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Transplant / Immunology

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Presentation on theme: "Transplant / Immunology"— Presentation transcript:

1 Transplant / Immunology

2 What cells are MHC class I expressed on?
All nucleated cells What T cells does it interact with? CD8 Main role in immunology Target for cytotoxic T cells What cells are MHC class II found? B cells Dendrites Monocytes APCs What T cells do they interact with? CD4 Activator of helper T cells Stimulate antibody formation

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

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

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

6 What do natural killer cells recognize?
Cells that lack self-MHC Not restricted by MHC, do not require previous exposure, don’t require antigen presentation Is it a B or T cell? Neither

7 Antibodies Types of antibodies?
IgM IgG IgA IgD IgE Which Ab is involved in allergic reactions and parasite infections? Which are opsonins? IgM & IgG Which can fix complement?

8 Most abundant type of antibody? 2 structural regions of antibodies?
Largest antibody? IgM Most abundant type of antibody? IgG 2 structural regions of antibodies? Variable - antigen recognition Constant - recognized by PMNs and macrophages

9 Hypersensitivity reactions
Type I Type II Type III Type IV ABO incompatibility Contact dermatitis IgE bound to mast cells and basophils Serum sickness Anaphylaxis IgG or IgM antibody reacts with cell-bound antigen Tuberculin skin test

10 Immunosuppression

11 Cyclosporin (CSA) MOA? Side effects? Mechanism of metabolism?
Binds cyclophilin protein and inhibits genes for cytokine synthesis (IL-2, IL-3, IL-4, INF- gamma) Side effects? Nephrotoxicity Hepatotoxicity HUS Tremors Seizures Mechanism of metabolism? Hepatic metabolism with biliary excretion Normal trough?

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

13 FK-506 (Prograf) What are the intracellular receptors for FK-506?
FK- binding proteins Inhibits T-cell activation and maturation similar to cyclosporin Side effects? Nephrotoxicity Anorexia and wt loss (more GI sym than CSA) neurotoxicity What drugs can increase FK-506 levels? Verapamil Ketoconazole Erythromycin Diltiazem Fluconazole cimetidine What drugs and decrease FK-506 levels? Phenytoin Phenobarbital Carbamazepine Rifampin

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

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

16 OKT3 MOA? Indication? Side effects?
Monoclonal antibody that blocks the antigen recognition function of T cells by binding CD3 Indication? Severe rejection Side effects? Fever Chills Pulmonary edema shock

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?
Infection Other complications include: HTN Cushing’s Thrombophlebitis Malignancy Pancreatitis Avascular necrosis of femoral head What is the most common cause of death in transplant recipients? Infection (check this answer)

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

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

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

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

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

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

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

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

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

28 Pancreas Most common route of exocrine pancreatic drainage?
Enteric drainage 2nd 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?
Retinopathy Neuropathy Nerve conduction velocity Autonomic dysfunction (gastroparesis) Orthostatic hypotension What is not? Vascular disease

30 Pancreas # 1 complication? thrombosis

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

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

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

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

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

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

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

38 With regard to the MHC, which of the following statements is/are correct?
The MHC refers to a gene cluster on chromo 6 that codes for proteins important to the process of rejection Part of the MHC codes for some components of the complement cascade Class I antigens are coded for by the D region of the MHC Class II antigens are important for presenting antigens to the immune system Class I antigens are present only on nucleated cells

39 With regard to antibodies, which of the following statements is/are correct?
Antibodies are composed of a variable region, which interacts with the host, and a constant region, which interacts w/ an antigen Antibody molecules are composed of 4 polypeptide chains consisting of 2 heavy chains and 2 light chains stabilized by interchain and intrachain disulfide bonds IgA is able to bind complement and function as an opsonin IgG is the largest antibody, w/ a pentameric structure of the basic antibody IgM is the major antibody produced during the primary immune response

40 Match each immunoglobulin with the appropriate statement(s) in the right column
IgA IgG IgE IgM IgD Binds mast cells Major antibody of the secondary immune response Most prevalent serum immunoglobulin May bind complement Found particularly in secretions Mediates type I hypersensitivity reactions Function is essentially unknown

41 Bladder drainage of a transplanted pancreas is associated with:
Nongap metabolic acidosis Recurrent UTIs Urethral stricture formation in males Reflux pancreatitis

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

43 The long term results of a successful kidney/pancreas transplant include:
Stabilization of proliferative retinopathy Reduced risk of diabetic nephropathy Improvement in nerve conduction velocity Reversal of peripheral vascular disease

44 Which of the following patients are acceptable candidates for liver transplantation?
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 A 48 yr old Hispanic man with advanced cirrhosis from hepatitis C w/ a 3 cm hepatoma in the right lobe of the liver A 48 yr old woman w/ cirrhosis from hepatitis B who is DNA-negative, surface Ag-pos., & surface Ab-negative A 50 yr old Caucasian woman given a transplant 6 yrs ago who had hepatitis C & now has recurrent hepatitis C, cirrhosis, & uncontrollable ascites A 55 yr old alcoholic man with medically refractory ascites, grade II encephalopathy, prolonged INR of 3, and abstinent from alcohol for 12 months A has 5 yr survival of less than 20%

45 Which of the following is/are absolute contraindication(s) to orthotopic liver transplantation?
Hx of alcohol abuse Age greater than 60 yrs Portal vein thrombosis HIV Chronic hepatitis C infection

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

47 FK 506 (Prograf) has a mechanism of action similar to that of:
Imuran OKT3 Cyclosporine Prednisone

48 Donor organs for pediatric liver transplantation are acquired from the following:
Donor of similar size and habitus Splitting of an adult cadaver liver and transplanting the appropriate segment Resection 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?
Hepatitis C is an absolute contraindication to organ donation All hepatitis B surface antigen-positive patients are poor renal transplant candidates Hepatitis C-positive recipients have an extremely poor prognosis None of the above All 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? Chronic excessive alcohol intake Hepatitis B Hepatitis C Primary biliary cirrhosis Primary sclerosing cholangitis

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

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