Kuby Immunology 6/e

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Transplantation
Transplantation: the process of taking cells,
tissues, or organs from one individual and
placing them into a different individual or different
site of the same individual
• Graft:
transplanted cells, tissues, or organs.
• Donor: the individual who provides the graft.
• Recipient: the individual who receives the
graft. Also called the host.
 Different

types of Transplants
Autograft
○ Self tissue transferred from one part of body to
another(skin,blood vessel)

Isograft
○ Tissue transferred between genetically identical
individuals(syngeneic )

Allograft
○ Tissue transferred between genetically different members of
same species
 Most of our transplants

Xenograft
○ Tissue transferred between different species

Transplantation of cells or tissues from
one individual to a genetically nonidentical individual invariably leads to
rejection of the transplant due to an
adaptive immune response.
ADAPTIVE IMMUNE RESPONSES TO
ALLOGRAFTS
What is the target for rejection?

Major histocompatibility antigens (MHC molecules) are
expressed on all nucleated cells (class I) and on B cells
APC,cells, monocytes/macrophages (class II) They are
targets for rejection,
Minor histocompatibility antigens: They are peptides
derived from polymorphic cellular proteins bound to
MHC class I molecules
 Other alloantigens :Human ABO blood group
antigens and Some tissue specific antigens

Schematic diagrams of the process of graft acceptance and rejection.
Specificity and Memory in Allograft Rejection
Immunologic memory is demonstrated when a
second strain-B graft is transferred to a previously
engrafted strain-A mouse === anti-graft reaction
develops more quickly, with complete rejection
occurring within 5 to 6 days.
 Specificity can be demonstrated by grafting skin
from an unrelated mouse of strain C at the same
time as the second strain-B graft === Rejection
of the strain-C graft proceeds according to the
slower 1st, whereas the strain-B graft is rejected in
an accelerated 2nd


T cells play key role in allograft rejection
 Both CD4+ and CD8+ populations present
Recognition of Alloantigens by T Cells

Allogeneic MHC molecules of a graft can be presented for
recognition by the recipient’s T cells in two fundamentally
different ways, called the direct and indirect pathways
1.
Direct Recognition of MHC Alloantigens on Donor Cells :
In
the case of direct recognition, intact MHC molecules displayed
by cells in the graft are recognized by recipient T cells without a
need for processing by host APCs.
Indirect Recognition of Alloantigens : In the indirect pathway,
donor (allogeneic) MHC molecules are captured and processed
by recipient APCs, and peptides derived from the allogeneic
MHC molecules are presented in association with self MHC
molecules.
2.
Activation and Effector Functions of Alloreactive T
Lymphocytes
When lymphocytes recognize alloantigens, they become
activated to proliferate, differentiate, and perform effector
functions that can damage grafts.

1) Activation of Alloreactive T Lymphocytes :
The T cell response to an organ graft may be initiated in
the lymph nodes that drain the graft. (sensitization )
doner APCs express donor MHC molecules as
well as costimulators. migrate to regional lymph
nodes and present, on their surface, unprocessed
allogeneic MHC molecules to the recipient’s T
cells
  Host dendritic cells from the recipient may also
migrate into the graft, pick up graft alloantigens,
and transport these back to the draining lymph
nodes, where they are displayed


In addition to recognition of alloantigen,
costimulation of T cells primarily by B7
molecules on APCs is important for
activating alloreactive T cells. Rejection of
allografts, and stimulation of alloreactive T
cells, can be inhibited by agents that block B7
molecules.
Effector Functions of Alloreactive T Cells
Alloreactive CD4+ and CD8+ T cells that are activated by
graft alloantigens cause rejection by distinct mechanisms
2) Effector T cells migrate back into the graft
and mediate rejection.

CD8+ CTLs that are generated by direct
allorecognition of donor MHC molecules on donor
APCs can recognize the same MHC molecules on
parenchymal cells in the graft and kill those cells
by CTL-mediated killing of graft cells.

CD8+ CTLs that are generated by the indirect
pathway are self MHC restricted, and they will not
be able to kill the foreign graft cells because these
cells do not express self MHC alleles displaying
allogeneic peptides. (the principal mechanism of
rejection is inflammation caused by the cytokines
produced by the effector T cells.
Activation of Alloreactive B Cells and
Production and Functions of Alloantibodies.
 Antibodies against graft antigens also contribute to
rejection.
 Most high-affinity alloantibodies are produced by
helper T cell–dependent activation of alloreactive
B cells, much like antibodies against other protein
antigens(donor HLA molecules, including both
class I and class II MHC proteins).
 Engage
effector
mechanisms,
including
complement activation, and targeting and
activation of neutrophils, macrophages, and NK
cells through Fc receptor binding.

IN SAMARY
The Sensitization Stage of Graft Rejection: which
occurs shortly after transplantation when antigen
reactive lymphocytes (CD4+ and CD8+ T cells) of
the recipient proliferate in response to alloantigens
on the graft ,
 Effector Stage of Graft Rejection: in which immune
destruction of the graft takes place. cytokines
secreted by TH cells play a central role. For
example, IL-2 and IFN-γ produced by TH1 cells,
important mediators of graft rejection, which
promote T-cell proliferation (including CTLs), DTH
responses, and the synthesis of IgG by B cells, with
resulting complement activation.

The acceptance or rejection of a transplant is determined by:
*1
Class I & II MHC proteins on the donor cells, with class II
playing the major role, especially DR locus. These alloAg activate Tcells(both helper & cytotoxic). The activated T-cell proliferate & then
react against the alloAg on the donor cells. CD8 +ve cytotoxic cells
do the most of the killing of the allograft cells. Foreign MHC proteins
activate more T-cells.
*2
Both CD4 & CD8 T-cells have involved in allograft rejection, of
which removal of them by using monoclonal Ab (antiCD4 & antiCD8)
result in long-term survival of allograft.
*3
Dendritic cells play a role in rejection as well, of which, it can
present Ag in the context of class I MHC molecules, giving CD8 +ve
T-cell the opportunity to recognize alloAg.
*4
*5
Difference in minor histocompatibility loci.
ABO blood group.
Note: difference in blood group and major histocompatibility Ags are
responsible for the most intense graft rejection reaction.
Clinical Manifestations of Graft Rejections:
different classes of allograft rejection phenomena are classified according
to their time of activation & the type of effector mechanism that
predominates. These are:

Hyperacute
○ Within hours: Hyperacute rejection is characterized
by thrombotic occlusion of the graft vasculature
that begins within minutes to hours after host blood
vessels are anastomosed (joined) to graft vessels
and is mediated by preexisting antibodies in the
host circulation that bind to donor endothelial
antigens
Clinical Manifestations of Graft Rejection

Hyperacute
 Pre-existing
recipient
antibodies
 Graft never
become
vascularized
○ Acute
○ Within weeks: Acute rejection is a process of
injury to the graft parenchyma and blood
vessels mediated by alloreactive T cells and
antibodies.
• Acute Cellular Rejection :The principal mechanisms of
acute cellular rejection are inflammation caused by
cytokines produced by helper T cells and CTL-mediated
killing of graft parenchymal cells and endothelial cells
• Acute Antibody-Mediated Rejection:Alloantibodies cause
acute rejection by binding to alloantigens, mainly HLA
molecules, on vascular endothelial cells, causing
endothelial injury and intravascular thrombosis that
results in graft destruction

Chronic
As therapy for acute rejection has improved, the major
cause of the failure of vascularized organ allografts
has become chronic rejection.
A dominant lesion of chronic rejection in vascularized
grafts is arterial occlusion as a result of the
proliferation of intimal smooth muscle cells, and the
grafts eventually fail mainly because of the resulting
ischemic damage HOW?
Months to years . Due to various mechanisms: cellmediated, deposition of antibodies or antigen antibody
complexes with subsequent obliteration of blood
vessels and interstitial fibrosis
What is graft versus Host Reaction ?

When grafted tissue has mature T cells, they will attack host
tissue leading to GVHR.
 Major problem for bone marrow transplant.
 Because it is the source of pluripotent hematopoietic stem
cells, it can be used to reconstitute myeloid, erythroid, &
lymphoid cells in a recipient who has lost these cells as a result
of malignancy or chemotherapeutic regimens.
 Because B.M. is a source of some mature T lymphocytes, it is
necessary to remove these cells before transplantation to
avoid the appearance of graft-versus-host disease in the
recipient. In this special case of rejection, any mature T cells
remaining in the B.M. inoculums can attack allogeneic MHCbearing cells of the recipient & cause widespread epithelial cell
death accompanied by rash, jaundice, diarrhea, &
gastrointestinal hemorrhage.
Tests for donor & recipient:
Blood typing & ABO compatibility.
 HLA typing by microcytotoxicity test .
 Mixed lymphocyte reaction (MLR) for T-helper cell activation .
 Screening for preformed antibody and crossmatching.
In cases where a living donor may be used for tissue transplantation,
tissue-typing to match the HLA antigens of the recipient & donor is
needed. Routine HLA typing focuses only on HLA-A, HLA-B, &
HLA-DR.
Patients awaiting organ transplants are screened for the presence
of preformed antibodies reactive with allogeneic HLA
molecules. These can arise because of previous pregnancies,
transfusion, or transplantation & can mediate hyperacute graft
rejection if they exist.

Mixed lymphocyte reaction (MLR) for T-helper cell
activation

Test [cross-matching] is the most important
level of compatibility testing that occurs prior to
solid organ transfer. The most common method
used today is the [Luminex assay], which
employs fluorochrome-labeled microbeads
impregnated (loaded) with specific HLA
proteins
TISSUE TYPING
 Microcytoxicity assay for
MHC haplotypes
 If antigen is present on
cell, complement will lyse
it, and it will uptake dye
(blue)
 Donor 1 has antigens in
common with recepient
Prevention of rejection:
General immunosuppressive therapy as,
Mitotic inhibitors that inhibit T-cell proliferation.
Anti-inflammatory agents as corticosteroid.
Fungal metabolite that act as immunosuppressive
agents.
D. Total lymphoid irradiation, for all organ except B.M.
The goal of immunosuppression is to block cell
proliferation.
2. Specific treatment:
A. Monoclonal Ab as
* antiCD3, so ↓mature T-cell.
* Ab to surface adhesion molecule , so no signal.
* Ab to cytokine as anti IL-2.
B. Block co-stimulatory signal e.g.Ab to CD40L so
block binding of CD40-CD40L.
1.
A.
B.
C.
Sites of action
for various
agents used in
clinical
transplantation.

Xenotransplantation
○ Shortage of human donors
○ Obstacles with immune system
○ Closely related species have more success
- However, taking risk of creating new viruses by
recombination in graft
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