypertension, and hypernatremia.

hyperlipidemia and bone marrow suppression.

Ultimately, a subset of patients with long-term

Sirolimus use has become more popular because

steroid use may develop Cushing’s syndrome.

of lower rates of chronic rejection relative to

Transplant physicians and surgeons are con-

cyclosporine-based therapy.15

stantly adjusting immunosuppression on a per-

The second drug added to the immunosup-

sonalized patient basis for the life of the allograft

pression regimen is often mycophenolate mofetil

and patient. These judgments are made based

(Cellcept, MMF), mycophenolic acid (Myfortic,

on each patient’s clinical presentation, labora-

enteric-coated MMF), or azathioprine (Imuran).

tory values, and other associated or unassoci-

Azathioprine was one of the first drugs devel-

ated illnesses. In general, patients require higher

oped for immunosuppression and has a storied

levels of immunosuppression early in their post-

role in the early progression of kidney and liver

operative course; however, immunosuppression

transplantation. It decreases both T- and B-cell

may be weaned to lower levels within 3–6 months

production by antagonizing purine metabolism.

posttransplant in most cases. The balance

As a result, it inhibits synthesis of DNA, RNA,

between excessive and inadequate imunosup-

and proteins. Azathioprine may also interfere

pression must be found. A steady-state immu-

with cellular metabolism and inhibit mitosis.

nosuppressive regimen may be altered by the

Azathioprine unfortunately has been associated

patient’s pharmacokinetics and dynamics or

with bone marrow suppression, pancreatitis,

a concomitant illness. As a result, immuno-

and has significant drug interactions. Myco-

suppression should be adjusted accordingly.

phenolate mofetil and mycophenolic acid pri-

Over-immunosuppression may result in an opp-

marily decrease B-cell production, although

ortunistic infection, malignancy, or PTLD.

they exert some effect on T-cells. They are selec-

Under-immunosuppression will almost inevita-

tive but reversible inhibitors of inosine mono-

bly result in organ rejection.

phosphate dehydrogenase, which is a critical

enzyme for the de novo synthesis of guanosine

Rejection

nucleotides. They have been found to decrease

the incidence of antibody-mediated rejection

Organ rejection manifests as an innate immu-

and reduce the prevalence of chronic rejec-

nologic reaction to donor tissue. There are four

tion.13,16 They have some minor bone marrow

main types: hyperacute, accelerated, acute, and

suppressive effects, but their primary side effect

chronic. The outcome may result in organ dam-

is gastrointestinal disturbance, which may be

age with the possible eventual loss of the

decreased with the enteric-coated form.

allograft. Moreover, only acute rejection is com-

Corticosteroids are the third drug class in the

pletely responsive to therapy. Hyperacute rejec-

armamentarium of maintenance therapy. They

tion is extremely rare and, in most cases,

are usually used in the IV or PO forms, methyl-

preventable. These are the so-called pre-formed

prednisolone or prednisone, respectively. Ster-

antibodies that immediately attack the foreign

oids have a broad set of physiologic effects and

organ.Anti-HLA antibodies within the serum of

subsequent side effects. In the field of solid

the recipient react towards the donor organ. The

organ transplantation, they are employed in the

onset is nearly immediate within minutes to

prevention as well as the treatment of rejection.

hours. Vascular damage begins immediately

With regard to immunosuppression, they inhibit

resulting in inflammation, congestion, throm-

T-cells, IL-2, and antibody formation. Unfor-

bosis, and necrosis. Unfortunately, the only

tunately,steroids have serious deleterious effects.

recourse is to remove the offending organ.

Centrally, they can often cause mood swings and

Accelerated rejection is a more indolent form

psychoses as well as cataracts and glaucoma.

of hyperacute rejection. There is usually a low

From a gastrointestinal standpoint, they are

level of circulating non-HLA antibody against

associated with increased appetite and weight

donor tissue. The onset occurs 3–10 days