Methods of immunosuppression

METHODS OF
IMMUNOSUPPRESSION
Presented by–
Dr. Shahanur Rahman

Immunosuppression
Involves an act that reduces the
activation or efficacy of the immune
system.

Immunosuppression is induced by-
medications
surgery (spleen removal),
plasmapharesis, or
radiation

History
Initial attempts at immunosuppression tried with
Total body radiation  all the patients expired.
First immunosuppressant identified  Cortisone
 side-effects limited its use.
Research work by Sir Peter B. Medowar (1940) 
led to a better understanding of Immuno system
 considered to the birth of Transplant
immunobiology.

First to report a series of human-to-human
kidney transplants in the 1940s  Yu Yu
Voronoy (Russian surgeon)  outcomes were
dismal.
Long-term success Joseph E. Murray in
Boston, (1954) identical twins no
immunosuppression required.

Pharmacological immunosuppression era
 6-mercaptopurine  azathioprine
(1960s)
Primary immunosuppressive regimen 
azathioprine and steroids (1962 and
1964)
Polyclonal antilymphocyte globulin
1967.

Nobel Prize in Physiology/Medicine
Dr. Joseph Murray, 1990
(immunosuppression).
Mycophenolate mofetil (1994)
replaced azathioprine (almost
universally)
Tacrolimus (1994) replaced
cyclosporine

Immunosuppression is performed to
Prevent rejection of organ transplant,
Treat graft-versus-host disease after a bone
marrow transplant,
Treat auto-immune diseases such as
 systemic lupus erythematosus, rheumatoid
arthritis,
 Crohn's disease, ulcerative colitis,
 multiple sclerosis, myasthenia gravis,
 focal segmental glomerulosclerosis,
 Behcet's Disease, pemphigus.

Immunobiology
• Immune system has two complementary
divisions:
Innate immune system: acts during ischemia,
necrosis or trauma.
Acquired immune system: specifically recognizes
foreign substances (peptide or carbohydrate
moieties) and do disposition. It has immunologic
memory also.
 Cellular  T cell  T cell receptor (TCR)
 Humoral  B cell  B cell receptor (antibody)

B cell receptor (antibody): can identify its epitope
directly without preparation of the antigen.
T cells: only recognize specific epitope after it has
been processed and bound to histocompatibility
proteins.
 Major histocompatibility complex (MHC) – cluster of
highly conserved polymorphic genes located on short
arm of chromosome 6.
 In human its called HLA (human leukocyte antigen) –
these MHC molecules binds to peptide antigens 
processed it and present to TCR  called antigen
presentation responsible for human transplant
rejection.

Types of MHC molecules -
 HLA class I
 HLA class II
 HLA class III
HLA antigens:
 Are the most common cause of graft rejection.
 Their physiological function is to act as antigen
recognition units.
 Are highly polymorphic (amino acid sequence
differs widely between individuals).
 HLA-A, -B (class I) and -DR (class II) are most
important in organ transplantation.

HLA class I molecules –
Comprises of HLA-A, -B and –C.
Present on all nucleated cell and platelet.
Specific for CD8+ T cells.
T cell activation occurs when-
CD8+ T cells binds to free antigen bound with class
I MHC.
Cross-presentation: when APCs (dendritic cells)
take up and process exogenous antigen and
present it on class I molecules to CD8+ T cells.
Direct allo-response: in case of transplantation T
cells directly interact with the graft tissue class I
MHC antigens.

HLA class II molecules –
Comprises of HLA-DR, -DP and –DQ.
Present on antigen presenting cells (macrophage,
dendritic cell, B cells, activated T cells) and can appear on
parenchymal cells in case of cytokine release cause by
transplantation.
Specific for CD4+ T cells.
T cell activation occurs when-
CD4+ T cells binds to free antigen bound with class I
MHC.
Indirect allo-response : when APCs (dendritic cells)
take up and process exogenous antigen and present it
on class II molecules to CD4+ T cells.
Direct allo-response: in case of transplantation T cells
directly interact with the graft tissue class II MHC
antigen because trauma of surgery or ischemia can up-
regulate class I molecules on all cells of an allograft .

HLA class III molecules –
Examples – TNF-alfa, TNF-beta, HSP-70, and
component of complement cascade.
Blood group antigens of ABO system –
ABO antigens must be consider in transplantation, takes
part in hyperacute and acute rejection.
Rh antigens however not considered.
Minor histocpmpatibility complex –
Exists in the genome outside of HLA locus.
Play a minor role in transplant rejection.
Point to be noted is that even HLA identical individuals
are subjected to rejection on the basis of this minor
antigens.

Co-stimulation
Recognition of the antigen-MHC complex via TCR
(signal 1) binding is not sufficient to generate a
response in naïve T cell.
Co-stimulatory pathway (signal 2) required
optimal T cell activation.
In absence of co-stimulation (signal 2) T cells fails
achieve activation  leads to a state of
inactivation/anergy.
There are two co-stimulatory pathway-
 CD28-B7 pathway
 CD154-CD40 pathway

 CD28-B7 pathway:
CD28 presents on T cells and B7(CD80 & CD86) on APCs.
CTLA-4 is a ligand for CD80 & CD86 (upregulated and
expressed on activated T cells)  binds B7 receptors (10 to
20 times greater affinity than CD28)  negative regulatory
effect on T cell activation and proliferation.
CTLA-4 Ig (abatacept): binds to B7 molecules  prevents
costimulation via CD28.
 CD154-CD40 pathway:
CD154 primarily found on activated T cell and CD40 found
on cell surface of endothelium, Dendritic cells and B cells.
TCR signaling  up-regulation of CD154 on T cells  CD154
binds to CD40 of APCs  signal for B cell activation and
proliferation and co-stimulate cytotoxic T cells.

HLA typing:
HLA matching has a relatively small but definitive role
on renal allograft survival (HLA-DR>HLA-B>HLA-A)
Well matched renal allograft recipient may require
less intensive immunosuppression and encounter less
rejection episodes.
HLA identical allograft – matched at all HLA loci
(though not an isograft, still differ genetically at other
genetic loci)
HLA haploidentical allograft – matched at half of HLA
loci.
Degree of HLA mismatch:
‘000 mismatch’ - complete match
‘012 mismatch’ – matched at HLA-A loci, one mismatched at
HLA-B loci and Both mismatch at HLA-DR loci.

 Allograft rejection manifests itself as functional failure of
the transplant and is confirmed by histological examination.
 Biopsy material is obtained
 renal and pancreas grafts by needle biopsy, and
 hepatic grafts by percutaneous or transjugular liver biopsy.
 Cardiac grafts are biopsied by transjugular endomyocardial
biopsy and
 lung grafts by transbronchial biopsy.
 small intestinal transplantation, mucosal biopsies are obtained
from the graft stoma or more proximally by endoscopy.
 A standardised histological grading system, termed the
Banff classification defines the presence and severity of
allograft rejection after organ transplantation

Types of allograft rejection
Type Time Pathological
findings
Mechanism Treatment
Hyperacute
Rejection
Minutes to
hours
Thrombosis,
necrosis
Preformed antibody
and complement
activation (type II
hypersensitivity)
None,
Only prevention
Acute
Rejection
5-30 days Vasculitis
Cellular
infiltration
Antibody, T and B
lymphocytes
CD4 and CD8 T cells
(type IV
hypersensitivity)
Removal of antibody
through
plasmapheresis,
Increase
immunosuppression
Chronic
Rejection
> 30 days Fibrosis,
scarring
Immune and non-
immune mechanisms
Minimise drug toxicity,
control hypertension
and hyperlipidaemia

Hyperacute rejection
 A very rapid type of rejection, occurs immediately,
within minutes to hours.
 Triggered by preformed antibodies against the
donor’s HLA or ABO blood group antigens.
 Ab Arises from
previous blood transfusion,
a failed transplant,
pregnancy or
ABO incompatible organ transplantation.
 Resulting in irreversible graft destruction
immediately after organ reperfusion.

• Characterised by Intravenous thrombosis, interstitial
haemorrhage and necrosis.
 Example: Kidney transplants are particularly vulnerable
to hyper-acute graft rejection. Liver is resistant to
hyperacute rejection (dual blood supply)
 No treatment available.
• Prevented by: ensuring ABO blood group compatibility
and by performing a cross-match test on recipient
serum(in which the donor’s cells are mixed with the
recipient’s serum and then destruction of the cells is
observed).

Acute Rejection
Occurs usually within a few days or
weeks post-transplant (5-30 days)
The most common type of rejection.
Mediated by: predominantly T
lymphocytes but allo-antibodies play an
important role.
Characterized by: mononuclear cell
infiltration of the graft.

The diagnosis: of acute rejection is based on
the results of
biopsies of the transplanted organ,
special immunologic stains and
laboratory tests.
Treatment: Most episodes of acute rejection
can be reversed by additional
immunosuppressive therapy.

Acute renal allograft rejection with a heavy
mononuclear cell infiltrate and intimal arteritis.

Acute renal allograft rejection, widespread staining for the
complement component C4d within the peritubular capillaries
that indicates alloantibody binding to the graft vasculature.

Some Laboratory tests are:
elevated creatinine levels in kidney
transplant recipients,
elevated liver function values in
liver transplant recipients,
and elevated levels of glucose,
amylase and lipase in pancrease
transplant recipients).

Chronic rejection
is a slow type of rejection, occurs after 30 days
posttransplant to the first six months,
progresses gradually over several years.
is a major cause of allograft failure.
The mechanism: Immune and non-immune
mechanisms.

Organ-specific features of chronic
graft rejection
Kidney: glomerular sclerosis and tubular atrophy;
Pancreas: acinar loss and islet destruction;
Heart: accelerated coronary artery disease
(cardiac allograft vasculopathy);
Liver: vanishing bile duct syndrome;
Lungs: obliterative bronchiolitis.

The histological picture of chronic rejection
after organ transplantation:
myointimal proliferation in graft arteries (vascular
changes)  ischaemia and fibrosis.
Pathologic changes eventually lead to fibrosis
and loss of graft function.

Chronic renal allograft rejection, The arteriole shows severe
myointimal proliferation and luminal narrowing, resulting in
ischaemic fibrosis.

Graft versus host disease (GVHD)
• Mechanism: Bone marrow and some donor
organs (particularly liver and small bowel) contain
large numbers of lymphocytes  these donor T
cells recognize the allogeneic HLA antigens (MHC
molecules) or the minor histocompatibility
antigens of the host  initiate an inflammatory
immune response against host tissue  leading
to graft-versus-host disease (GVHD).
frequently involves the skin, causing a
characteristic rash on the palms and soles.
It may also involve
 the liver (after small bowel transplantation) and
 the gastrointestinal tract (after liver transplantation).

?How to overcome the risk of GVHD
Taking graft from:
Genotypic identical sibling.
Other family members.
Matched unrelated donor.
(Though the probability that any two
unrelated persons will match, is extremely
low)

Immunosuppressive drugs
 Small-molecule drugs
 Immunophilin-binding drugs
 Calcineurin inhibitors
 Cyclophilin-binding drugs: cyclosporine
 FKB12-binding drugs: tacrolimus,
modified release tacrolimus
 Target-of-rapamycin inhibitors: sirolimus,
everolimus
 Inhibitors of nucleotide synthesis
 Purine synthesis (IMDH)
inhibitors Mycophenolate mofetil,
Enteric-coated mycophenolic acid (EC-MFS)
 Mizoribine (MZR)
 Pyrimidine synthesis (DHODH)
inhibitors LeflunomideFK778
 Antimetabolites: azathioprine (Aza)
 Sphingosine-1-phosphate-receptor
antagonists: FTY720
 Glucocorticoids
 Protein drugs
 Depleting antibodies (against T cells, B cells, or
both)
 Polyclonal antibody: horse or rabbit
antithymocyte globulin
 Humanized monoclonal anti CD-52 antibody
(alemtuzumab)
 B-cell-depleting monoclonal anti-CD-20
antibody (rituximab)
 Mouse monoclonal anti-CD3 antibody
(muromonab-CD3)
 Nondepleting antibodies and fusion proteins
 Humanized or chimeric monoclonal anti-
CD25 antibody (daclizumab, basiliximab)
 Fusion protein with natural binding
properties: CTLA4-Ig (Belatacept)
 Intravenous gammaglobulin
 C5 inhibitor Eculizumab
 Protease inhibitor Bortezomib

Immunosuppressive agents. Principal mode of action
Corticosteroids Widespread anti-inflammatory effects
Azathioprine Prevents lymphocyte proliferation
Mycophenolic acid
Preperations
Prevents lymphocyte proliferation
Calcineurin inhibitors Blocks IL-2 gene transcription
mTOR inhibitors Blocks IL-2 receptor signal transduction
ALG Depletion and blockade of lymphocytes
Anti-CD52 mAb Depletion of lymphocytes
Anti-CD25 mAb Targets activated T cells
CTLA-4Ig Blocks T-cell costimulation
Anti-CD20 Depletion of B lymphocytes

Site of action of immunosuppressive agents on T cell.

Immunosuppression is delivered in two phases
A. Induction (started immediately post-transplant, when the risk of
rejection is highest) and done with anti-T-lymphocyte–depleting
or non-depleting antibodies.
B. Maintenance (usually started within days post-transplant and
continued for the life of the recipient or graft) and conventionally
done with calcineurin inhibitors, anti-proliferative agents, and
corticosteroids.
Thus, the level of immunosuppression is highest in the first 3
to 6 months post-transplant; during this time, prophylaxis against
various bacterial, viral, or even antifungal opportunistic infections
is also given.

• Dual Therapy: Calcineurin inhibitors +
Antiproliferative agents / Corticosteroids.
• Triple Therapy: Calcineurin inhibitors +
Antiproliferative agents + Corticosteroids.
• Quadriple Therapy: Polyclonal antibodies +
Calcineurin inhibitors + Antiproliferative
agents + Corticosteroids. (Risk of Acute
Rejection)

Induction
Includes the use of depleting (polyclonal) antibodies
or non-depleting antibodies within the first month
post-transplant.
Advantages: induction with antibody regimens may
prevent acute rejection, potentially leading to
improved graft survival and the use of less
maintenance immunosuppression.

Atgam (which has largely been replaced
by Thymoglobulin) is a purified gamma
globulin obtained by immunizing horses
with human thymocytes.

Thymoglobulin
(Rabbit anti-thymocyte globulin) is a purified gamma
globulin obtained by immunizing rabbits with human
hymocytes.
Contains antibodies to T cells and B cells, integrins
and other adhesion molecules, thereby resulting
in rapid depletion of peripheral lymphocytes.
Doses: total dose 6 mg/kg (more doses and
prolonged duration increase the risk of infection
and the potential occurrence of lymphoma.)

Thymoglobulin
Pre-medications: causes a cytokine release
syndrome, so pre-medications (acetaminophen and
diphenhydramine) are usually given.
Adverse effects:
 fever, chills, arthralgias,
 thrombocytopenia, leukopenia, and
 increased incidence of a variety of infections.

Alemtuzumab (Campath)
 anti-CD52 monoclonal antibody.
 Mode of Action: causes cell death by complement-mediated
cytolysis, antibody-mediated cytotoxicity and apoptosis 
profound lymphocyte-depleting effects.
 Doses: One dose alone (30 mg) depletes 99% of lymphocytes.
 Recovery:
 Monocyte recovery can be seen at 3 months post-transplant;
 B-cell recovery at12 months; and
 T-cell recovery, albeit only to 50% of baseline at 36 months.

Alemtuzumab (Campath)
Premedications: causes a significant cytokine
release reaction and often requires
premedications (steroids and antihistamines).
Complications: Because of the long-lasting T-cell
depletion, there is always risks of infection and
post-transplant lymphoproliferative disorder
(PTLD).
Currently, alemtuzumab is available only
through a limited distribution program, not
through commercial medication distributors.

Rituximab
 A chimeric anti-CD20 (anti-B cell) monoclonal
antibody.
 Currently FDA approved for treating lymphoma.
 The CD20 antigen is expressed early in the B-cell
cycle but is absent on mature plasma cells.
 The variable region binds to CD20, cause B cell
depletion through three different mechanisms:
(a) antibody dependent cell cytotoxicity,
(b) complement-dependent cell killing, and
(c) induction of apoptotic cell death.

Rituximab
 Use: treatment of antibody-mediated rejection and
use in desensitization protocols.
Usually used in conjunction with plasmapheresis,
steroids, and intravenous immunoglobulin(IVIG).

Muromonab-CD3
MOA: This agent displaces the T3 molecule
from antigen receptors, captures all mature T
cells, and prevents alloantigen recognition.
The reversal rate of first acute rejection
episodes is 94%.
Muromonab-CD3 is sometimes used as the
first-line agent for severe vascular rejections.
A second course of muromonab-CD3 may be
given for recurrent rejection.
The success rate in recurrent episodes is
approximately 40-50%.

IL-2 Receptor Antibodies (Basiliximab/Daclizumab)
Basiliximab (Simulect)
is an anti-CD25/ IL-2 receptor monoclonal
antibody.
MOA: The alpha subunit of the IL-2 receptor, also
known as CD25 or Tac, is found exclusively on
activated T cells. Blockade of CD25  prevents IL-2
induced T-cell activation.
Uses: Usually, it is followed by the use of
calcineurin inhibitors, corticosteroids and MMF as
maintenance immunosuppression.

Basiliximab (Simulect)
 Advantages: Its selectivity in blocking IL-2 mediated
responses makes it a powerful induction agent
without the added risks of infections, malignancies
or other major side effects.
 Disadvantages: No lymphocyte depletion occurs with
Basiliximab; it is not designed to be used to treat
acute rejection.
 Currently, basiliximab is the only available anti-CD25
monoclonal antibody approved for clinical use.

Belatacept (CTLA4-Ig)
MOA: Antibody against the cytotoxic T-
lymphocyte–associated protein 4 (CTLA4) 
binds to CD80 and CD86  blocks T-cell
costimulation pathway.
Disadvantages: Belatacept was not inferior to
cyclosporine in both patient and allograft
survival rates, but was associated with a
higher rate of biopsy proven acute cellular
rejection.

Belatacept (CTLA4-Ig)
 Adverse effects: an increased risk of posttransplant
lymphoproliferative disorder (PTLD); the greatest risk is in
recipients who are Epstein-Barr virus (EBV)-seronegative
pretransplant.
 Uses: New drug for maintenance immunosuppression in renal
transplants only.
 The FDA recommends the use of belatacept only in
seropositive recipients. Studies in liver transplant recipients
were halted early because of increased mortality rates.

Maintenance
 Cyclosporine
 Tacrolimus
 Mycophenolate mofetil
 Azathioprine
 Corticosteroids
 Sirolimus
 Belatacept

Cyclosporine (A calcineurin inhibitor)
Mode of Action: binds with its cytoplasmic receptor
protein, cyclophilin  inhibits the activity of
calcineurin  decreasing the expression of several
critical T-cell activation genes, the most important
being for IL-2  T-cell activation is suppressed.
Gengraf and Neoral, are micro-emulsified with
improved bioavailability.
Doses: intravenously or orally to maintain trough
levels of 250 to 350 ng/mL for the first 3 months post-
transplant  it can be tapered to 150 to 250 ng/mL.

Cyclosporine (A calcineurin inhibitor)
 Uses: Used in maintenance protocols.
 Adverse effects:
 nephrotoxic - constrict the afferent arteriole in a
dose-dependent, reversible manner.
 hyperkalemia and hypomagnesemia.
 Neurotoxicity - headaches, tremor, and seizures
also have been reported.
 undesirable cosmetic effects, including hirsutism
and gingival hyperplasia noted.
 It is associated with a higher incidence of
hypertension and hyper-lipidemia than
tacrolimus.

Gingival hyperplasia due to
Cyclosporine

 Its more effective in acute rejection (primary
immunosuppression and rescue therapy).
 This calcineurin inhibitor is now the backbone of most
immunosuppressive regimens.
 Used as mainstay of maintenance protocols.
 Mode of Action: binds to FKBPs  inhibition of IL-2
production (10 to 100 times more potent than cyclosporine).
 Route: intravenously, orally, or sublingually
 Doses: to maintain trough levels of 8 to 12 ng/mL for the first
3 months post-transplant; then it can be tapered to 6 to 10
ng/mL.
Tacrolimus (Prograf)

Tacrolimus (Prograf)
Adverse effects: causes a higher incidence of
post-transplant new-onset diabetes than does
cyclosporine.
Other side effects:
 alopecia,
 nephrotoxicity,
 neurotoxicity,
 hypertension,
 hyperkalemia, hypomagnesemia, and
 an increased incidence of certain types of
infection

mTOR Inhibitors
(Sirolimus/Everolimus)
Sirolimus
The first mTOR (mammalian target of Rapamycin) inhibitors to
enter clinical use was sirolimus (Rapamune).
 MOA: bind to FK506-binding protein (FKBP) sirolimus-FKBP
complex binds to mTOR (In response to proliferation signals
provided by cytokines like IL-2, this key regulatory kinase, mTOR
changes cells from the G1 to S phase in the cell
cycle)Sirolimus inhibits G1 to S phase cell cycle change.
 also inhibits proliferation of vascular smooth muscle cells (thus
inhibit the vasculopathy and progressive fibrosis that can affect
allografts).
 Uses: to help withdraw or completely avoid the use of steroids.
Used as an alternative to tacrolimus or cyclosporine, in a
calcineurin-sparing protocol.

Adverse effects of Sirolimus
Hypertriglyceridemia (a condition that may be
resistant to statins and fibrates.)
Hypercholesterolemia, Hyperlipidemia,
Impaired wound healing (immediately in post-
transplant period), Wound dehiscence,
Interstitial lung disease
Anemia, Leukopenia, Thrombocytopenia
Hepatic Artery Thrombosis
Peripheral edema
(these problems are exacerbated when it is used
in combination with MMF).

Drugs or substances that may increase the level
of Cyclosporine, Tacrolimus or Sirolimus.
Antibiotics Antifungals Calcium Channel
Blockers
Others
Azithromycin Fluconazole Diltiazem Protease inhibitors for
HBV
Clarithromycin Ketoconazole Verapamil Protease inhibitors for
HIV
Erythromycin Itraconazole Danazol
Voriconazole Grapefruit products
Terbinafine
Caspofungin

Mycophenolate Mofetil (MMF)
 Approved for preventing acute rejection after kidney
transplants.
 MMF has now been incorporated into routine maintenance
regimens for many solid organ transplants.
 Effective for primary immunosuppression in combination with
tacrolimus.
 Mode of Action: inhibitor of inosine monophosphate
dehydrogenase (IMPDH), involved in the de novo pathway of
purine synthesis  Leads to blockage of DNA replication in T
and B lymphocytes.
 Doses:
 1000-1500mg bid MMF (250 and 500 mg capsules) or
 360-720 BID MPA(delayed release form of MMF )

Adverse effects of MMF
The most common is GI in nature-
 diarrhea, nausea, dyspepsia, and bloating.
 Esophagitis and gastritis
(occur in roughly 5% of recipients and may represent a
cytomegalovirus (CMV) or herpes virus family
infection).
The others are-
 leukopenia, anemia, and thrombocytopenia .
(Leukopenia can sometimes be reversed by lowering
the MMF dose and discontinuing other agents like
valganciclovir).

Azathioprine (AZA)
Mode of Action: AZA is converted to 6-
mercaptopurine  inhibits both the de novo
purine synthesis and salvage purine synthesis.
 AZA decreases T-lymphocyte activity and
decreases antibody production.
Uses: It is preferred in recipients who are
considering conceiving a child, (because MMF
is teratogenic in females and can cause birth
defects).
AZA might be an option for recipients who
cannot tolerate the gastrointestinal (GI) side
effects of MMF.

Azathioprine
 Adverse effects:
 Bone marrow suppression (most significant)
 Leukopenia (often reversible with dose reduction or
temporary cessation of the drug).
 Hepatotoxicity, Pancreatitis,
 Anemia,
 Pulmonary fibrosis, and
 Neoplasia
 Its most significant drug interaction is with allopurinol,
which blocks AZA’s metabolism, increasing the risk of
pancytopenia. Recommendations are to not use AZA
and allopurinol together, or if doing so is unavoidable,
to decrease the dose of AZA by 75%.

Corticosteroids
 An integral component of most immunosuppressive
protocols, for both induction and maintenance.
 First-line agents in the treatment of acute rejection.
 Mode of Action: binds to gluco-corticoid-responsive
elements in DNA  prevent the transcription of
cytokine genes and cytokine receptors.
In addition, have an impact on
 Causes lymphocyte depletion,
 Decrease in cell-mediated immunity and
 Reduce T-cell activation of many phases of rejection.

Corticosteroids
Doses:
 Perioperatively Large doses and
 immediate postoperative period  5 to 15 mg/day.
Used: in induction, maintenance and treatment
of acute rejection.
Adverse effects:
 acne, mood changes,
 diabetes (hyperglycemia), hypertension,
 osteoporosis, cataracts, myopathy,
 increased appetite, weight gain and
 impaired wound healing.

 Cyclosporine, Tacrolimus or Sirolimus are the
backbone of maintenance immunosuppresion.
Addition of other agents (Steroids, MMF,
Azathioprine) can be used to decrease risk of
rejection or allow for lower doses of the primary
agents.
50% of post-OLT deaths are directly/indirectly
related to immunosuppressive medications.
Control of blood pressure, treatment of
hyperlipidemia, and management of diabetes are
the current mainstays of treatment for graft
preservation.

Length of treatment
Immunosuppressive medications appear to be
necessary for the life of the transplanted organ.
Episodes of acute cellular rejection have occurred
after the cessation of medication even 20 years
after transplantation.
For patients with stable graft function, individual
components of the treatment regimen may be
gradually diminished or completely discontinued;
however, in most patients, some degree of
immunosuppression must be continued.
Some patients with severe resistant infections or
malignancy related to immunosuppressants
require the discontinuation of these medicines.

Early infections:
In the immediate postoperative period(i.e.,
infections occurring within 1 month
posttransplant)
due to a wide spectrum of pathogens
(bacterial, viral, and fungal).
Surgical infections: generalized peritonitis,
intra-abdominal abscesses, and wound
infections.
Medical infections: include respiratory,
urinary tract, and bloodstream infections.

Late infections:
primarily are due to chronic
immunosuppression, (the depression of cell-
mediated immunity that renders recipients
susceptible to viruses, fungi, and parasites).
Viral infections are: CMV, EBV, HSV, HPV (have
a higher incidence if seronegative recipient
receiving allografts from seropositive donors).

CMV infection
The incidence of CMV has been greatly reduced
with 12-week Acyclovir prophylaxis.
Symptomatic infections and all tissue-invasive
CMV disease:
Rx intravenous (IV) gancyclovir,
a reduction in immunosuppression, or
both.

EBV infection
Can cause:
 mild mononucleosis syndrome,
 to severe hepatitis and
 PTLD.
PTLD ranges from
 a localized tumor to
 a progressive, diffuse infiltration of various organs
including the brain.
Mx:
patients with early lesions, the first line of treatment
is to reduce immunosuppression.
For those with more advanced PTLD, rituximab is
used.

HPV infection
 An increasingly recognized problem associated with immunosuppression is
BK virus nephropathy. This virus, a member of the human papovavirus
family, lives in the human genitourinary tract and replicates in some
patients who are immunosuppressed, leading to allograft dysfunction.
 While antiviral agents such as cidofovir and leflunomide are active against
the BK virus, the mainstay of therapy is a reduction in
immunosuppression. Concurrent renal allograft rejection was treated with
pulse steroid therapy and a reduction in immunosuppression.
 The results of one study found that a combination of monthly screening
for polyoma BK virus nephropathy (PVN) using PCR and a modest decrease
in immunotherapy is a safe and effective in preventing PVN and may
significantly decrease cytomegalovirus and Epstein-Barr virus in renal
transplant patients.
 The results of another study found that monthly nucleic acid testing
during the first 6 months post renal allograft and immediate reduction of
immunosuppression is effective in preventing BK polyomavirus virus
nephropathy (BKVN) in viremic patients.

Blastomyces dermatitidis  treatment is IV
amphotericin B.
Coccidioides immitis  The first line of
treatment is high-dose amphotericin B.
Histoplasma capsulatum CNS involvement
 Rx prolonged (3 to 13 months)
administration of oral itraconazole.
invasive Candida or Aspergillus infections 
Prophylaxis with fluconazole (liver recipients).
Pneumocystis jiroveci  Trimethoprim-
sulfamethoxazole (TMP-SMX) is the effective
prophylaxis.
Invasive fungal infections (6 months posttransplant)

Malignancies in Immunosuppression
Chronic immunosuppression increases the risk
of developing certain types of malignancies.
Recipients had at least a fivefold increase risk
of malignancies (as compared with the
general population).
Examples:
 Kaposi’s sarcoma,
 Non-melanoma skin cancer,
 Non-Hodgkin’s lymphoma, PTLD and
 Cancer of the liver, anus, vulva, and lip.

Malignancies
 In addition, recipients had a statistically significant
increase in
 Melanoma,
 Hodgkin’s lymphoma, and
 Cancer of the lung, kidney, colon, rectum, and
pancreas.
 Immunosuppressive drugs causing malignacy:
Cyclosporine
Azathioprine
Alemtuzumab (PTLD)
Belatacept (PTLD)

The cause of death of approximately 27% of
patients who die with a functioning graft is
related to infectious or malignant
complications.
This highlights the question of the appropriate
amount of immunosuppression required to
balance the aspects of graft function with
complications related to therapy.

Pregnancy
 Current data suggest that protocols involving
cyclosporine, azathioprine, and steroids are associated
with low rates of birth defects, although patients are
treated with high-risk pregnancy strategies.
 However, also note that children born to parents with
previous transplants are often small for gestational
age.
 Preliminary data also suggest the safety of tacrolimus.
 Mycophenolate mofetil animal data and some early
human studies show adverse effects on fetal
development.
 Presently, few data exist regarding sirolimus and
pregnancy.

Immunosuppression after solid organ
transplantation is complex. Over the past 50 years, the
medical community has witnessed great advances in
the care of patients receiving organ transplants.
Improved therapeutic strategies have been associated
with better patient and graft survival rates; however,
the adverse effects associated with these agents and
the risks of long-term immunosuppression present a
number of challenges for the clinician. With all the
successes of immunosuppressive therapies come the
obligations to tailor treatments to meet the individual
patient's characteristics and to balance the risks and
benefits of these medications.
Summary

Methods of immunosuppression

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Methods of immunosuppression