Transplantation Immunology - PowerPoint Presentation

Slide1

Transplantation Immunology

Chapter 17Slide2
Slide3

Transplantation

is a widely used

treatment

for

replacement

of nonfunctioning organs and tissues with healthy organs or tissues

Technically, transplantation is the process of taking

cells

,

tissues

, or

organs

, called a

graft

, from one individual and placing them into a (usually) different individual

Donor, Recipient,

Transfusion

refers to the transfer of

circulating blood cells

or

plasma

from one individual to anotherSlide4
Slide5

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

responseSlide6

A graft transplanted from one individual to the same individual is called an

autologous

graft

. A graft transplanted between two genetically identical or

syngeneic

individuals is called a

syngeneic

graft

. A graft transplanted between two genetically different individuals of the same species is called an

allogeneic

graft (or allograft).

A graft transplanted between individuals of different species is called a

xenogeneic

graft (or

xenograft

).

The molecules that are recognized as foreign on

allografts

are called

alloantigens

, and those on

xenografts

are called

xenoantigens

. The lymphocytes and antibodies that react with

alloantigens

or

xenoantigens

are described as being

alloreactive

or

xenoreactive

, respectively.Slide7

The molecules responsible for almost all

strong (rapid) rejection reactions

are called

major

histocompatibility

complex (MHC)

molecules

Allogeneic

MHC molecules of a graft may be presented for recognition by the T cells of the recipient in two fundamentally different ways, called

direct

and

indirect

Initial studies showed that the T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft, and this is called

direct presentation

of

alloantigens

Subsequent studies showed that sometimes, the recipient T cells

recognize graft MHC molecules

only

in the context of the recipient’s MHC molecules

, implying that the recipient’s MHC molecules must be presenting

allogenic

graft MHC proteins to recipient T cells. This process is called

indirect presentation

,Slide8

Direct Presentation of MHC AlloantigensSlide9

Indirect Presentation of AlloantigensSlide10
Slide11

In the setting of any transplant between genetically

nonidentical

donor and recipient, there will be polymorphic antigens other than MHC molecules against which the recipient may mount an immune response. These antigens typically induce weak or slower (more gradual) rejection reactions than do MHC molecules and are therefore called

minor

histocompatibility

antigens

. Most minor

histocompatibility

antigens are proteins that are processed and presented to host T cells in association with self MHC molecules on host APCs (i.e., by the

indirect pathway

)Slide12

Activation of Alloreactive

LymphocytesSlide13

The Mixed Lymphocyte Reaction

The response of

alloreactive

T cells to foreign MHC molecules can be analyzed in an

in vitro

reaction called the

mixed lymphocyte reaction (MLR)

The MLR is used as a

predictive test of T cell–mediated graft rejection

. Studies of the MLR were among the first to establish the role of class I and class II MHC molecules in activating distinct populations of T cells (CD8+ and CD4+, respectively)Slide14

The Mixed Lymphocyte ReactionSlide15

PATTERNS AND MECHANISMS OF ALLOGRAFT REJECTIONSlide16

Hyperacute Rejection

Hyperacute

rejection is characterized by

thrombotic occlusion

of the graft vasculature that begins within

minutes to hours

after host blood vessels are anastomosed to graft vessels and is mediated by

preexisting antibodies

in the host circulation that bind to donor endothelial antigens

In the early days of transplantation,

hyperacute

rejection was often mediated by

preexisting IgM alloantibodies,

which are present at high titer before transplantation. Such “

natural antibodies

” are believed to arise in response to carbohydrate antigens expressed by bacteria that normally colonize the intestine. The

best known examples

of such alloantibodies are those directed against the

ABO blood group antigens

expressed on red blood cells

One possible mechanism of this

resistance to

hyperacute

rejection

is

increased expression of complement regulatory proteins on graft endothelial cells

, a beneficial adaptation of the tissue that has been called

accommodationSlide17

Hyperacute RejectionSlide18

Acute Rejection

Acute rejection is a process of injury to the graft parenchyma and blood vessels mediated by

alloreactive

T cells

and

antibodies

In

Acute Cellular Rejection

, the principal mechanism of acute cellular rejection is

CTL-mediated killing of cells in the graft

. On

histologic

examination, this type of rejection is characterized by

infiltrates of lymphocytes

, which invade and destroy graft components. There are many lines of evidence that support the

role of CTLs in acute cellular rejection

In

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 destructionSlide19

Acute RejectionSlide20

Chronic Rejection and Graft Vasculopathy

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 damageSlide21
Slide22

PREVENTION AND TREATMENT OF ALLOGRAFT REJECTIONSlide23

Methods to Reduce the Immunogenicity of Allografts

To avoid

hyperacute

rejection, the

ABO blood group

antigens of the graft donor are selected to be

identical

to those of the recipient

In kidney transplantation, the larger the number of

MHC alleles that are matched

between the donor and recipient, the better the graft survival

Patients in need of

allografts

are also tested for the

presence of preformed antibodies against donor MHC molecules

or

other cell surface antigens

. Two types of tests are done to detect these antibodies. In the

panel reactive antibody test

, patients waiting for organ transplants are screened for the presence of preformed antibodies reactive with

allogeneic

HLA molecules prevalent in the populationSlide24

Methods to Reduce the Immunogenicity of Allografts

If a potential donor is identified, the

cross matching test

will determine whether the patient has

antibodies that react specifically with that donor’s cells

. The test is performed by mixing the recipient’s serum with the donor’s blood lymphocytes.

Complement-mediated

cytotoxicity

tests

or

flow

cytometric

assays

can then be used to determine if antibodies in the recipient serum have bound to the donor cellsSlide25

Methods to Induce Donor-Specific Tolerance

Costimulatory

blockade

Hematopoietic

chimerism

:

transfusion of donor blood cells into the graft recipient inhibits rejection

Transfer or induction of regulatory T cells

Administration of soluble MHC proteins or peptides under conditions predicted to induce toleranceSlide26

XENOGENEIC TRANSPLANTATION

A major immunologic barrier to

xenogeneic

transplantation is the presence of

natural antibodies

that cause

hyperacute

rejection

Even when

hyperacute

rejection is prevented,

xenografts

are often damaged by a form of

acute vascular rejection

that occurs within 2 to 3 days of transplantation

Xenografts

can also be rejected by

T cell–mediated immune responses

to

xenoantigensSlide27

BLOOD TRANSFUSION AND THE ABO AND

Rh

BLOOD GROUP ANTIGENS

If such individuals are given blood cells expressing the target antigen, the

preexisting antibodies bind to the transfused cells

, activate complement, and cause transfusion reactions, which can be life threateningSlide28

ABO Blood Group AntigensSlide29

Lewis Antigen

The same glycoproteins that carry the ABO determinants can be modified by other

glycosyl

transferases

to generate

minor blood group antigens

Lewis antigens have recently received much attention from immunologists because these carbohydrate groups serve as

ligands

for E-

selectin

and P-

selectinSlide30

Rhesus (Rh

) Antigen

Rh antigens are

nonglycosylated

, hydrophobic cell surface proteins

found in

red blood cell

membranes and are structurally related to other red cell membrane glycoproteins with transporter functions

Rh

proteins are encoded by two tightly linked and highly homologous genes, but only one of them, called

RhD

, is commonly considered in clinical blood typing

The major clinical significance of

anti-

Rh

antibodies

is related to hemolytic reactions

associated with pregnancy

that are similar to transfusion reactions

Subsequent pregnancies in which the

fetus is

Rh

positive

are at risk because the

maternal anti-

Rh

antibodies

can cross the placenta and mediate the destruction of the fetal red blood cells. This causes

erythroblastosis

fetalis

(hemolytic disease of the newborn)

and can be lethal for the fetusSlide31

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Examples of such diseases that can be cured by hematopoietic stem cell transfer are adenosine

deaminase

(ADA) deficiency

, X-linked

severe combined immunodeficiency disease

, and hemoglobin mutations such as

beta-

thalassemia

major

and

sickle cell disease

Allogeneic

hematopoietic stem cells are

rejected by even a minimally

immunocompetent

host, and therefore the donor and recipient must be

carefully matched at all MHC loci

The mechanisms of rejection of bone marrow cells

are not completely known

, but in addition to

adaptive immune mechanisms

, hematopoietic stem cells may be rejected by

NK cellsSlide32

Graft-Versus-Host Disease (GVHD)

GVHD is

caused by the

reaction of grafted mature T cells

in the marrow inoculum with

alloantigens

of the host

Acute GVHD

is characterized by

epithelial cell death in the skin, liver

(mainly the

biliary

epithelium), and

gastrointestinal tract

. It is manifested clinically by

rash

,

jaundice

,

diarrhea

, and

gastrointestinal hemorrhage

. When the epithelial cell death is extensive, the skin or lining of the gut may slough off. In this circumstance, acute GVHD

may be fatal

Chronic GVHD

is characterized by

fibrosis and atrophy of one or more of the same organs

, without evidence of acute cell death. Chronic GVHD may also involve the

lungs

and produce obliteration of small airways. When it is severe, chronic GVHD leads to complete dysfunction of the affected organ.Slide33

Immunodeficiency After Bone Marrow Transplantation

Radiation therapy

and

chemotherapy

used to prepare recipients for transplantation are likely

to deplete the patient’s memory cells

and

long-lived plasma cells

,

Recipients are susceptible to

viral infections

, especially

cytomegalovirus infection

, and to many

bacterial

and

fungal

infections

They are also susceptible to

Epstein-Barr virus

–provoked B cell lymphomas

Recipients commonly receive

prophylactic antibiotics

and

anti-cytomegalovirus therapy

and are often actively

immunized against capsular bacteria

such as

pneumococcus

before transplantationSlide34

There is great interest in the use of

pluripotent

stem cells

to

repair tissues

with little natural regenerative capacity, such as

cardiac muscle

,

brain

, or

spinal cord

One approach is to use

embryonic stem cells

, which are

pluripotent stem cells

derived from the blastocyst stage of human embryosSlide35