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Transplant
Immunology
WHY TRANSPLANT TISSUES OR ORGANS?
Replace dysfunctional/nonfunctional tissue or organs
------------------------------------------------------------------------------ High technology medicine
Specialized healthcare professionals
Specialized facilities
Specialized support
Pathology
Radiology
- Life saving
- Very Expensive
------------------------------------------------------------------------------
DEFINITIONS OF TYPES OF TRANSPLANTS:
---------------------------------------------------------------------Classification scheme: depends upon:
- the species of donor and recipient
- same or different?
- genetic similarity of donor & recipient (assuming
both are form the same species)
- identical versus
- non-identical
----------------------------------------------------------------------
NOMENCLATURE: Donor (graft) & Recipient (host)
IMPORTANT!
Same
Genetically Type of
Species Identical
transplant / tissue
-----------------------------------------------------------------------------Self-> Self Yes
Yes
Autologous graft
Autograft
Twin A -> B* Yes
Yes
Isogeneic graft (syngeneic)
Isograft (syngeneic graft)
Person
A --> B
Yes
No
Allogeneic graft
Allograft**
Species
A --> B
No
No
Xenogeneic graft
Xenograft
-----------------------------------------------------------------------------*
Also applies to individuals of an inbred strain (e.g., inbred mice)
**
Most common type of transplant in humans
IMPORTANT!
WHAT ARE THE RULES OF TRANSPLANTATION?
Type of Graft
Graft fate without
immunosuppression of
the recipient (host)
---------------------------------------------------------Autograft
Accepted
Isograft
Accepted
Allograft
Rejected*
Xenograft
Rejected*
---------------------------------------------------------* Graft (donor) and Host (recipient) are
antigenically dissimilar
Tissue
Autograftt
Twin “A”
TWIN “B”
Tissue
Isograft (syngeneic graft)
Tissue
Allogeneic graft (allograft)
Tissue
Xenograft
CLASSIFICATION BY GRAFT LOCATION
Orthograft:
transplanted organ is placed in the
normal organ location (heart)
Heterotopic:
transplanted organ is placed in an
unnatural location (kidney in pelvis)
WHAT ARE THE TRANSPLANTATION ANTIGENS?
IMPORTANT!
Transplantation
Relative
Antigens
Polymorphism
-----------------------------------------------------------------------------1) ABO
Limited
2) Major histocompatibility
complex (MHC)*
Very high
3) Minor histocompatibility
antigens(non-MHC antigens)
Limited
4) Xenoantigens
Extremely high
-----------------------------------------------------------------------------* Human MHC = HLA Complex, class I and
class II MHC
HOW DOES THE RECIPIENT RECOGNIZE THE
DONOR AS FOREIGN?
--------------------------------------------------------------------------H o s t (Recipient) TCR and B cell receptors
recognize
d o n o r (graft) antigens as f o r e i g n
---------------------------------------------------------------------------
IMPORTANT
CONCEPT:
------------------------------------------------------------------------------ the greater the difference in peptide sequences
between graft and recipient
- the stronger the immune response to the graft (donor)
------------------------------------------------------------------------------
HOW CAN FOREIGN CLASS II MHC
PRESENT PEPTIDES TO HOST TCRs?
Classification of the phases of tissue rejection
Minutes- Hours
Days
Weeks
Months
Years
Hyperacute
Acute
Subacute
Chronic
Pre-existing immunity to graft antigens
Yes
Antibody
No
CMI
CMI
Antibody + CMI
Hyperacute
Acute
Subacute
Chronic
Minutes- Hours
Days
Weeks
Months
Years
Type of
Phase
T ime
Mechanism Donor - Recipient
frame
Mismatch
-----------------------------------------------------------------------------Hyperacute Minutes
-hours
Pre-existing
ABO
antibodies
MHC
anti-ABO,
anti-MHC
Acute vascular
obstruction
(2 0 set rejection)
------------------------------------------------------------------------------
Type of
Phase
T ime
Mechanism Donor - Recipient
frame
Mismatch
-----------------------------------------------------------------------------Acute*
Days
Reactivation
of sensitized
T cells; 2 nd set
rejection
Class I or II
MHC; minor
histocompatibility
-----------------------------------------------------------------------------* some sources refer to this as “accelerated ”
Type of
Phase
T ime
Mechanism Donor - Recipient
frame
Mismatch
-----------------------------------------------------------------------------Subacute
Days
10 activation
Class II
-weeks
of T cells
MHC
“1 st set rejection”
------------------------------------------------------------------------------
Type of
Phase
T ime
Mechanism Donor - Recipient
frame
Mismatch
-----------------------------------------------------------------------------Chronic
Months
Cell-mediated
Class I
-Years
and AbMHC, Minor
mediated;
histocompatiImmune
bility
complexes*
-----------------------------------------------------------------------------* initial first set rejection evolves into a
second set rejection
TIME TO TISSUE REJECTION IN MICE
-------------------------------------------------------------------------Skin graft in mice
strain A -->
Immune
strain B
response
First set rejection
11 - 15 days
Primary
Second set rejection
6 - 8 days
Secondary
---------------------------------------------------------------------------
IMPORTANT
First Kidney Transplant Surgery: 1950
Transplantation
From Kidney to Stem cell
History of Transplantation in
Iran
1st kidney transplantation in 1967 in Shiraz
Dr. Sanadi Zadeh
1985
2 transplantation teams were
organized and started to work
actively
274 kidney transplant in 2 years
L.R.D
L.U.R.D.
cadaveric
1988
• L.U.R.D program organized and managed
successfully
• Number of transplant teams grow to < 20
• To the end of 2002 => 14888 kidney
transplant
• Today => 1500 kidney transplant/yr in Iran
THE NUMBER OF RENAL TRANSPLANTS
PERFORMED IN IRAN FROM 1984 - 2002
1800
1650
1600
1422
Number of Txs
1400
1681
1169
1200
1000
813
800
755
1184 1186
853 827
687
583
600
453
400
200
500
245
98
6
158
18
0
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99 2000 2001 2002
SOURCES OF KIDNEY
DONATION IN IRAN ; 1984 - 2002
LURD
79%
(N=11 292)
LRD
19.2%
(N=2746)
CAD
1.8%
(N=250)
PATIENT AND GRAFT SURVIVAL RATE IN LIVING
RELATED (LRD) AND LIVING UNRELATED (LURD)
RENAL TRANSPLANTATION
In Hashemi Nejad Hospital , Tehran
100
90
80
70
60
% 50
40
30
20
10
0
Patient survival
P<0.05
Graft survival
LRD (N=469)
LURD (N=881)
1
2
3
4
5
6
Years Post Transplant
7
8
9
10
GRAFT SURVIVAL RATES IN HLA IDENTICAL,
ONE HLA HAPLOTYPE MATCH AND LIVING
UNRELATED RENAL TRANSPLANT
In Hashemi Nejad Hospital , Tehran
100
90
80
70
60
50
% 40
30
20
10
0
P<0.001
P=0.35
HLA Identical (n=141)
One HLA Haplo (n=307)
Living Unrelated (n=881)
1
2
3
4
5
6
7
Years Post Transplant
8
9
10
Other Organ transplants
Bone Marrow, Liver & Heart
1991
1ST BMT in Shariati Hospital (Dr.
Ghavamzadeh et al
1991-2006
Total of 1468 BMT
Allogenic 1044
Autologous 324
New Topics
Human Stem cell Repertoire
What are stem cells?
• A stem cell is a cell whose job in the body is not yet
determined
• Every single cell in the body stems from this type of cell
• Stem cells wait for signals to tell them what to become
• Until it receives a signal, it must wait patiently and divide
slowly
• When it receives a signal, begin to differentiate
• The signals tell stem cell to turn on certain cell type it
supposed to become
• These Super cell have a magic clinical
potential in tissue repair
• They represent the future relief of a wide
range of incurable diseases
• They could replace defective organ and
tissues
• They can restore the function of
dysfunctional or non functional organs
Where do they come from?
Early embryonic stages
Some Fetal tissues
The Umbilical Cord
Several Adult organs
–Bone Marrow
–Peripheral blood
–Fat tissues
–Etc…
Adult stem cell?
• Every single organ has it’s own stem
cell
• Bone Marrow
• Heamatopoietic stem cell (HSC)
• Endothelial stem cell (ESC)
• Mesenchymal stem cell (MSC)
Mesenchymal Stem Cells (MSCs)
• MSCs are adult stem cells from BM that can
differentiate into multiple nonhematopoietic cell
lineages.
• They can differentiate into osteoblast, adipocytes,
chondrocytes, myocytes, cardiomyocytes,
astrocytes, oligodenrocytes and neurons.
• They have potential to down regulate and inhibit
immune response in both recognition and
elimination phases
• Possible clinical application proposed for MSC
include:
• stem cell transplantation
• Stem cell strategies for the repair of damaged
organ and gene therapy
• MSCs due to their immunomodulatory potential
theoretically, they can be used allogenically
The role of Mesenchymal Stem Cells in relationship with injured
somatic tissue and non-immune cells
CAN STEM CELLS BE
ISOLATED AND USED?
If so under what conditions
and restrictions?
The low frequency of MSC in bone marrow
necessitate the in vitro expansion prior to
clinical use
• We evaluated the effect of long term culture
on the senescence of these cells
• Surprisingly , MSC loses their characteristic
after several passages
Therefore:
It is much better to consider them for therapy
early on
BM MSC culture (passage 6)
The goal of our stem cell therapy
studies
• Assessing the safeness of the stem
cell injection
• The patients improvement from a
clinical point of view
• The degree of damaged tissue repair
Mesenchymal Stem Cell
therapy for Multiple
Sclerosis and Heart
Diseases
Results of MS treatment
• 10 MS patients with secondary
progressive disease has been
transplanted
• One patient improved 2.5 score in
EDSS (expanded disability status scale)
• 4 others showed some degree of
improvement
• 5 patients after MSCT has not
hastened disease progress
Results of MSCT in Heart disease
Cardiac functional parameters of mean 18 month fallow up in test group
Parameters
Base line± SD
After MSC ± SD
P value
NYHA
LVEF
SPECT
2.75 ± 0.70
38.75 ± 13
11 ± 2
1.38 ± 0.51
48.75± 6.4
7.75 ± 1.1
.000
.005
.002
Cardiac functional parameters of mean 18 month fallow up in control group
Parameters
Base line ± SD
After pro. ± SD
P value
NYHA
LVEF
2.75 ± 0.70
41.88 ± 8.42
2.13 ± 0.35
42.50 ± 8.86
.049
NS
SPECT
10.88 ±1.95
9.75 ± 1.58
.007
Comparison of cardiac function in
two groups.
Groups
Test group
NYHA
LVEF
before
after
before
2.75
1.38
38.75
41.88
Control group
2.75
P value
NS
2.13
.005
NS
SPECT
after
before
after
48.75
11
7.75
42.50
10.88
NS
NS
9.75
.013
Potential Tumorigenicity of
these cells
Finally
• It seems, like all other issues,
– We must first consider all potential results and
possibilities
– BEFORE ANY INTERVENTION
• Because
– NOTHING COMES TO US WITHOUT A
DEGREE OF RISK