Immunopharmacology

ImmunopharmacologyImmunopharmacology

Fen-Fei GaoFen-Fei Gao

Elements of the Immune SystemElements of the Immune System

Normal Immune ResponsesNormal Immune Responses The innate immune systemThe innate immune system: :

• The first line of defenseThe first line of defense• Including Including physicalphysical (eg, skin), (eg, skin), biochemicalbiochemical (eg, com (eg, com

plement(plement( 补体 ), lysozyme(), lysozyme( 溶菌酶 )), and ), and cellularcellular (macrophages, neutrophils) (macrophages, neutrophils) componentscomponents

The adaptive immune systemThe adaptive immune system::• Humoral immunityHumoral immunity – B lymphocytes: antibodies – B lymphocytes: antibodies• Cell-mediated immunityCell-mediated immunity – T lymphocytes – T lymphocytes

Abnormal Immune ResponsesAbnormal Immune Responses Hypersensitivity:Hypersensitivity:

• Immediate hypersensitivityImmediate hypersensitivity: usually antibody-mediated.: usually antibody-mediated. Type :ⅠType :Ⅰ cross-linking of membrane-bound IgE on blood basophils( cross-linking of membrane-bound IgE on blood basophils( 嗜

碱细胞 ) or tissue mast cells() or tissue mast cells( 肥大细胞肥大细胞 ) by antigen.) by antigen. Type :ⅡType :Ⅱ the formation of antigen-antibody complexes between foreign the formation of antigen-antibody complexes between foreign

antigen and IgM or IgG immunoglobulins(antigen and IgM or IgG immunoglobulins( 免疫球蛋白 ). eg, blood transf). eg, blood transfusion reactions and hemolytic disease of the newborn.usion reactions and hemolytic disease of the newborn.

Type :ⅢType :Ⅲ the presence of elevated levels of antigen-antibody complexes the presence of elevated levels of antigen-antibody complexes that cause tissue damage.that cause tissue damage.

• Delayed hypersensitivityDelayed hypersensitivity: cell-mediated. Induces a local inflammator: cell-mediated. Induces a local inflammatory response and causes extensive tissue damage characterized by ty response and causes extensive tissue damage characterized by the influx of antigen-nonspecific inflammatory cells.he influx of antigen-nonspecific inflammatory cells.

Autoimmunity: Autoimmunity: an immune response against itself due to failure tan immune response against itself due to failure to distinguish self tissues and cells from foreign (nonself) antigeno distinguish self tissues and cells from foreign (nonself) antigens.s.

Immunodeficiency diseases: Immunodeficiency diseases:

Immunosuppressive DrugsImmunosuppressive Drugs

Common characteristic:Common characteristic:①① Deficiency in specific or selectivityDeficiency in specific or selectivity::

②② More effective in the first immume response More effective in the first immume response action than in that of the secondaction than in that of the second..

③③ Action related to the time of administration of Action related to the time of administration of drugs, the interval of antigen stimulation and drugs, the interval of antigen stimulation and subsequencesubsequence..

④④ Non-specific anti-inflammatory effectNon-specific anti-inflammatory effect..

CyclosporinCyclosporin Fat-soluble peptide antibiotic Fat-soluble peptide antibiotic PharmacokineticsPharmacokinetics

Slowly and incompletely absorbed after oral administrSlowly and incompletely absorbed after oral administration.ation.

Almost totally metabolized and excreted in the bile.Almost totally metabolized and excreted in the bile. Pharmacological EffectsPharmacological Effects::

Act at an early stage in the antigen receptor-induced Act at an early stage in the antigen receptor-induced differentiation of T cells and block their activation.differentiation of T cells and block their activation.

Inhibit the gene transcription of IL-2, IL-3, IFN-Inhibit the gene transcription of IL-2, IL-3, IFN-γγ, and , and other factors produced by antigen-stimulated T cells, other factors produced by antigen-stimulated T cells, but it does not block the effect of such factors on primbut it does not block the effect of such factors on primed T cells nor does it block interaction with antigen.ed T cells nor does it block interaction with antigen.

MechanismsMechanisms cyclosporin + cyclophilincyclosporin + cyclophilin → → complex complex →→ calcineurin( calcineurin( 钙调磷酸酶钙调磷酸酶 ))

↓↓→ → dephosphorylation of nuclear factors of activated T cells↓ dephosphorylation of nuclear factors of activated T cells↓ →→ gene transcription↓ gene transcription↓ → → IL-2,3,4↓, TNF-IL-2,3,4↓, TNF-αα↓, IFN-↓, IFN-γγ↓↓

cyclosporin → TGF-cyclosporin → TGF-ββ↑↑ → proliferation of T cells induced by IL-2 → proliferation of T cells induced by IL-2 ↓, cytotoxic T cells↓↓, cytotoxic T cells↓

Clinical Uses Clinical Uses Organ transplantation Organ transplantation Autoimmune disordersAutoimmune disorders

Adverse Effects and CautionsAdverse Effects and Cautions Nephrotoxicity(Nephrotoxicity( 中毒性肾损害 ), ), Transient liver dysfunctionTransient liver dysfunction secondary infection: viral infectionsecondary infection: viral infection Lymphoma and other cancers (Kaposi’s sarcoma, skin cancer)Lymphoma and other cancers (Kaposi’s sarcoma, skin cancer)

Tacrolimus (FK506)Tacrolimus (FK506) Macrolide(Macrolide( 大环内酯 ) antibiotic produced by ) antibiotic produced by streptomycestreptomyce

s tsukubaensiss tsukubaensis(( 链霉菌属 ).). It is not chemically related to cyclosporine, but their macIt is not chemically related to cyclosporine, but their mac

hanisms of action are similar, both bind to cytoplasmic phanisms of action are similar, both bind to cytoplasmic peptidyl(eptidyl( 肽基 )-prolyl()-prolyl( 脯氨酰 ) isomerases() isomerases( 异构酶 ). ).

For liver, kidney, heart, pancreas, and bone marrow tranFor liver, kidney, heart, pancreas, and bone marrow transplant applications.splant applications.

Toxic effects: nephrotoxicity, neurotoxicity, hyperglycemiToxic effects: nephrotoxicity, neurotoxicity, hyperglycemia (requiring insulin therapy), gastrointestinal dysfunction.a (requiring insulin therapy), gastrointestinal dysfunction.

Some studies suggested the higher efficacy and the highSome studies suggested the higher efficacy and the higher incidence of serious toxicities of tacrolimus than cycloer incidence of serious toxicities of tacrolimus than cyclosporine in the management of of liver transplant patients.sporine in the management of of liver transplant patients.

Adrenocortical HormonesAdrenocortical Hormones

Lympholytic(Lympholytic( 淋巴细胞溶解 ) properties) properties Interfere with the cell cycle of activated lymphoid Interfere with the cell cycle of activated lymphoid

cells.cells. Their immunologic effects are due to their ability Their immunologic effects are due to their ability

to modify cellular functions rather than to direct cto modify cellular functions rather than to direct cytotoxicity.ytotoxicity.

Immunosuppressive and anti- inflammatory propImmunosuppressive and anti- inflammatory properties.erties.

Indications include organ transplantation and autIndications include organ transplantation and autoimmune disorders.oimmune disorders.

AntimetaboliteAntimetabolite Including Including AzaAza, , MTXMTX, , 6-MP6-MP, et al., et al. Aza is an imidazolyl(Aza is an imidazolyl( 咪唑咪唑 ) derivative of 6-MP.) derivative of 6-MP. Aza is the purine analog that interferes with nucleic acid Aza is the purine analog that interferes with nucleic acid

metabolism at steps that are required for the wave of lymmetabolism at steps that are required for the wave of lymphoid cell proliferation which follows antigenic stimulation.phoid cell proliferation which follows antigenic stimulation.

T cells is more sensitive than B cellsT cells is more sensitive than B cells. Benefit in maintaining renal allograft(Benefit in maintaining renal allograft( 同种异基因移植物同种异基因移植物 )) Treatment of autoimmune disorders: rheumatoid arthritisTreatment of autoimmune disorders: rheumatoid arthritis

(( 类风湿关节炎类风湿关节炎 ), systemic lupus erythematosus(), systemic lupus erythematosus( 系统性系统性红斑狼疮红斑狼疮 ), et al. ), et al.

Adverse reactions: bone marrow suppression, gastrointeAdverse reactions: bone marrow suppression, gastrointestinal symptoms, hepatic dysfunction. stinal symptoms, hepatic dysfunction.

Alkylating(Alkylating( 烷化 ) agent) agent

CyclophosphamideCyclophosphamide ( (CTXCTX) destroys prolifer) destroys proliferating lymphoid cells but also appears to alating lymphoid cells but also appears to alkylate some resting cells.kylate some resting cells.

B cells is more sensitive than T cells.B cells is more sensitive than T cells. Organ transplants, autoimmune disorders.Organ transplants, autoimmune disorders. Adverse reactions: bone marrow suppressiAdverse reactions: bone marrow suppressi

on, gastrointestinal symptoms, hemorrhagion, gastrointestinal symptoms, hemorrhagic cystitis(c cystitis( 出血性膀胱炎 ).).

Antilymphocyte Globulin (ALG)Antilymphocyte Globulin (ALG) Antiserum is usually obtained by immunization of Antiserum is usually obtained by immunization of

large animals with human lymphoid cells or by thlarge animals with human lymphoid cells or by the hybridoma(e hybridoma( 杂交瘤 ) technique for monoclonal ) technique for monoclonal antibody generation.antibody generation.

Antithymocyte(Antithymocyte( 抗胸腺细胞的 ) globulinglobulin (ATG).(ATG). Destruction or inactivation of the T cells. Destruction or inactivation of the T cells. primary immune responseprimary immune response ＞＞ secondary immune secondary immune

responseresponse Adverse reactions are mostly those associated Adverse reactions are mostly those associated

with injection of a foreign protein obtained from hwith injection of a foreign protein obtained from heterologous serum.eterologous serum.

Mycophenolate Mofetil (RS-61443)Mycophenolate Mofetil (RS-61443)

A semisynthetic derivative of mycophenolic acid A semisynthetic derivative of mycophenolic acid (MPA), isolated from the mold (MPA), isolated from the mold Penicillium glaucuPenicillium glaucumm..

MPA is the inhibitor of IMPDH. Inhibit the de novMPA is the inhibitor of IMPDH. Inhibit the de novo(o( 重新 ) pathway of purine synthesis.) pathway of purine synthesis.

Inhibit a series of T and B lymphocyte responses.Inhibit a series of T and B lymphocyte responses. Kidney and liver transplant, et al.Kidney and liver transplant, et al. Adverse reactions are mainly gastrointestinal .Adverse reactions are mainly gastrointestinal .

LeflunomideLeflunomide

A prodrug of an inhibitor of pyrimidine syntA prodrug of an inhibitor of pyrimidine synthesis rather than purine synthesis.hesis rather than purine synthesis.

Inhibit DHODH through AInhibit DHODH through A771726771726.. It is orally active, and the active metabolite It is orally active, and the active metabolite

has a long half-life of several weeks.– shohas a long half-life of several weeks.– should be started with a loading dose.uld be started with a loading dose.

Mainly for rheumatoid arthritis.Mainly for rheumatoid arthritis. Toxicities: liver damage, renal impairment, Toxicities: liver damage, renal impairment,

teratogenic(teratogenic( 致畸致畸 ) effects.) effects.

ImmunostimulantsImmunostimulants

Increase the immune responsiveness of Increase the immune responsiveness of patients who have either selective or patients who have either selective or generalized immunodeficiency.generalized immunodeficiency.

Use for immunodeficiency disorders, Use for immunodeficiency disorders, chronic infectious diseases, and cancer.chronic infectious diseases, and cancer.

Immune AdjuvantImmune Adjuvant

Bacillus Calmette-Guerin-Vaccine (BCG) iBacillus Calmette-Guerin-Vaccine (BCG) is a viable(s a viable( 可培育的可培育的 ) strain of ) strain of MycobacteriMycobacteriumum(( 分支杆菌分支杆菌 ) ) bovisbovis(( 牛型牛型 ) that has been ) that has been used for immunization against tuberculosis.used for immunization against tuberculosis.

Also been employed as a nonspecific adjuAlso been employed as a nonspecific adjuvant or immunostimulant in cancer therapy.vant or immunostimulant in cancer therapy.

CytokinesCytokines

Interferon (INF):Interferon (INF): INF-α,β,γ INF-α,β,γ Antiviral, anticancer, immunomodulating effects.Antiviral, anticancer, immunomodulating effects. Antiviral effects : INF-α,βAntiviral effects : INF-α,β ＞ ＞ INF-γINF-γ immunomodulating effects: INF-γimmunomodulating effects: INF-γ Adverse Effects: flu-like symptoms, fatigue(Adverse Effects: flu-like symptoms, fatigue( 疲乏 ), ma), ma

laise(laise( 不适 )) Interleukin-2 (IL-2)Interleukin-2 (IL-2)

T cell proliferation, TT cell proliferation, THH, NK, LAK cell activation, NK, LAK cell activation Treatment of Treatment of malignant melanoma( 恶性黑素瘤 ), rena

l cell carcinoma, Hodgkin disease Adverse Effects: fever, anorexia(Adverse Effects: fever, anorexia( 食欲缺乏 ), et al. ), et al.

Other ImmunomodulatorsOther Immunomodulators

EntanerceptEntanercept Transfer Factor (TF)Transfer Factor (TF) ThymosinThymosin Levamisole (LSM)Levamisole (LSM) IsoprinosineIsoprinosine