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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
HistoryInitial 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-stimulationRecognition 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.
T cell costimulaion
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 rejectionType Time Pathological
findingsMechanism 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 severemyointimal 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 acidPreperations
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)
InductionIncludes 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-CD3MOA: 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)
SirolimusThe 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 SirolimusHypertriglyceridemia (a condition that may be
resistant to statins and fibrates.)Hypercholesterolemia, Hyperlipidemia, Impaired wound healing (immediately in post-
transplant period), Wound dehiscence, Interstitial lung diseaseAnemia, Leukopenia, ThrombocytopeniaHepatic Artery ThrombosisPeripheral 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 productsTerbinafineCaspofungin
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) or360-720 BID MPA(delayed release form of MMF )
Adverse effects of MMFThe 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.
CorticosteroidsDoses:
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 infectionThe 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 infectionCan 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 ImmunosuppressionChronic 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:
CyclosporineAzathioprineAlemtuzumab (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.
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