Drugs affecting immune function

Drugs affecting Drugs affecting immune functionimmune function

ImmunopharmacologyImmunopharmacology

Immunomodulating agentsImmunomodulating agents- Classification -- Classification -

• Immunosuppressive agents Immunosuppressive agents (i(immunosuppressants)mmunosuppressants)

• Immunopotentiating agents Immunopotentiating agents (i(immunostimulants)mmunostimulants)

• ImmunizationImmunization (prophylaxis)• Vaccines; Immune globulin

ImmunosuppressantsImmunosuppressants

• 1.1. GlucocorticoidsGlucocorticoids (( 糖皮质激素类糖皮质激素类 )) ：：• prednisolone prednisolone (( 泼尼松龙泼尼松龙 )) , , methylprednisolone methylprednisolone (( 甲泼尼松龙甲泼尼松龙 ))

• 2. Calcineurin inhibitors 2. Calcineurin inhibitors (( 钙调磷酸酶抑制剂钙调磷酸酶抑制剂 )) ：：• cyclosporine cyclosporine (CsA, (CsA, 环孢素环孢素 ),), tacrolimustacrolimus (FK506, (FK506, 他克莫司他克莫司 ))

• 3. Antiproliferative and antimetabolic drugs 3. Antiproliferative and antimetabolic drugs (( 抗增殖抗增殖 // 抗代谢类抗代谢类 )) ：：• rapamycin rapamycin (( 雷帕霉素雷帕霉素 , sirolimus , sirolimus 西罗莫司西罗莫司 ), ), mycophenolate mofetil mycophenolate mofetil (MMF, (MMF, 霉酚酸霉酚酸

酯酯 ), ), azathioprine azathioprine (Aza, (Aza, 硫唑嘌呤硫唑嘌呤 ) ,) , cyclophosphamide cyclophosphamide (CTX, (CTX, 环磷酰胺环磷酰胺 ))

• 4. Antibodies 4. Antibodies (( 抗体类抗体类 )) ：：• antithymocyte globulin antithymocyte globulin (ATG, (ATG, 抗胸腺细胞球蛋白抗胸腺细胞球蛋白 ))

• 5. Active TCM components 5. Active TCM components (( 中药有效成分中药有效成分 )) ：：• tripterygium tripterygium glycosides (( 雷公藤总苷雷公藤总苷 ))

ImmunosuppressantsImmunosuppressants- application -- application -

• 1.1. Organ transplantation therapyOrgan transplantation therapy • Multitiered approach to immunosuppressive drug therapyMultitiered approach to immunosuppressive drug therapy• Established rejection:Established rejection: blocking activated T lymphocytes, such as hiblocking activated T lymphocytes, such as hi

gh dose glucocorticoids, polyclonal antilymphocyte antibodies, or muromgh dose glucocorticoids, polyclonal antilymphocyte antibodies, or muromonab-CD3 mAbonab-CD3 mAb

• Maintenance immunotherapy:Maintenance immunotherapy: such as calcineurin inhibitors, glucosuch as calcineurin inhibitors, glucocorticoids and mycophenolate mofetil corticoids and mycophenolate mofetil

• Intensive induction and lower-dose maintenanceIntensive induction and lower-dose maintenance

• 2. Autoimmune diseases2. Autoimmune diseases• Rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erRhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus er

ythematosus, polyarthritis nodosa, nephritic syndrome, ythematosus, polyarthritis nodosa, nephritic syndrome, etc.etc.

• 3. Others 3. Others hypersensitivity hypersensitivity

ImmunostimulantsImmunostimulants

• 1. Microbial products: 1. Microbial products: • Bacillus Calmette-Guerin Bacillus Calmette-Guerin (BCG,(BCG, 卡介苗卡介苗 ))

• 2. Immunological products from human or anim2. Immunological products from human or animals:als:

• interferons interferons (( 干扰素干扰素 ),), interleukin-2 interleukin-2 (IL-2, (IL-2, 白介素白介素 -2)-2)

• 3. Chemical drugs:3. Chemical drugs:• levamisole levamisole (( 左旋咪唑左旋咪唑 ))

• 4. Others: 4. Others: • polysaccharides polysaccharides (( 多糖类多糖类 ),), active TCM components active TCM components

ImmunostimulantsImmunostimulants - application -- application -

• 1. Immunodeficient diseases1. Immunodeficient diseases

• 2. Chronic refractory2. Chronic refractory infectionsinfections

• 3. Tumors3. Tumors

• - Adjuvant therapy -- Adjuvant therapy -

ImmunosuppressantsImmunosuppressants

Cell-mediated and humoral immune responsesCell-mediated and humoral immune responses

Immune responses and the actions of immunomodulating agents Immune responses and the actions of immunomodulating agents

1. Glucocorticoid drugs1. Glucocorticoid drugs

PrednisonePrednisone

泼尼松泼尼松PrednisolonePrednisolone

泼尼松龙泼尼松龙HH

Effects on immuneEffects on immune

Suppressing immunological functions and allergySuppressing immunological functions and allergy

a) inhibiting all stages of immune responsesa) inhibiting all stages of immune responses

b) inducing apoptosis of T and B lymphocytesb) inducing apoptosis of T and B lymphocytes

c) inhibiting transcription factor c) inhibiting transcription factor －－ such assuch as nuclear nuclear factor factor B (NF-B (NF-B) B) oror activating protein-1 (AP-1) activating protein-1 (AP-1) activityactivity


One of glucocorticoids’ actions:One of glucocorticoids’ actions:

Inhibition of gene transcription (AP-1 and NFInhibition of gene transcription (AP-1 and NFBB))


Clinical usesClinical uses

(1) Autoimmune disorders:(1) Autoimmune disorders: reumatic fever, reumatic carreumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, ditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, syndrome, etc.etc.

(2) Rejection of organ transplantation(2) Rejection of organ transplantation

(3) Allergic diseases:(3) Allergic diseases: urticaria, serum sicknss, contact derurticaria, serum sicknss, contact dermatitis, drug allergic reactions, chronic severe asthma, status matitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, asthmaticus, angioneurotic edema, etcetc. .


2. Calcineurin inhibitors2. Calcineurin inhibitors

环孢素环孢素他克莫司他克莫司 (FK506)(FK506)


• Cyclosporin (cyclosporin A, CsA)Cyclosporin (cyclosporin A, CsA)

• Pharmacological effectsPharmacological effects

• Suppressing T-cell-dependent immune mechanismsSuppressing T-cell-dependent immune mechanisms. .

• Inhibiting antigen-triggered signal transduction in T-cellInhibiting antigen-triggered signal transduction in T-cellss, , blunting expression of many cytokines including IL-2, and the expressioblunting expression of many cytokines including IL-2, and the expression of antiapoptotic proteinsn of antiapoptotic proteins. .

• Forming a complex with cyclophilin (Forming a complex with cyclophilin ( 环孢素受体环孢素受体 ) , which binds to calcineurin, inhi) , which binds to calcineurin, inhibiting Cabiting Ca2+2+-stimulated dephosphorylation of the cytosolic component of NFAT. This p-stimulated dephosphorylation of the cytosolic component of NFAT. This prevents NFAT dephosphorylation such that NFAT does not enter the nucleus, gene trrevents NFAT dephosphorylation such that NFAT does not enter the nucleus, gene transcription is not activated, and the T lymphocyte fails to respond to specific antigenanscription is not activated, and the T lymphocyte fails to respond to specific antigenic stimulationic stimulation. .

• Increasing TGF-Increasing TGF-ββ expression expression, , so inhibiting IL-2-stimulated T-cell pso inhibiting IL-2-stimulated T-cell proliferation and generation of cytotoxic T lymphocytesroliferation and generation of cytotoxic T lymphocytes..


• Clinical usesClinical uses

• Organ transplantationOrgan transplantation (kidney, liver, heart, and (kidney, liver, heart, and other organs) other organs)

• Autoimmune disordersAutoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, psoriasis rheumatoid arthritis, psoriasis (( 银屑病银屑病 )), , etcetc.).)


• Adverse reactionsAdverse reactions

• Renal dysfunction: Renal dysfunction: especially combined with other renal toxic despecially combined with other renal toxic drugsrugs

• Hepatic toxicityHepatic toxicity

• CNS toxicity: CNS toxicity: tremor, convulsion, coma, tremor, convulsion, coma, etcetc..

• Increased risk of neoplasiaIncreased risk of neoplasia

• Increased susceptibility to infectionsIncreased susceptibility to infections

• Others: Others: hirsutism, hypertension, hyperlipidemia, and gum hyperplhirsutism, hypertension, hyperlipidemia, and gum hyperplasia , asia , etcetc..


• Tacrolimus (FK506)Tacrolimus (FK506)

• Binding to FKBP (FK506-binding protein)Binding to FKBP (FK506-binding protein)

• Used in organ transplantationUsed in organ transplantation

• CNS, renal, reproductive toxicitiesCNS, renal, reproductive toxicities

3. Antiproliferative and antimetab3. Antiproliferative and antimetabolic drugsolic drugs

西罗莫司西罗莫司霉酚酸酯霉酚酸酯


• RapamycinRapamycin (Rapa, sirolimus) (Rapa, sirolimus)

• Pharmacological effectsPharmacological effects

• Inhibiting T-cell activation and proliferation downstreaInhibiting T-cell activation and proliferation downstream of the IL-2 and other T-cell growth factor receptorsm of the IL-2 and other T-cell growth factor receptors

• It binds to and inhibits a protein kinase, designated It binds to and inhibits a protein kinase, designated mammaliamammalian target of rapamycin (mTOR)n target of rapamycin (mTOR), which is a key enzyme in cell-cycle , which is a key enzyme in cell-cycle

progressionprogression



• prophylaxis of organ transplant rejection in cprophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glombination with a calcineurin inhibitor and glucocorticoidsucocorticoids



• Gastrointestinal effectsGastrointestinal effects

• Other adverse effects:Other adverse effects: anemia, leukopenia, tanemia, leukopenia, thrombocytopenia, hypokalemia or hyperkalemihrombocytopenia, hypokalemia or hyperkalemia, fever. Delayed wound healing may occur with a, fever. Delayed wound healing may occur with sirolimus use.sirolimus use.


• Mycophenolate mofetil (MMF)Mycophenolate mofetil (MMF)

• A prodrug of mycophenolic acid (MPA)A prodrug of mycophenolic acid (MPA)

• Pharmacological effectsPharmacological effects• a selective, noncompetitive, and reversible inhibitor

of inosine monophosphate dehydrogenase (IMPDH, 次黄嘌呤单核苷磷酸脱氢酶 ) , which is an important enzyme in the de novo pathway of guanine nucleotide ( 鸟嘌呤苷酸 ) synthesis and B and T lymphocytes are highly dependent on this pathway for cell proliferation



• Prophylaxis of transplant rejectionProphylaxis of transplant rejection, and it typic, and it typically is used in combination with glucocorticoids and ally is used in combination with glucocorticoids and

a calcineurin inhibitor, but not with azathioprinea calcineurin inhibitor, but not with azathioprine

• Systemic lupus erythematosus, rheumatoid aSystemic lupus erythematosus, rheumatoid arthritis, psoriasisrthritis, psoriasis ( ( 银屑病银屑病 ) , ) , etcetc..



• Gastrointestinal and hematologic toxicities including diarrhea, vomiting and leukopenia


• Azathioprine (Aza)Azathioprine (Aza)


Phamacological effectsPhamacological effects

• Interfering purine nucleotide synthesis in lyInterfering purine nucleotide synthesis in lymphocytesmphocytes.

• Azathioprine appears to be a more potent immunosuAzathioprine appears to be a more potent immunosuppressive agent than 6-mercaptopurine, which may rppressive agent than 6-mercaptopurine, which may reflect differences in drug uptake or pharmacokinetic eflect differences in drug uptake or pharmacokinetic differences in the resulting metabolitesdifferences in the resulting metabolites.



• Organ transplantation, systemic lupus erytheOrgan transplantation, systemic lupus erythematosus, rheumatoid arthritis, matosus, rheumatoid arthritis, etcetc..



• Bone marrow suppressionBone marrow suppression, including leukopenia , including leukopenia (common), thrombocytopenia (less common), and/or (common), thrombocytopenia (less common), and/or anemia (uncommon) bone marrow suppression, inclanemia (uncommon) bone marrow suppression, including leukopenia (common), thrombocytopenia (less uding leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon)common), and/or anemia (uncommon)

• Increased susceptibility to infectionsIncreased susceptibility to infections (especial(especially varicella and herpes simplex viruses),ly varicella and herpes simplex viruses),

• Hepatotoxicity, alopecia, GI toxicity, pancreatHepatotoxicity, alopecia, GI toxicity, pancreatitis, and increased risk of neoplasiaitis, and increased risk of neoplasia

4. Antibodies4. Antibodies• Antithymocyte globulinAntithymocyte globulin ( ( 抗胸腺细胞球蛋白抗胸腺细胞球蛋白 ))

• Inducing immunosuppression:Inducing immunosuppression: renal transplant patients renal transplant patients with delayed graft functionwith delayed graft function to avoid early treatment with the ne to avoid early treatment with the nephrotoxic calcineurin inhibitors and thereby aid in recovery frophrotoxic calcineurin inhibitors and thereby aid in recovery from ischemic reperfusion injury. m ischemic reperfusion injury.

• Also used for Also used for acute rejectionacute rejection of other types of organ transplant of other types of organ transplants and for s and for prophylaxis of rejection.prophylaxis of rejection.

• Inducing allergic reactionsInducing allergic reactions, including fever and chills with , including fever and chills with the potential for hypotension. including fever and chills with ththe potential for hypotension. including fever and chills with the potential for hypotension. e potential for hypotension.

4. Antibodies4. Antibodies

• Muromonab-CD3 Muromonab-CD3 (OKT3, (OKT3, 莫罗单抗莫罗单抗 -CD3,-CD3,• anti-CD3 monoclonal antibodies )anti-CD3 monoclonal antibodies )

• Binding to the εchain of CD3, a monomorphic component of the T-cell receptor complex involved in antigen recognition, cell signaling, and proliferation

• Acute organ transplant rejectionAcute organ transplant rejection

• ““Cytokine release syndrome":Cytokine release syndrome": high fever, chills/rihigh fever, chills/rigor, headache, tremor, nausea/vomiting, diarrhea, abdgor, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, myalgias, arthralgias, and generominal pain, malaise, myalgias, arthralgias, and generalized weakness. alized weakness.

Documents

Drugs affecting immune function