장 기 이 식 과 면 역 학

Size: px

Start display at page:

Download "장 기 이 식 과 면 역 학"

종희 포
5 years ago
Views:

1 Transplant Immunology ( ) 2,3 ysms91@wonjuyonseiackr 1 HLA class, class, class (B) 2 MHC (B) 3 T-cell, B-cell, (macrophage) (A) 4 T (cell surface marker) (B) 5 (A) 6 (histocompatibility) (rejection) (B) 7 (A) ) A:, B: C: mouse MHC molecule T-cell (induction of immune tolerance) 1?, (genetic disparity) (autograft), ( ) (allograft), (xenograft) Genetic disparity Ex Autograft None Skin graft Isograft Minimal Bewteen monozygotic twin Allograft Between same species, genetically different persons Xenograft Maximal Between different species 2 Brief History : lst successful kidney TLX by DrMurray between identical twin : lst successful liver TLX by DrStarzl in child with hepatoblastoma : ( Medawar,Murphy,Dausset,Terasaki ) 4 Late 1970 : Development of cyclosporine, OKT-3(monoclonal anti-lymphocyte antibody) 5 Late 1980 : Development of FK-506, MMF, polyclonal anti-lymphocyte antibody(atg) : First hepatic xenograft by Dr Starzl: Baboon liver to Human trial Written by MSKim 1 / 14 page

3 3, 3 (cosmas)(damian) (leg transplantation) 19, 1920 1954 (Murray) 1963(Starzl), 1966 (Kelley), 1967 (Barnard), 1968 (Cooley) 1997 25,649, 7,189, 308, / 915, 38,65, 1,207, (Azathioprine, Imuran)

2 3 3, 3 (cosmas)(damian) (leg transplantation) 19, (Murray) 1963(Starzl), 1966 (Kelley), 1967 (Barnard), 1968 (Cooley) ,649, 7,189, 308, / 915, 38,65, 1,207, (Azathioprine, Imuran) 1961, (Anti-lymphocyte globulin) 1966, 1970 (Cyclosporine) (OKT3) FK-506, MMF, Rafamycin %, 75-80% % 1984 cyclosporine A 80% ,, Written by MSKim 2 / 14 page

3 (MHC) (donor) (recipient) 30 ( ), (major histocompatibility antigens) (minor

mismatch ( A B ) hyperacute rejection minor mismatch ( O A ) hemolytic reaction ( )

non-self, 6 (short arm of 6th autosomal chromosome) (genetic loci) ( gene level ) HLA

3 3 (MHC) (donor) (recipient) 30 ( ), (major histocompatibility antigens) (minor histocompatibility antigen) 2 ABO (donor) O universal donor AB universal recipient major mismatch ( A B ) hyperacute rejection minor mismatch ( O A ) hemolytic reaction ( ) (Major Histocompatibility Complex, MHC) HLA (Human Leukocyte Antigen System) HLA non-self, 6 (short arm of 6th autosomal chromosome) (genetic loci) ( gene level ) HLA 1958 (Dausset), HLA A,B,C,D,DR,DQ,DP (locus) (Mendel), HLA 50% 25%, 25%, 50% :, Written by MSKim 3 / 14 page

4 A 2 Host-versus-graft response = recipient s response to foreign molecule Ex) graft rejection Graft-versus-host response = donor lymphocyte attacks the recipient s organ Ex) Bone marrow

4 4 A 2 Host-versus-graft response = recipient s response to foreign molecule Ex) graft rejection Graft-versus-host response = donor lymphocyte attacks the recipient s organ Ex) Bone marrow transplantation B : antigen (APC) (Antigen processing & presentation) IL(Interleukin)-1 T (Helper T-lymphocyte) T IL-2 T (Cytotoxic T-lymphocyte) (cellular immune reaction) T B (B lymphocyte) ( ) - (complement), (coagulation) (Kinin) (humoral immune reaction), C (1) Antigen processing and presentation by antigen presenting cell(apc), (2) Antigen recognition by T-cell via TCR complex, (3) Antigen recognition via costimulatory signals, (4) T-cell activation, (5) (Effector mechanism) Written by MSKim 4 / 14 page

(1) Antigen processing and presentation Antigen APC MHC molecule antigen MHC molecule virus bacteria infection class I molecule, extracellular pathogen parasite class II molecule cytotoxic(cd8+)

endosome antigen antigen ( ) APC APC T-cell (2) Antigen recognition via TCR complex APC Alloantigen T- cell receptor(tcr) donor-derived peptide peptide antigen MHC molecule T-cell (MHC restriction)

5 (1) Antigen processing and presentation Antigen APC MHC molecule antigen MHC molecule virus bacteria infection class I molecule, extracellular pathogen parasite class II molecule cytotoxic(cd8+) T-cell helper(cd4+) T-cell antigen antigen proteasome peptide endoplasmic reticulum(er) TAP(transport associated with antigen processing) peptide ER class I molecule class II molecule antigen endosome antigen antigen ( ) APC APC T-cell (2) Antigen recognition via TCR complex APC Alloantigen T- cell receptor(tcr) donor-derived peptide peptide antigen MHC molecule T-cell (MHC restriction) APC peptide antigen MHC MHC peptide alloantigen alloantigen APC (indirect recognition) (direct recognition) APC MHC+peptide alloantigen T-cell (direct recognition) MHC MHC MHC (altered self) (direct recognition) alloantigen APC(passenger leukocytes = interstitial dendritic cells) MHC+peptide alloantigen T-cell T-cell, Written by MSKim 5 / 14 page

6 T-cell (trnscription factor) T-cell T-cell cytokine cyclosporine clacineurin Written by MSKim 6 / 14 page

(3) Antigen recognition via costimulatory signals T-cell TCR-MHC+peptide alloantigen ( 1, first

T-cell (Dual signal theory) 1 T-cell anergy, 2 T-cell co-stimulator signal T-cell accessory

CD28/CTLA-4 co-stimulator signal accessory molecule monoclonal antibody Abbreviation) LFA :

7 (3) Antigen recognition via costimulatory signals T-cell TCR-MHC+peptide alloantigen ( 1, first signal ) (accessory molecule, cell-adhesion molecule) (adhesion) 2 (secondary signal) T-cell 2 T-cell (Dual signal theory) 1 T-cell anergy, 2 T-cell co-stimulator signal T-cell accessory molecule CD28/CTLA-4 ( B7-1/B7-2 in APC), CD2 ( LFA-3 in APC), LFA-1 ( ICAM-1 in APC) CD28/CTLA-4 co-stimulator signal accessory molecule monoclonal antibody Abbreviation) LFA : lymphocyte functioned antigen, ICAM- 1 : Intracellular adhesion molecule-1 Written by MSKim 7 / 14 page

(4) Immune effector mechanism T-cell cell-mediated immunity( ) antibody(humoral)-mediated immunity( ) helper-t-cell antigen helper T-cell TH1 TH2 TH1 cell IFNγ TNFβ macrophage delayed type

miscrovasculature (vascular endothelium) renal tubule, pancreatic islets of Langerhans, cardiac myocyte target cell Induction and expression of immunity 1 Induction mechanism of rejection(afferent Ar

8 (4) Immune effector mechanism T-cell cell-mediated immunity( ) antibody(humoral)-mediated immunity( ) helper-t-cell antigen helper T-cell TH1 TH2 TH1 cell IFNγ TNFβ macrophage delayed type hypersensitivity(dth) cytotoxic T-cell cytotoxicity( cytolysis) TH2 cell IL-4,5,6,10 B-cell coagulation system, complement system, Kallikrein system (endothelium), T-cell cytokine (target cell) miscrovasculature (vascular endothelium) renal tubule, pancreatic islets of Langerhans, cardiac myocyte target cell Induction and expression of immunity 1 Induction mechanism of rejection(afferent Ar ) : Double Signal Theory : Most T-helper cell receptor(tcr) recognizes foreign antigen + self-class ll(mhc-restriction), that is first signal, and activated by IL-I which is produced by the APC, that is so called second signal : T cell to B cell interaction 2 Expression of immunity(efferent Arc ) : Cell-mediated tissue injury: cellular infiltration/ctl : Antigen/antibody mediated injury : Activation of coagulation system/ complement system/ Kallikrein system : Result from interactions of the above molecular cascade system : Vascular permeability / Membrane damage / Cellular chemotaxis : Vascular occlusion / Vascular spasm Written by MSKim 8 / 14 page

9 Function of cytokines Cytokine Source Targets Effects IL-1 macrophage Lymphocyte activation T-cell Macrophage stimulation B-cell Leukocyte/endothelial adhesion Macrophage Pyrexia, acute phase proteins T-cell proliferation/differentiation Il-2 T-cell T-cell Tc cell activation Macrophage activation IL-3 T-cell Stem cells Multilineage colony stimulating factor IL-4 T-cell B-cell B-cell growth factors, isotype selection IL-5 T-cell B-cell B-cell growth factors, IgA selection IL-6 T-cell, B-cell macrophage Macrophage Lymphocyte Mast cells T-cell B-cell, Hepatocyte B-cell growth factors, Induce acute phase protein Activation of macrophage, granulocyte and cytotoxic cells Macrophage TNFα Leukocyte/endothelial adhesion Granulocyte Pyrexia, acute phase proteins Tissue cells TNFβ Enhanced MHC class I production MHC class I induction IFNα leukocytes Tissue cells Antiviral effect Stimulation of NK cells IFNβ Leukocytes MHC class I and II induction T-cell Tissue cells Macrophage activation IFNγ NK cell Th2 cell Leukocyte/endothelial adhesion M-CSF Monocytes Proliferation of macrophage precursors G-CSF Macrophage Stimulation division and differentiation Stem cell T-cell GM-CSF Proliferation of granulocyte and macrophage precursors macrophage 5 (1) ABO blood typing (minor mismatch= compatable), - plasmapheresis (2) HLA typing HLA typing DNA-PCR antiserum lymphocyte HLA typing NIH standard, Amos Amos modified NIH anti-complementary factors wash step NIH (3) Lymphocyte Cross matching (LCM) : serum HLA-Ag Ab : Hyperacute Rejection : ( ) serum + cell cell destruction if cell death>29%, positive cell death< 5%, negative Complement dependent cytotoxicity method flow cytometry Lymphocytotoxicity crossmatching type Written by MSKim 9 / 14 page

10 T cell B cell Modified NIH method Johnson s method : T cell sensitivity extended incubation time Warm (37oC) Cold (4oC) Cold B-cell antibody blockingantibody (3) PRA (Panel Reactive Antibody) HLA specific preexisting antibodies lymphocyte panel cross matching High PRA cross match cadaveric donor PRA 6, 1 (cell-mediated immune reaction) Rejection after renal transplantation Classification Hyperacute Acute Chronic Kinetics Very rapid onset, Minutes to hours after Tx Rapid onset, usually early after Tx Slow onset, usually late after Tx Immunologic target Vessel; large, small Parenchyme, small vessel Vessel;large, intermediate Parenchyme Immunologic Humoral Cellular >> Humoral Humoral > Cellular response Pathology Granulocytic infiltates, Vasculitis, hemorrhage Interstital edema, Mononuclear mixed cell Inflammation Sclerotic vascular change 2nd ischemic change Interstitial fibrosis Treatment Graft nephrectomy Steroid pulse therapy Anti-lymphocyte antibody (OKT3, ALG, ATG) Tx: Transplantation no specific management Finally convert to dialysis or retransplantation, (presence of preformed antibody against donor cell) - (platelet) (polymorphonuclear leukocyte) (lymphocyte cross matching) ABO 2 3 T small lymphocyte inflammatory cell (, steroid pulse therapy, methyprednisolone 500 mg/day for 4-5 days), OKT3(monclonal) (ALG ro ATG)(polyclonal) FK-506 rescue Written by MSKim 10 / 14 page

therapy 80% 6 / (ischemic and reperfusion injury), (CMV infection),,, (hyperfiltration, mismaching of donor/recipient size in kidney transplantation) (chronic graft dysfunction) (arteriosclerosis)

11 therapy 80% 6 / (ischemic and reperfusion injury), (CMV infection),,, (hyperfiltration, mismaching of donor/recipient size in kidney transplantation) (chronic graft dysfunction) (arteriosclerosis) (ischemic necrosis) 7 / immunologic tolerance (1), (2) A HLA matching effect HLA-identical B Immunosuppressive agents 3 (1) (Induction therapy): acceptance (2) (maintenance therapy) : (defense mechanism) (3) (reverse a rejection): Written by MSKim 11 / 14 page

(1), (2), (3) (1) cyclosporine FK-506 IL-2 synthesis blocker, (2) steroid, (3) azathipurine MMF anti-metabolite (maintenance immunosuppressive agent) (1) high dose steroid, (2) OKT3, ALG, ATG

12 (1), (2), (3) (1) cyclosporine FK-506 IL-2 synthesis blocker, (2) steroid, (3) azathipurine MMF anti-metabolite (maintenance immunosuppressive agent) (1) high dose steroid, (2) OKT3, ALG, ATG (anti-lymphocyte antibody), (3) FK- 506 MMF (rescue therapy) Immunosuppressive Agents Mechanism Agents Inhibition of Antigen processing, Corticosteroid, 15-DS (Deoxyspergualin), Presentation and reception Anti-lymphocyte antibodies - monoclonal : OKT3 polyclonal : ATG, ALG Lymphokine synthesis inhibitors Cyclosporine, FK-506(Tacrolimus), Antisense Oligonucleotides Cytokine signal transduction Sirolimus (Rapamycin), Leflunomide(HWA 486), Inhibitors IL-2 receptor antagonist Nucleoside synthesis inhibitors Azathioprine, Mycophenolic acid(mmf, RS-61443) Cf) Undelying medication : currently clinical use (1) AZA and Mycophenolate mofetil(mmf, Cellcept ) : (DNA RNA) (Bone marrow suppression) (triple therapy, cyclosporine+steroid+azathiopurine) (2) Steroid : (anti-inflammatory reaction) macrophage APC (expression) (prednisolone 10~15 mg/day) (maintain immunosuppression), (methyprednisolone 500 mg x 3~4 days),,, (moon face), 1980 (30~55%) 1980 Deflazacort (3) CsA(cyclosporin, cyclosporine, Sandimmun Neoral ) and FK-506(Tacrolimus, Prograf ) : 1970 (Cyclosporine) Interleukin-2 Written by MSKim 12 / 14 page

1980 FK-506 1980 FK-506 FK-506 FK-506 (bioavailability) FK-506, (tremor),, (gum hyperplasia), (Hypercholesterolemia),,, (4) ALG/OKT3/ATG(Atgam ) : 1966 (Starzl) (anti-lymphocyte globulin, ALG),

13 1980 FK FK-506 FK-506 FK-506 (bioavailability) FK-506, (tremor),, (gum hyperplasia), (Hypercholesterolemia),,, (4) ALG/OKT3/ATG(Atgam ) : 1966 (Starzl) (anti-lymphocyte globulin, ALG), (anaphylaxis),,, (ALG) monoclonal antibody OKT OKT polyclonal antibody ATG(anti-thymocyte globulin, ATGAM ) ALG OKT3 (5) New immunosuppressive agents : FK-506(1980 ) azathiopurine purine analogs MMF(1990 ), blocking of signal transduction rapamycin(1990 ), Interleukin-2 (Interleukin 2 receptor antibody)(1990 ) monoclonal antibody TCR/CD3 complex, accessory molecule(anti-cd2, anti-cd4, anti-lfa-1, anti-icam-1), IL-2 receptor target ** (1) immunosuppressive effect(ise), (2) non-immunodeficient toxicity(nit), (3) immunodeficient toxicity(idt) dose-dependent (potency) (therapeutic window) Written by MSKim 13 / 14 page

14 (infection) (malignancy) (recipient s net state of immunosuppression) (1),, (2) leukocytopenia, (3),, (4) metabolic abnormality hyperurecemia, hyperglycemia malnutrition, (5) (CMV, EBV, HBV, HCV, HIV) Common Side Effects of Immunosuppression 1 Infection 2 Malignancy atypical infection virus : CMV, HSV, HCV, VZV, EBV, HIV fungus : cryptococcus, candidiasis mycobacteria : atypical M etc : pneumocystis carinii community-acquired infection respiratory : influenza, RSV, adenovirus enteric bacterial : nontyphoidal salmonella Cyclosporine (Sandimmun ) Nephrotoxicity Hypertension Hyperkalemia Tremor Hirsutism Seizure Hypercholesterole mia Hyperuricemia Hepatotoxicity FK-506 (Prograft ) Similar complication CsA with Virus origin cancer Hematologic : PTLD(post-transplant lymphoproliferative disorder) lymphoma skin cancer Urogenital : Cervix cancer Bladder cancer Etc : Karposi s sarcoma Drug specific side effects Prednisone Azathioprine OKT3 ALG/ATG(Atgam ) Weight gain Cushingoid stigmata Cataracts Easy bruising Avascular necrosis of bone mood swings osteoporosis Deflazacort (Calcort ) Milder complication than p-l Neutropenia Anemia Thrombocytopenia? hepatotoxicity Mycophenolic acid (MMF, Cellcept )) G-I trouble (abdominal pain, vomiting, diarrhea) Infection risk Relative contraindicated for pediatric/pregnant women Fever, chill fever, chill pancytopenia serum sickness anaphylaxis PTLD (post-transplant lymphoproliferative disease, lymphoma) Rapamycin (Sirolimus ) Cytopenia(thromboc ytopenia, granulocytopenia, anemia) Hyperlipidemia Rare nephrotoxicity Written by MSKim 14 / 14 page

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract