Transplantation Unit

8/29: Basic immunology of transplantation

8/31: Pathology lab: hypersensitivity and rejection
9/5: Pharmacology of immunosuppressive drugs
9/6: Clinical Case Discussion: Transplant cases

Immunology of Transplantation
Major barrier to organ/tissue
transplantation is immunological
Immune system recognizes transplant
as foreign and destroys it
Memory and specificity have properties
of immune response
Memory is transferred by T cells
(antibodies also can contribute)
Terminology of Transplantation
Autograft (e.g. skin grafts for burns, etc.)
Syngraft (genetically identical twins;
possibly therapeutic cloning)
No immunologic rejection for these two types
Allograft (genetically distinct member of
same species; almost all medical transplants)
Xenograft (different species; attractive due
to shortage of organs for transplants)
Very severe rejection problems
Histocompatability Antigens
I. ABO blood group antigens
Pre-existing antibodies to A or B antigens lead to
hyperacute rejection if not matched properly
II. Major histocompatability antigens
Encoded by the MHC, originally discovered for their
role in skin graft rejection in mice
III. Minor histocompatability antigens
Allelic variants of normal cellular proteins
Structures of A, B, O blood group
antigens
The A and B alleles of the
ABO genetic locus encode
very similar glycosyl-
transferases, the O allele
encodes a defective version
with no activity (leaving the
H antigenic structure
unmodified)
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Red blood cell antigens and Blood
transfusions
The ABO antigen system provides a potential
problem for blood transfusions
People who lack A or B antigens have preexisting
antibodies to these antigens, which can combine with
RBCs, fix complement, and cause transfusion reaction

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Mostly IgM
Rh antigen and hemolytic disease of
newborn
Mother is Rh-negative and father is Rh-positive
Mother is immunized at birth of first Rh-positive child
Small amounts of antigen enter mother during pregnancy
with 2nd Rh-positive child
This induces secondary antibody response, high levels of
IgG are produced, enter fetal circulation and attach to
RBCs of fetus
Treated by giving anti-Rh antibody to pregnant woman
once during gestation and within 72 hr. after birth of
first child to inhibit primary response
Histocompatability Antigens
I. ABO blood group antigens
Pre-existing antibodies to A or B antigens lead to
hyperacute rejection if not matched properly
II. Major histocompatability antigens
Encoded by the MHC, originally discovered for their
role in skin graft rejection in mice
III. Minor histocompatability antigens
Allelic variants of normal cellular proteins
MHC Class I and Class II genes are highly polymorphic and are all closely
linked; most of the time, they are inherited as a block (called a haplotype)
TCR specificity and self-MHC
MHC molecules are highly polymorphic
During development in the thymus, T cells are selected
for moderate/weak binding to self-MHC + self-
peptides (positive selection)
During development in the thymus, T cells are killed
(or become regulatory T cells) if they have strong
binding to self-MHC + a self-peptide (negative
selection)

Do the T cells of one person see MHC molecules
from another person?


TCR specificity and self-MHC
MHC molecules are highly polymorphic
During development in the thymus, T cells are selected
for moderate/weak binding to self-MHC + self-
peptides (positive selection)
During development in the thymus, T cells are killed
(or become regulatory T cells) if they have strong
binding to self-MHC + a self-peptide (negative
selection)

Do the T cells of one person see MHC molecules
from another person? Actually about 1% of T cells
bind such MHC with self peptide strongly--like a
microbial antigen/MHC complex--and become
activated (alloreactive T cells)
Do Alloreactive T cells need
costimulation?

Ordinarily immune responses require co-stimulation
(B7/CD28)
Blocking costimulation with CTLA4-Ig, belatacept
protects against acute graft rejection in kidney
patients (phase III clinical trials published in 2010;
FDA approval in 2011)
Most likely explanation:
-ischemia, stress to organ, release of DAMPs can
induce expression of co-stimulators
-may explain why live donor organs have superior
outcomes for kidney transplants compared to
cadaver donor organs
Direct presentation in transplantation
(MHC+peptide: MHC is from graft)
Graft dendritic cell is induced to mature,
express co-stimulatory molecules (B7) and
migrate to lymph node by stress of surgery, etc.
DC in lymph node activates allo-MHC recognizing
CD4
+
T cells and/or CD8
+
T cells
Activated T cells expand and then home to sites
of inflammation where they find allo-MHC on
graft cells and secrete cytokines/kill graft cells
This is the critical pathway for CD8 T cell
response
Direct Presentation in Graft Rejection
see also Abbas and Lichtman Fig. 10-8
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Blue: host cell; pink: graft cell
killing
CD8
T cell
Indirect presentation in transplantation
(MHC+peptide: MHC is from host, peptide may
be from graft MHC)
Dendritic cells, monocytes, or B cells of host enter
sites of inflammation of graft, pick up antigens (e.g.
allo-MHCs), and load peptides from these allo-MHC
onto their own MHC, migrate to lymph nodes and
activate T cells
CD4
+
T cells are activated and then migrate to sites of
inflammation where they are activated by host
macrophages presenting graft antigens, leads to
inflammatory reaction and tissue damage
Also, important for production of antibodies to MHC
molecules
This pathway is probably responsible for chronic
rejection (rejection after 1 year)

Indirect Presentation in Graft
Rejection
see also Abbas and Lichtman Fig. 10-8
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In graft
tissue
In draining
lymph node
B cell specific
for allo-MHC
Allografts: a medical procedure
Allografts: a medical procedure
Except for pregnancy!
Fetus is not rejected by mother
Mechanism preventing rejection is not well
understood
there is typically an antibody response to paternal
class I MHC molecules
but not a T cell response to allogeneic cells at the
maternal-fetal interface
Evidence for local suppression and low expression
of MHC I by trophoblasts
Pre-existing
antibody
T cell immune
response (CD4
and/or CD8 T cells)
Humoral acute
rejection also occurs
in some people
(accelerated rejection)
Mechanism uncertain;
does not seem to be
blocked by calcineurin
inhibitors (worst for
lung; best for liver)
Immunosuppression to prevent acute
graft rejection
Cyclosporine and Tacrolimus (FK506): block
calcineurin, which is important for signaling by TCR
(disadvantage: has some toxicity for kidney)


Mechanism of
immunosuppression
by cyclosporin
NF-AT: nuclear factor of activated T cells
NF-AT is required for transcription of the
IL-2 gene and some other cytokine genes

NF-AT cannot be activated in presence of
cyclosporin
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Mechanism of immunosuppression by
calcineurin inhibitors
FK-506 (tacrolimus) has an essentially similar
mechanism of action except that the initial
binding protein is FK-506 binding protein
(FKBP-12) instead of cyclophilin
Mechanism of immunosuppression by
tacrolimis and sirolimus
FK-506 (tacrolimus) binds to FK-506
binding protein (FKBP) and inhibits
calcineurin

Rapamycin (sirolimus) binds FKBP and
this complex has a different target,
mTOR (mammalian target of
rapamycin); mTOR regulates protein
synthesis for a broad subset of genes
involved in proliferation
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Immunosuppression to prevent acute
graft rejection
Cyclosporine and Tacrolimus (FK506): block
calcineurin, which is important for signaling by TCR
(disadvantage: has some toxicity for kidney)
Corticosteroids: anti-inflammatory and block T cell
activation
Mycophenolate mofetil, azathioprine: inhibit purine
biosynthesis, lymphocyte proliferation (biochemistry
explained in lecture on Friday)
Sirolimus (Rapamycin): blocks T cell response to IL-2


Immunosuppression to prevent acute
graft rejection
Cyclosporine and Tacrolimus (FK506): block calcineurin, which is
important for signaling by TCR (disadvantage: has some toxicity
for kidney)
Corticosteroids: anti-inflammatory and block T cell activation
Mycophenolate mofetil, azathioprine: inhibit purine biosynthesis,
lymphocyte proliferation
Sirolimus (Rapamycin): blocks T cell response to IL-2
Antibodies that block T cells in one way or another(used to treat
acute rejection episode)
Anti-thymocyte globulin (polyclonal Ab made in animals): depletes T
cells via antibody effector functions
Anti-IL-2R monoclonal antibody: blocks response to IL-2 and/or
depletes activated T cells
Anti-CD3 monoclonal antibody (OKT3): abortive activation of T cells
Belatacept (modified CTLA4-Ig): blocks co-stimulation (alternative
to cyclosporine in combination with next two types of drugs)

Graft vs. Host Reaction
T cells from graft can attack host, reacting to
MHC differences or minor antigens

Primarily seen in immunocompromised host
(e.g., immunodeficiency patient with bone
marrow transplant or leukemia patient treated
with chemotherapy)
Graft vs. Host Reaction
Direct presentation pathway
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Stem Cell Transplantation
(bone marrow transplant; future therapies)
Strategies to avoid immunological rejection
1. Use stem cells from patient
Adult stem cells seem to be less useful, but work
in some situations (iPS methods in development)
2. Use embryonic stem cells
A) Match MHC and use immunosuppression (?)
B) Nuclear transplant of nucleus from recipient
into fertilized embryo: generate embryonic
stem cells and have no immunological rejection
(But: ethical issues!)