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Transplant / Immunology. What cells are MHC class I expressed on?What cells are MHC class I expressed on? All nucleated cellsAll nucleated cells What.

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Presentation on theme: "Transplant / Immunology. What cells are MHC class I expressed on?What cells are MHC class I expressed on? All nucleated cellsAll nucleated cells What."— Presentation transcript:

1 Transplant / Immunology

2 What cells are MHC class I expressed on?What cells are MHC class I expressed on? All nucleated cellsAll nucleated cells What T cells does it interact with?What T cells does it interact with? CD8CD8 Main role in immunologyMain role in immunology Target for cytotoxic T cellsTarget for cytotoxic T cells What cells are MHC class II found?What cells are MHC class II found? B cellsB cells DendritesDendrites MonocytesMonocytes APCsAPCs What T cells do they interact with?What T cells do they interact with? CD4CD4 Main role in immunologyMain role in immunology Activator of helper T cellsActivator of helper T cells Stimulate antibody formationStimulate antibody formation

3 MHC complexes Cluster of genes, coding for protein complexes, that are involved in antigen presentationCluster of genes, coding for protein complexes, that are involved in antigen presentation Located on chromosome 6Located on chromosome 6 In humans referred to as human leukocyte antigen (HLA)In humans referred to as human leukocyte antigen (HLA) Important characteristics about MHC (HLA) antigensImportant characteristics about MHC (HLA) antigens Extreme polymorphismExtreme polymorphism Produced by closely linked subloci that form inheritable HLA haplotypesProduced by closely linked subloci that form inheritable HLA haplotypes Codominant expression of HLACodominant expression of HLA What are the 3 functional products of the MHC genesWhat are the 3 functional products of the MHC genes Classes I, II, & IIIClasses I, II, & III What are the corresponding products of each?What are the corresponding products of each? Class I - HLA – A, B, & CClass I - HLA – A, B, & C Class II – HLA- DR, DQ, & DPClass II – HLA- DR, DQ, & DP Class III - complement cascadeClass III - complement cascade

4 Which of the following statements is true of the MHC proteins? A.O nly nonnucleated cells express MHC class I proteins B.B lymphocytes, antigen-presenting cells, and vascular endothelium express only MHC class II proteins C.M HC class I proteins are encoded by the HLA-D locus (DR, DP, and DQ) D.M HC class I proteins act as the major targets for antibody-mediated rejection of organ allografts and are detected by cross-matching techniques E.B cells recognize antigens bound to MHC class II proteins

5 Steps in antigen processing and presentation in response to a viral infection?Steps in antigen processing and presentation in response to a viral infection? 1.Infection 2.Endogenous viral protein production 3.Proteins bound to MHC I 4.MHC I expressed on cell surface 5.Recognition by CD8 cytotoxic T cells Steps in antigen processing and presentation in response to a bacteria infection?Steps in antigen processing and presentation in response to a bacteria infection? 1.Endocytosis 2.Proteins bound to MHC class II molecules 3.Expressed on cell surface 4.Recognition by CD4 helper T cells and B cells 5.B cells produce antibodies and are transformed into memory B cells and plasma cells

6 What do natural killer cells recognize?What do natural killer cells recognize? Cells that lack self-MHCCells that lack self-MHC Not restricted by MHC, do not require previous exposure, don’t require antigen presentationNot restricted by MHC, do not require previous exposure, don’t require antigen presentation Is it a B or T cell?Is it a B or T cell? NeitherNeither

7 Antibodies Types of antibodies?Types of antibodies? IgMIgM IgGIgG IgAIgA IgDIgD IgEIgE Which Ab is involved in allergic reactions and parasite infections?Which Ab is involved in allergic reactions and parasite infections? IgEIgE Which are opsonins?Which are opsonins? IgM & IgGIgM & IgG Which can fix complement?Which can fix complement? IgM & IgGIgM & IgG

8 Largest antibody?Largest antibody? IgMIgM Most abundant type of antibody?Most abundant type of antibody? IgGIgG 2 structural regions of antibodies?2 structural regions of antibodies? Variable - antigen recognitionVariable - antigen recognition Constant - recognized by PMNs and macrophagesConstant - recognized by PMNs and macrophages

9 Hypersensitivity reactions Type IType I Type IIType II Type IIIType III Type IVType IV ABO incompatibilityABO incompatibility Contact dermatitisContact dermatitis IgE bound to mast cells and basophilsIgE bound to mast cells and basophils Serum sicknessSerum sickness AnaphylaxisAnaphylaxis IgG or IgM antibody reacts with cell-bound antigenIgG or IgM antibody reacts with cell-bound antigen Tuberculin skin testTuberculin skin test

10 Immunosuppression

11 Cyclosporin (CSA) MOA?MOA? Binds cyclophilin protein and inhibits genes for cytokine synthesis ( IL-2, IL-3, IL-4, INF- gamma)Binds cyclophilin protein and inhibits genes for cytokine synthesis ( IL-2, IL-3, IL-4, INF- gamma) Side effects?Side effects? NephrotoxicityNephrotoxicity HepatotoxicityHepatotoxicity HUSHUS TremorsTremors SeizuresSeizures Mechanism of metabolism?Mechanism of metabolism? Hepatic metabolism with biliary excretionHepatic metabolism with biliary excretion Normal trough?Normal trough?

12 Azathioprine (Imuran) What is the active metabolite produced in the liver?What is the active metabolite produced in the liver? 6-mercaptopurine6-mercaptopurine MOA?MOA? Inhibits de novo purine synthesis (DNA synthesis), which inhibits T cellsInhibits de novo purine synthesis (DNA synthesis), which inhibits T cells Side effects?Side effects? myelosuppressionmyelosuppression

13 FK-506 (Prograf) What are the intracellular receptors for FK-506?What are the intracellular receptors for FK-506? FK- binding proteinsFK- binding proteins Inhibits T-cell activation and maturation similar to cyclosporinInhibits T-cell activation and maturation similar to cyclosporin Side effects?Side effects? NephrotoxicityNephrotoxicity Anorexia and wt loss (more GI sym than CSA)Anorexia and wt loss (more GI sym than CSA) neurotoxicityneurotoxicity What drugs can increase FK-506 levels?What drugs can increase FK-506 levels? VerapamilVerapamil KetoconazoleKetoconazole ErythromycinErythromycin DiltiazemDiltiazem FluconazoleFluconazole cimetidinecimetidine What drugs and decrease FK-506 levels?What drugs and decrease FK-506 levels? PhenytoinPhenytoin PhenobarbitalPhenobarbital CarbamazepineCarbamazepine RifampinRifampin

14 Mycophenalate MOA?MOA? Similar to azathioprine which was??Similar to azathioprine which was?? Inhibition or purine synthesisInhibition or purine synthesis

15 Thymoglobulin What is it derived from?What is it derived from? Rabbit polyclonal antibodiesRabbit polyclonal antibodies What is it used for?What is it used for? Induction therapyInduction therapy MOA?MOA? Antibodies directed against antigens on T cells (CD complexes)Antibodies directed against antigens on T cells (CD complexes) What other immunosuppressive agent has a similar mechanism and function?What other immunosuppressive agent has a similar mechanism and function? ATGAMATGAM

16 OKT3 MOA?MOA? Monoclonal antibody that blocks the antigen recognition function of T cells by binding CD3Monoclonal antibody that blocks the antigen recognition function of T cells by binding CD3 Indication?Indication? Severe rejectionSevere rejection Side effects?Side effects? FeverFever ChillsChills Pulmonary edemaPulmonary edema shockshock

17 Summary of main immunosuppressants Cyclosporine (CSA) Tacrolimus (FK-506) Sirolimus (rapamycin) Azathiprine Mycophenolate mofetil Glucocorticoids (prednisone, methylprednisolone) Antithymocyte globulin (ATG) Monomurab (OKT3) Basiliximab and daclizumab inhibits IL-2 prod by Th cells inhibits IL-2 action upon cells inhibits DNA synthesis, lymphocyte proliferation Inh DNA & RNA prod, inh nuclear factors that lead to cytokine prod, dec PMN, neutrophil, and macrophage chemotaxis and funct Binds to surface of T cells, inh prolif and funct Bind to IL-2 receptor, preventing action of IL-2

18 What is the most common complication of immunosuppression?What is the most common complication of immunosuppression? InfectionInfection Other complications include:Other complications include:HTNCushing’sThrombophlebitisMalignancyPancreatitis Avascular necrosis of femoral head What is the most common cause of death in transplant recipients?What is the most common cause of death in transplant recipients? Infection (check this answer)Infection (check this answer)

19 Most common types of fungal infections in immunosuppressed patients?Most common types of fungal infections in immunosuppressed patients? Candida albicansCandida albicans aspergillusaspergillus Most common protozoan infection in immunosuppressed patients?Most common protozoan infection in immunosuppressed patients? Pneumocystis cariniiPneumocystis carinii Most common viral infections in transplant recipients?Most common viral infections in transplant recipients? CMVCMV herpes simplexherpes simplex herpes zosterherpes zoster Most common viral agent thought to elicit rejection?Most common viral agent thought to elicit rejection? CMVCMV Reason for prophylaxis with trimethoprim and sulfamethoxazole (Bactrim) in transplant recipients?Reason for prophylaxis with trimethoprim and sulfamethoxazole (Bactrim) in transplant recipients? Prevention of Pneumocystis carinii infectionPrevention of Pneumocystis carinii infection

20 What are the 4 types of rejection and when do each occur?What are the 4 types of rejection and when do each occur? Hyperacute rejection – within minutes to hoursHyperacute rejection – within minutes to hours Accelerated acute rejection - < 1 weekAccelerated acute rejection - < 1 week Acute rejection - 1 week to 1 monthAcute rejection - 1 week to 1 month Chronic rejection – months to yearsChronic rejection – months to years

21 Cause of hyperacute rejection?Cause of hyperacute rejection? Preformed antibodies that activates the complement cascade and causes vessel thrombosisPreformed antibodies that activates the complement cascade and causes vessel thrombosis Tx?Tx? Emergent retransplantEmergent retransplant Cause of accelerated acute rejection?Cause of accelerated acute rejection? Sensitized T cells to donor antigensSensitized T cells to donor antigens Tx?Tx? Inc immunosuppressionInc immunosuppression Pulse steroidsPulse steroids Possibly OKT3Possibly OKT3

22 Cause of acute rejection?Cause of acute rejection? T cells (cytotoxic and helper T cells)T cells (cytotoxic and helper T cells) Tx?Tx? ImmunosuppressionImmunosuppression Pulse steroidsPulse steroids Possibly OKT3Possibly OKT3 Cause of chronic rejection?Cause of chronic rejection? Type IV hypersensitivity reaction & antibody formation leading to graft fibrosis and vascular damageType IV hypersensitivity reaction & antibody formation leading to graft fibrosis and vascular damage Tx?Tx? Immunosuppression or OKT3Immunosuppression or OKT3 No effective txNo effective tx

23 Kidney transplant Most common surgical complication?Most common surgical complication? Urine leakUrine leak Tx?Tx? Drainage and stentingDrainage and stenting Most common cause of external compression?Most common cause of external compression? LyphoceleLyphocele Tx?Tx? Perc drainage (1 st )Perc drainage (1 st ) Intraperitoneal marsupializationIntraperitoneal marsupialization

24 Kidney Most common cause of postop oliguria?Most common cause of postop oliguria? ATN (pathology shows hydrophobic changes)ATN (pathology shows hydrophobic changes) Tx of CMV infection?Tx of CMV infection? gangciclovirgangciclovir Tx of HSV infection?Tx of HSV infection? acycloviracyclovir

25 Kidney 5 yr survival of cadaveric transplants?5 yr survival of cadaveric transplants? 65%65% 5 yr survival of living donor transplants?5 yr survival of living donor transplants? 75%75%

26 Living kidney donors Most common complication?Most common complication? Wound infection (1%)Wound infection (1%) Most common cause of death?Most common cause of death? PEPE

27 Pancreas transplant What donor vessels are needed for the arterial supply?What donor vessels are needed for the arterial supply? Celiac & SMACeliac & SMA What donor vessels are needed for the venous supply?What donor vessels are needed for the venous supply? Portal veinPortal vein

28 Pancreas Most common route of exocrine pancreatic drainage?Most common route of exocrine pancreatic drainage? Enteric drainageEnteric drainage 2 nd portion of duodenum including ampulla of vater & pancreas (donor) is attached to recipient bowel2 nd portion of duodenum including ampulla of vater & pancreas (donor) is attached to recipient bowel

29 Pancreas What is improved by a successful kidney/pancreas transplant?What is improved by a successful kidney/pancreas transplant? RetinopathyRetinopathy NeuropathyNeuropathy Nerve conduction velocityNerve conduction velocity Autonomic dysfunction (gastroparesis)Autonomic dysfunction (gastroparesis) Orthostatic hypotensionOrthostatic hypotension What is not?What is not? Vascular diseaseVascular disease

30 Pancreas # 1 complication?# 1 complication? thrombosisthrombosis

31 Liver transplant Contraindications for transplant?Contraindications for transplant? Current ETOH abuseCurrent ETOH abuse Acute UCAcute UC Most common reason for transplant?Most common reason for transplant? Chronic hepatitisChronic hepatitis

32 Liver Tx of patients with hepatitis B antigenemia postoperatively?Tx of patients with hepatitis B antigenemia postoperatively? HBIG ( hepatitis B immunoglobulin)HBIG ( hepatitis B immunoglobulin) Lamivudine (protease inhibitor)Lamivudine (protease inhibitor) Most common hepatic arterial supply anomaly?Most common hepatic arterial supply anomaly? Right hepatic off of SMARight hepatic off of SMA

33 Liver #1 complication?#1 complication? Bile leakBile leak Tx?Tx? PTC and stentPTC and stent 5 yr survival rate?5 yr survival rate? 70%70%

34 Liver Is hepatitis B or C infection more likely to recur in the new liver?Is hepatitis B or C infection more likely to recur in the new liver? C – almost all infectedC – almost all infected Rate of hepatitis B reinfection?Rate of hepatitis B reinfection? 20% (with the use of HBIG)20% (with the use of HBIG)

35 Heart transplant How long can it be stored?How long can it be stored? 6 hrs6 hrs Cause of chronic rejection?Cause of chronic rejection? Progressive diffuse coronary atherosclerosisProgressive diffuse coronary atherosclerosis

36 Lung transplant #1 cause of early mortality?#1 cause of early mortality? Reperfusion injuryReperfusion injury Indication for a double lung transplant?Indication for a double lung transplant? CFCF Exclusion criteria for donor lungs?Exclusion criteria for donor lungs? AspirationAspiration Moderate to large contusionModerate to large contusion InfiltrateInfiltrate Purulent sputumPurulent sputum PaO2 <350 on 100% FiO2 & PEEP of 6PaO2 <350 on 100% FiO2 & PEEP of 6

37 Lung Path findings of acute rejection?Path findings of acute rejection? Perivascular lympocytosisPerivascular lympocytosis Path findings of chronic rejection?Path findings of chronic rejection? Bronchiolitis obliteransBronchiolitis obliterans

38 With regard to the MHC, which of the following statements is/are correct? A.T he MHC refers to a gene cluster on chromo 6 that codes for proteins important to the process of rejection B.P art of the MHC codes for some components of the complement cascade C.C lass I antigens are coded for by the D region of the MHC D.C lass II antigens are important for presenting antigens to the immune system E.C lass I antigens are present only on nucleated cells

39 With regard to antibodies, which of the following statements is/are correct? A.A ntibodies are composed of a variable region, which interacts with the host, and a constant region, which interacts w/ an antigen B.A ntibody molecules are composed of 4 polypeptide chains consisting of 2 heavy chains and 2 light chains stabilized by interchain and intrachain disulfide bonds C.I gA is able to bind complement and function as an opsonin D.I gG is the largest antibody, w/ a pentameric structure of the basic antibody E.I gM is the major antibody produced during the primary immune response

40 Match each immunoglobulin with the appropriate statement(s) in the right column IgAIgA IgGIgG IgEIgE IgMIgM IgDIgD Binds mast cellsBinds mast cells Major antibody of the secondary immune responseMajor antibody of the secondary immune response Most prevalent serum immunoglobulinMost prevalent serum immunoglobulin May bind complementMay bind complement Found particularly in secretionsFound particularly in secretions Mediates type I hypersensitivity reactionsMediates type I hypersensitivity reactions Function is essentially unknownFunction is essentially unknown

41 Bladder drainage of a transplanted pancreas is associated with: A.N ongap metabolic acidosis B.R ecurrent UTIs C.U rethral stricture formation in males D.R eflux pancreatitis

42 Match each cell type in the left column with the appropriate statement or statements in the right column. T cellsT cells MacrophagesMacrophages Natural killer cellsNatural killer cells Lymphokine-activated killer cellsLymphokine-activated killer cells Tumor-infiltrating lymphocytesTumor-infiltrating lymphocytes A.Type of lymphocyte B.May provide some type of antitumor surveillance C.Generated from culture in interleukin-2 (IL-2) D.Used for anticancer immunotherapy E.Produces interferon alpha

43 The long term results of a successful kidney/pancreas transplant include: A.S tabilization of proliferative retinopathy B.R educed risk of diabetic nephropathy C.I mprovement in nerve conduction velocity D.R eversal of peripheral vascular disease

44 Which of the following patients are acceptable candidates for liver transplantation? A.A 50 yr old man w/ cholangiocarcinoma (klatskin tumor), with no evidence of metastasis on CT & MRI scans, who has normal cardiac, renal, and pulmonary functions B.A 48 yr old Hispanic man with advanced cirrhosis from hepatitis C w/ a 3 cm hepatoma in the right lobe of the liver C.A 48 yr old woman w/ cirrhosis from hepatitis B who is DNA- negative, surface Ag-pos., & surface Ab-negative D.A 50 yr old Caucasian woman given a transplant 6 yrs ago who had hepatitis C & now has recurrent hepatitis C, cirrhosis, & uncontrollable ascites E.A 55 yr old alcoholic man with medically refractory ascites, grade II encephalopathy, prolonged INR of 3, and abstinent from alcohol for 12 months

45 Which of the following is/are absolute contraindication(s) to orthotopic liver transplantation? A.H x of alcohol abuse B.A ge greater than 60 yrs C.P ortal vein thrombosis D.H IV E.C hronic hepatitis C infection

46 Regarding blood transfusions to potential kidney recipients, which of the following is/are true? A.T hey should be avoided at all costs B.T hey uniformly decrease graft survival C.T hey result in prolonged graft survival of histocompatibilty antigen (HLA) mismatched grafts, especially if combined with azathioprine therapy D.T hey may sensitize the potential recipient

47 FK 506 (Prograf) has a mechanism of action similar to that of: A.I muran B.O KT3 C.C yclosporine D.P rednisone

48 Donor organs for pediatric liver transplantation are acquired from the following: A.D onor of similar size and habitus B.S plitting of an adult cadaver liver and transplanting the appropriate segment C.R esection of the left lobe of the left lateral segment of a liver from an adult living donor

49 With respect to hepatitis and renal transplantation, which of the following statements is/are true? A.H epatitis C is an absolute contraindication to organ donation B.A ll hepatitis B surface antigen-positive patients are poor renal transplant candidates C.H epatitis C-positive recipients have an extremely poor prognosis D.N one of the above E.A ll of the above

50 Of the following liver diseases resulting in end-stage cirrhosis, which one most commonly recurs in the new liver allograft utilizing current prophylactic measures? A.C hronic excessive alcohol intake B.H epatitis B C.H epatitis C D.P rimary biliary cirrhosis E.P rimary sclerosing cholangitis

51 Which of the following statements regarding the process of rejection is/are true? A.H yperacute rejection is a cell-mediated immune response B.A cute rejection occurs secondary to preformed antibodies, as with ABO blood group incompatibility C.A cute rejection is characterized by small lymphocyte and mononuclear cell infiltration D.C hronic rejection may occur against minor histocompatibility antigens E.C hronic rejection generally occurs within the first month and is easily treated with immunosuppressive therapy


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