Title: Immunosuppressants
1Immunosuppressants
- Courtney E.W. Sulentic
- Assistant Professor
- Department of Pharmacology Toxicology
2Topics
- Transplantation Rejection
- Autoimmunity
- Immunosuppressants
31. Transplantation Rejection Solid Organ
Rejection
Hyperacute Acute Chronic
Mechanism pre-formed antibodies and complement activation Cellular Rejection cytotoxic T cells Humoral Rejection nonsensitized B cells chronic inflammation mediated by T cells
Target blood type antigens on endothelial cells Cellular Rejection tissue antigens Humoral Rejection endothelial cells tissue antigens
Pathology thrombosis and ischemia Cellular Rejection interstitial and vascular damage Humoral Rejection acute vascular rejection proliferation of vasculature, scarring of graft, and organ failure
Time course minutes after reperfusion Cellular Rejection initial months Humoral Rejection 7-10 days months to years
Therapy match donor and recipient blood types immunosuppressive agents none
41. Transplantation Rejection Non-solid
Rejection Graft versus host disease (GVHD)
- Complication of bone marrow transplant for
leukemia or primary immunodeficiency
- Mechanism
- transplanted donor immune cells attack cells of
recipient
- Pathology
- severe inflammatory disease with rash,
pneumonitis, and diarrhea
- Therapy
- remove T cells from donor bone marrow before
transplant - immunosuppressive agents
Donor cells attack chemo-resistant tumor
cells graft versus leukemia effect (GVL)
51. Transplantation Rejection Transplantation
Therapy General Approach
Five Principles
ABO blood type-compatible HLA match for organ
donation
1
Multidrug approach to immunosuppressive therapy
2
Intensive induction with lower maintenance dose
3
Careful investigation of each episode of
transplant dysfunction
4
Reduce or withdraw if toxicity exceeds benefit
5
62. Autoimmunity Therapy
- Pharmacologic therapy does not match the
exquisite specificity of the pathophysiological
process - generalized immunosuppression rather than
targeting the specific pathophysiology
- More specific therapy is dependent on
understanding the molecular pathways leading to
autoimmune diseases - reveal new pharmacologic targets
73. ImmunosuppressantsSeven Mechanistic
Approaches
4
3
1
5
6
2
7
83.1 Transcriptional InhibitorsGeneral
Molecules that inhibit gene expression to
modulate inflammatory responses
- Glucocorticoids
- Endogenous cortisol
- Synthetic analogues
- Cortisone
- Prednisone
- Dexamethasone
- Hydrocortisone
- Prednisolone
- Triamcinolone
93.1 GlucocorticoidsGeneral
103.1 GlucocorticoidsPharmacokinetics
Therapeutic Uses
A
B
Numerous Therapeutic Indications
- graft-versus-host disease
- limit drug-induced allergic reactions
113.1 GlucocorticoidsMechanism
123.1 GlucocorticoidsToxicity Drug Interactions
Limiting and Profound Adverse effects
- growth retardation in children
- osteonecrosis and osteoporosis
Drugs altering serum protein binding and
metabolic enzymes alter bioavailability,
activity and toxicity of glucocorticoids
- increased appetite, weight gain, fat
redistribution
- hyperglycemia and diabetes
- acute adrenal insufficiency
133.1 GlucocorticoidsGeneral
143.2a AntimetabolitesGeneral
- Molecules that compete with essential components
of metabolic processes - direct cytotoxicity
- inhibition of cellular proliferation
- Mycophenolate mofetil (CELLCEPT)
- Methotrexate (RHEUMATREX, TREXALL)
153.2a AntimetabolitesAzathioprine Mechanism
Inhibition of de novo purine synthesis
163.2a Antimetabolites Azathioprine
- Therapeutic Uses
- transplantation therapy
- inflammatory bowel disease
- severe rheumatoid arthritis
- Toxicity
- bone marrow suppression
- infections and neoplasia
- hepatotoxicity
- pancreatitis
- GI toxicity
- alopecia
- Drug Interactions
- allopurinal
- myelosuppressive agents
- angiotensin-converting enzyme inhibitors
173.2a AntimetabolitesMycophenolate mofetil
Mechanism
183.2a Antimetabolites Mycophenolate mofetil
- Toxicity
- GI toxicity
- hematologic
- infections
- Therapeutic Uses
- transplantation therapy
- steroid refractory GVHD
- stem cell transplant?
- lupus nephritis
- rheumatoid arthritis
- dermatologic disorders
- Drug Interactions
- tacrolimus
- enterohepatic circulation
- tubular secretion
193.2a AntimetabolitesLeflunomide Mechanism
203.2a Antimetabolites Leflunomide
- Therapeutic Uses
- rheumatoid arthritis
- Wegeners granulomatosis
- systemic lupus erythematosis
- myasthenia gravis
- graft survival and GVHD?
- Toxicity
- GI toxicity
- reversible alopecia
- Drug Interactions
- enterohepatic circulation
213.2a AntimetabolitesMethotrexate Mechanism
Also increases adenosine levels which may
contribute to anti-inflammatory effects
223.2a Antimetabolites Methotrexate
- Therapeutic Uses
- anticancer therapy
- GVHD
- rheumatoid arthritis
- psoriasis
- Toxicity
- GI toxicity
- myelosuppression
- thrombocytopenia
- infections
- pneumonitis
- embryo toxicity
- hepatic fibrosis and cirrhosis
- Drug Interactions
- plasma protein binding
- tubular secretion
- reduced renal blood flow
- nephrotoxic
- weak organic acids
233.2b Alkylating AgentsGeneral
- Molecules that interfere with DNA replication and
gene expression by adding alkyl groups to DNA - direct cytotoxicity
- Cyclophosphamide (CYTOXAN)
243.2b Alkylating AgentsCyclophosphamide
Mechanism
253.2b Alkylating Agents Cyclophosphamide
- Therapeutic Uses
- anticancer therapy
- childhood nephritic syndrome
- severe systemic lupus erythematosus
- vasculitis syndromes
- Toxicity
- leukopenia
- infections
- cardiotoxicity
- alopecia
- GI toxicity
- reproductive toxicity
- nephrotoxicity (acrolein)
- mutagenicity
- Drug Interactions
- cytochrome P-450 enzymes
- myelosuppressive
- nephrotoxic
263.3a Calcineurin Inhibitors3.3b mTOR
InhibitorsGeneral
Molecules that specifically inhibit lymphocyte
signaling and activation
Calcineurin Inhibitors
- Cyclosporine A (SANDIMMUNE, NEORAL)
- Tacrolimus (FK506, PROGRAF)
mTOR Inhibitors
- Sirolimus (Rapamycin, RAPAMUNE)
- Everolimus (RAD-001, AFINITOR)
273.3a Calcineurin Inhibitors Cyclosporine A
Mechanism
283.3a Calcineurin Inhibitors Cyclosporine A
- Therapeutic Uses
- transplantation therapy
- rheumatoid arthritis
- psoriasis and atopic dermatitis
- uveitis and Behçets acute ocular syndrome
- inflammatory bowel disease
- nephrotic syndrome
- Toxicity
- nephrotoxicity and renal dysfunction
- tremor
- hirsutism
- hypertension
- hyperlipidemia
- hyperuricemia
- diabetogenic
- gum hyperplasia
- interstitial fibrosis
- infections and neoplasia
- Drug Interactions
- cytochrome P-450 enzymes
- sirolimus
- NSAIDS
- methotrexate
- prednisolone, digoxin statins
293.3a Calcineurin Inhibitors Tacrolimus
Mechanism
303.3a Calcineurin Inhibitors Tacrolimus
- Toxicity
- nephrotoxicity and renal dysfunction
- neurotoxicity
- GI toxicity
- hypertension
- hyperkalemia
- diabetogenic
- infections and neoplasia
- Therapeutic Uses
- transplantation therapy
- atopic eczema
- Drug Interactions
- cytochrome P-450 enzymes
- nephrotoxic
313.3b mTOR Inhibitors Sirolimus and Everolimus
Mechanism
323.3b mTOR Inhibitors Sirolimus and Everolimus
- Therapeutic Uses
- transplantation therapy
- coronary artery disease
- tolerizing effect in transplant rejection, GVHD,
and autoimmune disease? - Everolimus-positive clinical trials for relapsed
non-Hodgkins lymphoma and Hodgkins disease and
other cancers
- Toxicity
- increase serum cholesterol and triglycerides
- renal dysfunction
- Lymphocele
- anemia
- leucopenia
- thrombocytopenia
- fever
- GI toxicity
- hypokalemia or hyperkalemia
- delayed wound healing
- infections and neoplasia
- Drug Interactions
- cytochrome P-450 enzymes
- P-glycoprotein transport
- cyclosporine
333.4 TNFa, IL-1 and IL-6 InhibitorsGeneral
Molecules that neutralize the effect of specific
cytokines that mediate immune function
TNFa Inhibitors
IL-1 Inhibitor
IL-6 Inhibitor
- Certolizumab pegol (CIMZIATM)
343.4a TNFa Role in Inflammation and Disease
- central to many aspects of the inflammatory
response - implicated in autoimmune diseases
- inhibition has therapeutic efficacy against
rheumatoid arthritis and Crohns disease - does not reverse the underlying pathophysiology
Proposed Model of TNFa in Rheumatoid Arthritis
353.4a TNFa Inhibitors Pharmacological
Characteristics Part 1
Etanercept Infliximab Adalimumab
Structure soluble human TNF receptor dimer fused to Fc portion of human IgG1 partially humanized (chimeric) anti-TNFa monoclonal antibody human constant murine variable recombinant human IgG1 monoclonal antibody to TNFa
Mechanism binds both TNFa and TNFb prevents binding to the endogenous TNF receptor binds TNFa with high affinity prevents binding to the endogenous TNF receptor binds TNFa with high affinity prevents binding to endogenous TNF receptor
Pharmaco-kinetics subcutaneous intravenous intravenous
Therapeutic uses rheumatoid arthritisplus methotrexate psoriatic arthritis ankylosing spondylitis rheumatoid arthritis plus methotrexate unresponsive Crohns disease (active and moderate to severe) rheumatoid arthritis plus methotrexate psoriatic arthritis HIV arthropathy wasting syndromes
Toxicity injection-site reactions (erythema, itching, pain, or swelling) in 1/3 of patients serious infections (tuberculosis) infusion reaction serious infections (TB and urinary tract) antinuclear antibodies rarely lupus-like reaction similar to infliximab
363.4a TNFa Inhibitors Pharmacological
Characteristics Part 2
Certolizumab pegol Thalidomide TACE inhibitors
Structure fully humanized recombinant Fab fragment specific for TNFa linked to two chains of polyethylene glycol (PEG) chemical drug, safer analogs such as Lenalidomide (REVLIMID) are being developed chemical
Mechanism binds TNFa with high affinity prevents binding to the endogenous TNF receptor unclear but appears to alter TNFa levels inhibits TNFa converting enzyme (TACE) inhibit processing of pro-TNFa
Pharmaco-kinetics subcutaneous oral oral
Therapeutic uses Approved in 2008 for moderate to severe Crohns disease not responsive to conventional therapy Phase III trials with methotrexate for rheumatoid arthritis investigative for severe, refractory RA, lupus, Crohns disease, HIV, cancer under investigation in animal studies Phase I and II clinical trials not proving effective for RA
Toxicity headache, abdominal pain, cough, arthralgia, nausea,aggravated Crohns disease infections (nasopharyngitis, urinary tract infection, influenza, and tuberculosis) malignancies (including lymphoma), demyelinating disease well-known teratogenic use is highly regulated Liver toxicity
373.4a TNFa Inhibitors Structural Features
Human
Mouse
Adalimumab Recombinant human IgG1 monoclonal
antibody specific for TNFa
Certolizumab pegol Fab fragment from a humanized
anti-TNFa monoclonal antibody that has been
PEGylated
Binds both TNFa and TNFb
Binds only TNFa
383.4bc Role of IL-1 and IL-6 in Inflammation and
Disease
- Highly conserved cytokine, found in both
vertebrates and invertebrates
- Bridges innate and adaptive immunity
- Two forms IL-1a and IL-1b
- Mostly generated by activated mononuclear cells
- IL-1 receptor antagonist (IL-1RA) partially
mediates in vivo modulation of IL-1
- IL-1 stimulates IL-6 production
- IL-6 enhances expression of adhesion molecules
and stimulates cell proliferation
- IL-6 levels are elevated in both serum and joint
fluid from rheumatoid arthritis patients
393.4b IL-1 Inhibitor Anakinra
- Mechanism
- recombinant IL-1 receptor antagonist (IL-1RA)
- binds IL-1 and prevents binding to the endogenous
IL-1 receptor
- Toxicity
- injection-site reactions (subcutaneous injection)
- headache
- GI distress
- infections
- allergic reaction
- Therapeutic Uses
- rheumatoid arthritis
- modest effect on pain and swelling
- significant reduction in bony erosions
- combine with methotrexate
403.4c IL-6 Inhibitor Tocilizumab
- Mechanism
- humanized monoclonal IgG1 antibody against the
IL-6 receptor (mouse variable region) - binds IL-6 receptor and prevents activation
- Toxicity
- increased serum cholesterol in 44 of patients
- liver dysfunction
- leukopenia
- no anti-DNA antibodies (as seen with TNFa
antagonists)
- Therapeutic Uses
- Rheumatoid arthritis
- efficacious alone but more effective with
methotrexate - may reduce structural damage
413.5ab Polyclonal and Monoclonal AntibodiesGeneral
Antibodies that target cell-surface molecules
present on immune cells and trigger lysis of
these cells by the adaptive immune response
Polyclonal Antibodies
Monoclonal Antibodies
- Daclizumab (ZENAPAX) and Basiliximab (SIMULECT)
- Immune globulin intravenous
- Rho(D) immune globulin micro-dose
423.5a Polyclonal Antibody Immunosuppressants
Pharmacological Characteristics
Antithymocyte and antilymphocyte globulin (ATG and ALG) Immune Globulin Intravenous (IGIV) Rho (D) Immune Globulin Micro Dose
Source Antiserum obtained from large animals (horses, sheep) immunized with human thymocytes or lymphocytes polyclonal human Ig prepared from plasma pooled from thousands of healthy donors human IgG containing a high titer of antibodies against Rho(D) antigen on red blood cells
Mechanism recognize multiple epitopes on human T cells and opsonize for macrophage clearance target T cells and induce broad immunosuppression no specific antigen is targeted normalizing effect upon the patients immune network controversial mechanism passive administration at the time of antigen exposure blocks the hosts primary antibody response
Pharmaco-kinetics subcutaneous intravenous injection to mother within 24-72 hr after birth
Therapeutic uses Transplantation therapy induction of suppression initial rejections steroid-resistant rejection autoimmune disorders asthma prevent hemolytic disease of the newborn in Rh negative mothers
Toxicity injection-site reactions fever and headache infections cytokine release syndrome anaphylactic and serum sickness reactions acute renal failure aseptic meningitis syndrome wont work in Rh sensitized mothers local discomfort at injection site rarely a temperature elevation
433.5b Monoclonal Antibody Immunosuppressants
Pharmacological Characteristics Part 1
OKT3 Daclizumab and Basiliximab
Structure mouse monoclonal antibody against human CD3 cell surface signaling molecule important for T cell activation Daclizumab humanized IgG1 Basiliximab parially humanized (chimeric) bind CD25 (alpha subunit of IL-2 receptor) IL-2 mediates early steps in T cell activation
Mechanism CD3 expressed on CD4 and CD8 T cells binding to CD3 depletes T cells by complement activation and immune clearance CD25 only expressed on activated T cells targets and depletes T cells activated by an MHC-antigenic stimulus functions as an IL-2 antagonist
Therapeutic uses Transplantation therapy acute renal transplant rejection second line agent when CsA or GC fail Transplantation therapy acute renal transplant rejection induction therapy
Toxicity cytokine release syndrome through activation of CD3 signaling infection and neoplasia rapid clearance by host of mouse antibody decreasing efficacy hypersensitivity and anaphylaxis infections and neoplasia
443.5b Monoclonal Antibody Immunosuppressants
Pharmacological Characteristics Part 2
Rituximab Alemtuzumab
Structure partially humanized (chimeric) IgG1 against human CD20 cell surface molecule and signal transducer humanized IgG1 against CD52 lymphocyte cell surface molecule and perhaps a transducer of cell signaling
Mechanism CD20 expressed on only mature B cells complement-mediated lysis, ADCC, and induction of apoptosis decreased population of circulating B cells CD52 expressed on B cells, T cells, NK cells, monocytes, macrophages ADCC
Therapeutic uses non-Hodgkins lymphoma rheumatoid arthritis (newer indication) prolonged response combination with methotrexate transplantation therapy B cell chronic lymphocytic leukemia improved rheumatoid arthritis but not approved for use improved multiple sclerosis in clinical trials
Toxicity infusion reactions in 1/3 of patients no disruption of B cell lineage or normal plasma cells lymphopenia, neutropenia, anemia, thromocytopenia infections side effects prevented further study as an immunosuppressant in autoimmune disease
453.6 Costimulation InhibitorsGeneral
Molecules that block lymphocyte costimulation to
inhibit activation or to induce anergy
- Abatacept (CTLA-4 Ig, ORENCIA)
- Belimumab (BENLYSTA, formerly LymphoStat-B)
463.6 T Cell Activation Role of Costimulation
473.6 Costimulation Inhibitors Pharmacological
Characteristics
Alefacept Abatacept Belatacept
Structure chimeric protein of the CD2-binding portion of LFA-3 (CD58) fused to Fc portion of human IgG1 chimeric protein of the B7 binding region of CTLA-4 fused to Fc portion of human IgG1 structural congener of Abatacept
Mechanism Inhibits activation of T cells by binding to CD2 on T cell surface and interfering with CD2 binding to LFA-3 (lymphocyte function-associated antigen-3) on antigen presenting cells inhibit T cell activation and proliferation target cells inhibit cell killing by cytotoxic T cells, natural killer (NK) cells and lymphokine-activated killer (LAK) cells competitively inhibits CD28 by binding to CD80 (B7-1) and CD86 (B7-2) on antigen presenting cells prevent delivery of a B7-CD28 costimulatory signal and T cells become anergic or undergo apoptosis same as Abatacept but has increased affinity for B7-1 and B7-2
Therapeutic uses plaque psoriasis transplantation therapy rheumatoid arthritis Clinical trials acute renal transplant rejection (as effective as CSA)
Toxicity dose-dependent reduction of overall circulating T cells (may be cause for withdrawal) infusion reactions infections and neoplasia not fully characterized but less toxic than CSA
483.6 Costimulation Inhibitors Pharmacological
Characteristics
Belimumab Anti-CD40L antibody
Structure human monoclonal antibody against B-lymphocyte stimulator (BLyS) also known as B-cell activating factor (BAFF) humanized IgG1 against CD40 ligand (CD40L)
Mechanism binds BLyS (soluble protein) and blocks its interaction with BLyS receptors expressed on the B cell surface inhibit BLyS-induced stimulation of B-cell development reduce the levels of circulating B cells (precursor to plasma B cells) restore the potential for apoptosis in autoantibody-producing B cells binds CD40L (CD154) on T cells and prevents CD40L binding to CD40 expressed on antigen-presenting cells inhibits B cell activation, isotype switching, and affinity maturation inhibits B7 expression on macrophages
Therapeutic uses in clinical trials systemic lupus erythematosus (SLE) rheumatoid arthritis in animal models produce tolerance and long-term graft survival systemic lupus erythematosis in clinical trials lupus nephritis (suggested efficacy)
Toxicity not fully characterized study terminated early due to thromboembolic events (including myocardial infarction)
493.6 Costimulation Inhibitors Mechanism
B7 binding region of CTLA4
Fc of IgG1
503.7 Inhibitors of Lymphocyte TraffickingGeneral
Molecules that block cell adhesion or activate
lymphocyte homing to prevent localization of
inflammatory cells
Cell Adhesion Inhibitor
Lymphocyte Homing
513.7 Inhibitors of Lymphocyte Trafficking
Pharmacological Characteristics Part 1
Efalizumab Natalizumab
Structure humanized IgG1 against human LFA-1 humanized monoclonal antibody against a4 integrin
Mechanism inhibits LFA-1 and ICAM interaction LFA-1 expressed on thymocytes, T and B lymphocytes, granulocytes, monocytes, and macrophages ICAM expressed on endothelial cells, lymphocytes, and monocytes inhibit cell migration as well as antigen presentation and cellular cytotoxicity inhibits interactions of VLA-4VCAM-1 and LPAM-1MAdCAM-1 VLA-4 and LPAM-1 are expressed on leukocytes (same as LFA-1) VCAM-1 expressed on endothelial cells MAdCAM-1 expressed on endothelial cells of small blood vessels lining the walls of the gut and other mucosal surfaces
Therapeutic uses psoriasis under investigation for inflammatory bowel disease, multiple sclerosis and organ transplantation relapsing-remitting multiple sclerosis
Toxicity infections progressive multifocal leukoencephalopathy rare, usually fatal viral disease characterized by progressive damage or inflammation at multiple locations within the brain occurred during use for multiple sclerosis and Crohns disease withdrawn from the market in 2005 but was returned to market in 2006 and approved for relapsing-remitting multiple sclerosis
523.7 Inhibitors of Lymphocyte Trafficking
Pharmacological Characteristics Part 2
FTY720
Structure agonist for sphingosine 1-phosphate receptor (S1P-R)
Mechanism S1P-R expressed on T cells and B cells sphingosine kinase-2 phosphorylates FTY720 and the FTY720-phosphate binds S1P-R specifically and reversibly sequesters host lymphocytes into the lymph nodes and Peyers patches away from circulation does not impair lymphocyte function
Therapeutic uses acute rejection (combination therapy)
Toxicity lymphopenia negative chronotropic effect due to S1P-R expression on human atrial myocytes antagonize with b1-receptor agonists or the muscarinic receptor antagonist, atropine
533.7a Inhibitors of Lymphocyte TraffickingEfalizum
ab
LPAM-1
MAdCAM-1
54References
- Golan Principles of Pharmacology, 2nd ed.,
Chapter 44, Pharmacology of Immunosuppression
Required reading - The Scientist, Magazine of the life Sciences,
Autoimmunity supplement, 2007 Suggested reading
- Dayal, N.A. and Ruderman, E.M. Advances in RA
The next generation of therapies, Journal of
Musculoskeletal Medicine 23 (2006) 337-346
Suggested reading - Katzung Basic Clinical Pharmacology, 8th ed.,
Chapter 56, Immunopharmacology - Brunton Goodman Gilman, 11th ed., Chapter 52,
Immunosuppressants, Tolerogens, and
Immunostimulants - Parham, P The Immune System, 2nd ed.
- World Health Organization, International
nonproprietary names (INN) for biological and
biotechnological substances, INN Working Document
05.179