Transcript 17-transplantation

Transplantation:
Chapter 17
You are not responsible for:
Immunosuppressive therapies
Clinical aspects of specific organ transplants
Self-Test
Questions:
Intro: all
A.I: 1 – 5, 7, 8
A.II: 2 – 4
B: 2, 3, 5
C: 1
D: 4
E: 2
Transplants
Organ
in 2005
Cornea
47,000
Kidney
16,477
Liver
6444
Heart
2127
Lung
1408
Pancreas
570
Transplantation Immunology
1
What are different types of tissue transplants?
Sources
-- Living donor; & self
-- Cadaver
-- Animal
Autologous graft
-- e.g., skin, artery transplants
-- not rejected
Isograft
-- e.g., any organ
-- not rejected
Allograft
-- kidney, liver, heart transplants
-- rejected; unless Im privileged
Xenograft
-- rejected, unless non-antigenic
-- e.g., heart valves
Transplantation Immunology
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What are types of rejection?
Recipient Abs,
attack donor
cells
1. Host-vs-Graft
Hyperacute rejection
-- rapid: minutes to hours
-- humoral; existing Abs; complement
-- blood type
-- xenografts
Recipient
CTLs attack
donor cells
Acute rejection
-- humoral or cell mediated
-- days/weeks
Chronic rejection
Recipient Abs
against donor
MHC
-- months / years
-- despite immunosuppressive therapy
Long term not much improved
-- Kidney: half-life only 8-10 years
2. Graft-vs-Host (discussed later)
5 Year survival rate (2009)
Kidney: 69.3%
Heart: 74.9%
Liver: 73.8%
Lung: 54.4%
Transplantation Immunology
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What are the mechanisms
of Immune rejection
Direct vs Indirect
allo-recognition
Effector cells
Rejection mechanisms
Transplantation Immunology
4
What causes ‘Direct’
allo-recognition?
Primary mechanism of rejection
(10x greater than indirect)
Recipient T-cells are activated by:
Graft-MHC + Graft peptides
Why would T-cells bind to peptides
in non-self MHC?
Graft-MHC + peptide
can resemble …
Self-MHC + foreign peptide
MHC +
peptide
May contribute mostly toward
acute rejection
Transplantation Immunology
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What causes ‘Indirect’
allo-recognition?
Recipient T-cells are activated by
recipient MHC + graft (MHC) peptides
Analogous to normal T-cell response to
pathogens (or vaccines)
Recipient DCs migrate into graft
and phagocytose Ags
-- fewer T-cells respond (most AG being ‘self’)
but among these will also be…
-- MHC peptides
-- Minor Histocompatibility Antigens
May contribute mostly toward chronic
rejection
-- graft DCs soon removed from body
Transplantation Immunology
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When does Graft vs Host
Disease (GvHD) occur?
-- bone marrow
-- some solid organ
Immune cells of graft
react against recipient tissues
-- Allo-reactive antibodies
-- Cell-mediated attack
Occurs in 75%+ of bone marrow
transplants
But has beneficial effect against leukemic
and cancerous cells
Transplantation Immunology
7
What are the primary antirejection therapies?
1. Corticosteroids, e.g., prednisone
2. Anti-proliferatives, e.g., azothrioprine
Cyclosprine-A
3. T-cell signaling/activation disruptors
a) chemotherapeutic agents
-- IL-2 inhibitors; e.g., cyclosporine-A, rapamycin
b) humanized Mabs
-- anti-CD3
-- anti-IL2r (e.g., basiliximab)
-- anti-CD20, a B-cell AG) (e.g., rituximab)
c) fusion molecules
-- B7 antagonist (blocks B7/CD28 interaction)
-- e.g., Belatacept; CTL-4 + IgG FC
Transplantation Immunology
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Organ perfusion prior to transplant
can minimize direct acute rejection
-- why?
-- also improves organ performance
What are some experimental
anti-rejection therapies?
1. Bone marrow HSC transplants
-- transplant HSC from done to recipient
2. Thymic manipulation
-- inject donor AG into recipient thymus
3. Treg cell induction
-- in vitro or in vivo
4. and others…
Transplantation Immunology
9
How is tissue-matching
performed?
-- minimizes HLA incompatibility
1. Alloantibody Screening
-- Abs against specific HLA
2. HLA (tissue) matching
a) Serological
-- use HLA specific mABs
b) DNA analysis
-- look for HLA-allele specific
sequences
HLA typing at NY Blood Center
Serology
HLA Class I (A,B,C)
HLA Class I HLA-B27
DNA analysis
Not all HLA tested for… Why?
PCR- broad allele class resolution
HLA Class I (A,B,C)
DNA sequencing allele level resolution,
HLA Class I (A,B,C) by
HLA-Class II (DRB1)
HLA-Class II (DQB1)
http://www.nybloodcenter.org/HLATyping.do?sid0=92&page_id=185
Transplantation Immunology
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Not all HLA genes are
equally important
Why?
In Kidney
-- Little MHC-II expressed
6 HLA antigens examined:
-- HLA-A, HLA-B, and HLA-DR
e.g., HLA-A1 & A2, B7 & B8, DR2 & DR3
Liver
-- little MHC-I or -II expressed
-- usually only ABO matched
What about…
Cornea: No matching …Why?
Increased HLA matching yields
only minor improvements in
kidney survival
Heart: No matching …Why?
Transplantation Immunology
11