Transplant / Immunology

• 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

• Main role in immunology• Activator of helper T cells• Stimulate antibody formation

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

Which of the following statements is true of the MHC proteins?

A. Only nonnucleated cells express MHC class I proteins

B. B lymphocytes, antigen-presenting cells, and vascular endothelium express only MHC class II proteins

C. MHC class I proteins are encoded by the HLA-D locus (DR, DP, and DQ)

D. MHC 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

• Steps in antigen processing and presentation in response to a viral infection?

1. Infection2. Endogenous viral protein production3. Proteins bound to MHC I4. MHC I expressed on cell surface5. Recognition by CD8 cytotoxic T cells

• Steps in antigen processing and presentation in response to a bacteria infection?

1. Endocytosis2. Proteins bound to MHC class II molecules3. Expressed on cell surface4. Recognition by CD4 helper T cells and B cells5. B cells produce antibodies and are transformed into

memory B cells and plasma cells

• 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

Antibodies

• Types of antibodies?• IgM• IgG• IgA• IgD• IgE

• Which Ab is involved in allergic reactions and parasite infections?

• IgE• Which are opsonins?

• IgM & IgG• Which can fix complement?

• IgM & IgG

• Largest antibody?• IgM

• Most abundant type of antibody?• IgG

• 2 structural regions of antibodies?• Variable - antigen recognition• Constant - recognized by PMNs and

macrophages

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

Immunosuppression

Cyclosporin (CSA)

• MOA?• 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?• 200-300

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

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

Mycophenalate

• MOA?• Similar to azathioprine which was??

• Inhibition or purine synthesis

Thymoglobulin

• What is it derived from?• 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

OKT3

• MOA?• Monoclonal antibody that blocks the

antigen recognition function of T cells by binding CD3

• Indication?• Severe rejection

• Side effects?• Fever• Chills• Pulmonary edema• shock

Summary of main immunosuppressantsCyclosporine (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 prod by Th cells

inhibits IL-2 action upon cells

inhibits DNA synthesis, lymphocyte proliferation

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

Binds to surface of T cells, inh prolif and funct

Bind to IL-2 receptor, preventing action of IL-2

• What is the most common complication of immunosuppression?

• Infection• Other complications include:

HTNCushing’s ThrombophlebitisMalignancyPancreatitisAvascular necrosis of femoral head

• What is the most common cause of death in transplant recipients?

• Infection (check this answer)

• 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?• CMV

• Reason for prophylaxis with trimethoprim and sulfamethoxazole (Bactrim) in transplant recipients?

• Prevention of Pneumocystis carinii infection

• 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

• Cause of hyperacute rejection?• 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

• Tx?• Inc immunosuppression• Pulse steroids• Possibly OKT3

• Cause of acute rejection?• 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

• Tx?• Immunosuppression or OKT3• No effective tx

Kidney transplant

• Most common surgical complication?

• Urine leak• Tx?

• Drainage and stenting

• Most common cause of external compression?

• Lyphocele• Tx?

• Perc drainage (1st)• Intraperitoneal marsupialization

Kidney

• Most common cause of postop oliguria?

• ATN (pathology shows hydrophobic changes)

• Tx of CMV infection?• gangciclovir

• Tx of HSV infection?• acyclovir

Kidney

• 5 yr survival of cadaveric transplants?

• 65%

• 5 yr survival of living donor transplants?

• 75%

Living kidney donors

• Most common complication?• Wound infection (1%)

• Most common cause of death?• PE

Pancreas transplant

• What donor vessels are needed for the arterial supply?

• Celiac & SMA

• What donor vessels are needed for the venous supply?

• Portal vein

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

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

Pancreas

• # 1 complication?• thrombosis

Liver transplant

• Contraindications for transplant?• Current ETOH abuse• Acute UC

• Most common reason for transplant?

• Chronic hepatitis

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

Liver

• #1 complication?• Bile leak• Tx?

• PTC and stent

• 5 yr survival rate?• 70%

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)

Heart transplant

• How long can it be stored?• 6 hrs

• Cause of chronic rejection?• Progressive diffuse coronary

atherosclerosis

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

Lung

• Path findings of acute rejection?• Perivascular lympocytosis

• Path findings of chronic rejection?• Bronchiolitis obliterans

With regard to the MHC, which of the following statements is/are correct?

A. The MHC refers to a gene cluster on chromo 6 that codes for proteins important to the process of rejection

B. Part of the MHC codes for some components of the complement cascade

C. Class I antigens are coded for by the D region of the MHC

D. Class II antigens are important for presenting antigens to the immune system

E. Class I antigens are present only on nucleated cells

With regard to antibodies, which of the following statements is/are

correct?

A. Antibodies are composed of a variable region, which interacts with the host, and a constant region, which interacts w/ an antigen

B. Antibody molecules are composed of 4 polypeptide chains consisting of 2 heavy chains and 2 light chains stabilized by interchain and intrachain disulfide bonds

C. IgA is able to bind complement and function as an opsonin

D. IgG is the largest antibody, w/ a pentameric structure of the basic antibody

E. IgM is the major antibody produced during the primary immune response

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

Bladder drainage of a transplanted pancreas is associated with:

A. Nongap metabolic acidosisB. Recurrent UTIsC. Urethral stricture formation in malesD. Reflux pancreatitis

Match each cell type in the left column with the appropriate statement or statements in

the right column.• T cells

• Macrophages

• Natural killer cells

• Lymphokine-activated killer cells

• Tumor-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

The long term results of a successful kidney/pancreas transplant include:

A. Stabilization of proliferative retinopathyB. Reduced risk of diabetic nephropathyC. Improvement in nerve conduction velocityD. Reversal of peripheral vascular disease

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

Which of the following is/are absolute contraindication(s) to

orthotopic liver transplantation?

A. Hx of alcohol abuseB. Age greater than 60 yrsC. Portal vein thrombosisD. HIVE. Chronic hepatitis C infection

Regarding blood transfusions to potential kidney recipients, which of

the following is/are true?

A. They should be avoided at all costsB. They uniformly decrease graft survivalC. They result in prolonged graft survival of

histocompatibilty antigen (HLA) mismatched grafts, especially if combined with azathioprine therapy

D. They may sensitize the potential recipient

FK 506 (Prograf) has a mechanism of action similar to that of:

A. ImuranB. OKT3C. CyclosporineD. Prednisone

Donor organs for pediatric liver transplantation are acquired from

the following:

A. Donor of similar size and habitusB. Splitting of an adult cadaver liver and

transplanting the appropriate segmentC. Resection of the left lobe of the left lateral

segment of a liver from an adult living donor

With respect to hepatitis and renal transplantation, which of the

following statements is/are true?

A. Hepatitis C is an absolute contraindication to organ donation

B. All hepatitis B surface antigen-positive patients are poor renal transplant candidates

C. Hepatitis C-positive recipients have an extremely poor prognosis

D. None of the aboveE. All of the above

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. Chronic excessive alcohol intakeB. Hepatitis BC. Hepatitis CD. Primary biliary cirrhosisE. Primary sclerosing cholangitis

Which of the following statements regarding the process of rejection

is/are true?

A. Hyperacute rejection is a cell-mediated immune response

B. Acute rejection occurs secondary to preformed antibodies, as with ABO blood group incompatibility

C. Acute rejection is characterized by small lymphocyte and mononuclear cell infiltration

D. Chronic rejection may occur against minor histocompatibility antigens

E. Chronic rejection generally occurs within the first month and is easily treated with immunosuppressive therapy