transplantation physiology robert l. madden md, facs associate professor of surgery tufts university...
TRANSCRIPT
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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
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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.
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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.
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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.
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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
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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)
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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
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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
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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.
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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.
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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
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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.
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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)
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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
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vi. side effects:a. nephrotoxicityb. decreased resistance to
infection/tumorc. exacerbates hypertensiond. diabetagenice. hepatotoxicityf. tremorg. hirsutismh. gingival hyperplasia
vii. expensive
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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
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vi. side effects:a. similar side effect
profile to CsAb. more neurotoxic and
diabetagenic than CsAc. no hirsutism or gingival
hyperplasia
vii. expensive
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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
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vii. side effects:a. gastrointestinal
distressb. rare bone marrow
suppressionc. decreased resistance
to infection/tumorviii. expensive
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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
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vi. side effects:a. hyperlipidemiab. bone marrow
suppression; anemiac. decreased resistance
to infection/tumord. rashe. pneumonitisf. GI distress
viii. expensive
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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
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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
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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
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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
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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
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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
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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
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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)
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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.
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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.
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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
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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
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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
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