TRANSPLANTATIONTRANSPLANTATION PHYSIOLOGYPHYSIOLOGY

Robert L. Madden MD, FACSRobert L. Madden MD, FACSAssociate Professor of SurgeryAssociate Professor of Surgery

Tufts University School of MedicineTufts University School of MedicineBaystate Medical CenterBaystate Medical Center

Springfield, MASpringfield, MA

Part 4 of 4Part 4 of 4

Which one of the following statements is false.

Graft-versus-host-disease (GVHD) … :

a. is injury in a transplant recipient caused bydonor T cells.

b. can occur with bone marrow and small intestinal transplantation.

c. presents acutely with skin rash, jaundice,and diarrhea.

d. if severe, can be fatal.

e. is best treated with a decrease in immunosuppression to allow a rebound of the recipient’s immune activity.

d. if severe, can be fatal.

e. is best treated with a decrease in immunosuppression to allow a rebound of the recipient’s immune activity.

C. Graft-versus-host disease (GVHD)

1. Recipient injury caused by donor T cells(recognize alloAg of recipient) that weretransferred during transplant procedurea. bone marrow transplantationb. small intestine and lung transplantation

2. Acute GVHDa. necrosis of epithelial cells in skin,

liver (bile ducts), and GI tractb. clinical symptoms - skin rash,

jaundice, diarrheac. if severe, can be fatal

3. Chronic GVHDa. fibrosis of skin, liver, GI tract and lungs

without necrosisb. if severe, can lead to complete dysfunction

of involved organ and death

4. Donor NK cells may be responsible for recipientepithelial cell damage

5. Acute and chronic GVHD treated with intenseimmunosuppressive therapy - often moreresistant to treatment than allograft rejection(possibly because of NK cell involvement)

PREVENTION OF ALLOGRAFT REJECTION

A. Prevention strategies vary with transplant centerB. Two main approaches are utilized:

1. Render the allograft less immunogenica. elimination of MHC class II bearing

cells in allografti. allograft passenger leukocyte

depletion prior to transplan-tation

ii. prolongs allograft survival inanimal models

iii. not clinically applicable becausehuman endothelial cells expressclass II Ags

b. minimization of alloAg differencesbetween donor and recipienti. assure ABO compatibilityii. HLA matching used in donor

selection

2. Suppression of recipient immune system -immunosuppressiona. mainstay of successful clinical

transplantation

The mechanisms of action of cyclosporine andtacrolimus are similar in that they both … :

a. inhibit IL-2 transcription.

b. inhibit IL-1, IL-6 and TNF synthesis.

c. inhibit inosine monophosphate dehydro-genase and thereby block de-novo purinesynthesis

d. bind to the CD3 portion of the TCR and cause depletion of CD3+ T cells.

e. become incorporated into DNA and blocklymphocyte proliferation.

The mechanisms of action of cyclosporine andtacrolimus are similar in that they both … :

a. inhibit IL-2 transcription.

b. inhibit IL-1, IL-6 and TNF synthesis.

c. inhibit inosine monophosphate dehydro-genase and thereby block de-novo purinesynthesis

d. bind to the CD3 portion of the TCR and cause depletion of CD3+ T cells.

e. become incorporated into DNA and blocklymphocyte proliferation.

b. corticosteroids (methylprednisolone,prednisone, etc.)i. multiple anti-inflammatory

actionsii. block cytokine productioniii. inhibit IL-1, IL-6 and TNF

synthesisiv. dose: rapid taper after transplant -

low maintenance dosev. high dose - T cell lysis

vi. side effects:a. increased infection

susceptibilityb. impaired healingc. weight gaind. diabetagenice. fluid retentionf. avascular hip necrosisg. cataract formationh. peptic ulcer diseasei. exacerbate hypertensionj. etc.

c. azathioprine (Imuran)i. purine analog/antimetaboliteii. inhibits lymphocyte proliferationiii. dose: 1-2 mg/kg/dayiv. side effects:

a. bone marrow suppressionb. decreased resistance to

infection/tumorc. hepatoxicity (rare)

d. cyclosporine (Sandimmune, Neoral)(CsA) i. fungal metaboliteii. binds to cyclophilin in cytosoliii. complex binds to calcineurin -

blocks NFAT (transcriptionfactor) activation

iv. inhibits IL-2 transcriptionv. dose: bid dosing based on

blood levels

vi. side effects:a. nephrotoxicityb. decreased resistance to

infection/tumorc. exacerbates hypertensiond. diabetagenice. hepatotoxicityf. tremorg. hirsutismh. gingival hyperplasia

vii. expensive

e. tacrolimus (FK506, Prograf) (Tac) i. macrolide antibioticii. binds to FK binding protein

in cytosoliii. complex binds to calcineurin -

blocks NFATiv. inhibits IL-2 transcriptionv. dose: bid dosing based on

blood levels

vi. side effects:a. similar side effect

profile to CsAb. more neurotoxic and

diabetagenic than CsAc. no hirsutism or gingival

hyperplasia

vii. expensive

f. mycophenolate mofetil (RS-61443,CellCept) (MMF) i. ethyl ester of mycophenolic acidii. metabolized to mycophenolic

acidiii. inhibits inosine monophosphate

dehydrogenaseiv. blocks de-novo purine synthesisv. lymphocytes rely on de-novo

pathway (most other cells havegood salvage pathway forpurine synthesis)

vi. dose: bid based on levels

vii. side effects:a. gastrointestinal

distressb. rare bone marrow

suppressionc. decreased resistance

to infection/tumorviii. expensive

g. rapamycin (sirolimus, Rapamune)i. macrolide antibioticii. binds to FK binding protein

in cytosoliii. modulates the activity of mTOR

(mammalian Target of Rapamycin)iv. prevents IL-2 driven cell

proliferationv. inhibits T and B cell proliferation

vi. side effects:a. hyperlipidemiab. bone marrow

suppression; anemiac. decreased resistance

to infection/tumord. rashe. pneumonitisf. GI distress

viii. expensive

3. Maintenance immunosuppression a. protocols vary by transplant centerb. most US centers use “triple” or

“dual” therapyc. triple - CsA or Tac + azathioprine

or MMF or sirolimus + steroidsd. dual - CsA or Tac + steroidse. rationale similar to chemotherapy

rationale - use of multiple drug regimen reduces side effects asopposed to high-dose monotherapy

f. recipients must be compliant withimmunosuppressive regimens forlife of allograft

4. Induction immunosuppression (“sequential”)a. additional immunosuppressive

medication (given in addition tomaintenance immunosuppression)started at or immediately before thetransplant operation and continuedfor only 1-3 weeks

b. usually monoclonal or polyclonal Ab preparation

c. use varies with transplant centeri. some always use induction/

some neverii. some use selective induction

(eg., for delayed or poor initialallograft function, and/or forhighly sensitized recipients)

d. polyclonal antilymphocyte serum i. ALS, ATGAM, RATS,

Thymglobulinii. made in horse, goat, rabbit

iii. mechanism of action notcompletely understood -cause T cell depletion

iv. dose: given daily x 5-15 daysv. side effects:

a. anaphylaxisb. feverc. serum sicknessd. thrombocytopeniae. local phlebitisf. bone marrow suppression

vi. expensive - $500 - $1000/dose

e. anti-CD3 Ab (OKT-3)i. monoclonal murine Ab

(hybridoma)ii. specific for CD3 molecule on T

cells (part of TCR)iii. mechanism of action not

completely understood - causesT cell (CD3+) cell depletiona. T cell lysisb. T cell marginationc. T cell receptor blockaded. T cell loss of TCR

iv. dose: 5 mg/day x 10-14 days

v. side effects:a. anaphylaxisb. activating Ab - massive

cytokine release(“cytokine release syndrome”)i. pulmonary edemaii. feveriii. nausea/vomitiv. headachev. tremorvi. malaisevii. diarrhea

c. decreased resistance toinfection/tumor

vi. expensive - $300 - $500/dose

f. anti-CD25 Ab (anti-Tac, anti-IL-2R,Simulect, Zenapax)i. monoclonal Abs specific for

IL-2R ii. inhibit T cell activation by

blocking IL-2 bindingiii. dose: varies with manufacturer

(usually given for 2-5 dosesafter transplant)

iv. side effects: minimalv. expensive - $1000 - $2000/dose

TREATMENT OF ALLOGRAFT REJECTION

A. Treatment strategies vary with transplant center

B. Critical to make proper diagnosis

1. Many clinical entities can mimic rejection

2. Inappropriate use of anti-rejection therapy cancause significant morbidity and/or mortality

3. No highly sensitive/specific diagnostic tests)

4. Biopsy is often needed to confirm a diagnosisof rejection (but still not 100% accurate)

True or false:

Most US renal transplant centers initiate treatment of

an acute rejection episode with a combination of

allograft irradiation and high dose tacrolimus.

True or false:

Most US renal transplant centers initiate treatment of

an acute rejection episode with a combination of

allograft irradiation and high dose tacrolimus.

C. Treatment options:

1. High dose steroidsa. 250-1000 mg/day methylpredisolone

(some centers use oral)b. usually given for 3-5 daysc. reverses (stops) approx. 75% of

rejection episodesd. if inadequate response, change to

alternate treatment

2. Antibody preparationa. OKT-3 or Thymoglobulin used most

commonlyb. very potent anti-rejection therapiesc. reverses 75-90% of rejection episodes

3. Plasmapharesisa. removes Abs from bloodb. immunosuppressivec. often used in conjuction with

IVIg for humoral rejectiond. exact indications are not well-defined

4. “Rescue” therapya. used when other anti-rejection

therapies have failedi. high dose tacrolimusii. mycophenolate mofetil

5. Allograft irradiationa. most commonly used as a “last ditch”

effortb. dose: 100-150 cGy/day x 5 daysc. efficacy not well-known