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Ch. 17. Transplantation Immunology What is graft rejection? How is graft rejection controlled? What is the status of tr PowerPoint Presentation
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Ch. 17. Transplantation Immunology What is graft rejection? How is graft rejection controlled? What is the status of transplantation? Barriers surgical availability immune response. First successful human kidney transplant- 1954 Many organs have been transplanted successfully.

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slide1

Ch. 17. Transplantation Immunology

What is graft rejection?

How is graft rejection controlled?

What is the status of transplantation?

Barriers

surgical

availability

immune response

Ch. 17

slide2

First successful human kidney transplant- 1954

Many organs have been transplanted successfully

Key insight came from blood group work

(notion of incompatibility)

Medawar, 1940s- graft rejection is immune reaction

autografts are accepted, allografts are not

second grafts are rejected more rapidly than

the first (memory)

Discovery of MHC arose from transplant work

Ch. 17

slide3

Current goals: minimize graft rejection

(demand is high, availability of genetically

identical donors is low)

Minimize rejection without suppressing entire

immune response

Ch. 17

slide4

Types of grafts

Autograft- within same individual

Isograft- from genetically identical donor

Allograft- from genetically different member

of the same species

Xenograft- from a different species

future: transgenic species?

Ch. 17

slide5

p. 427

Ch. 17

slide6

p. 428

Ch. 17

slide7

p. 428

Ch. 17

slide8

Many antigens determine histocompatibility

MHC antigens produce most vigorous rejection

response

Mouse haplotype b/b and k/k produce a b/k

offspring (inbred mouse strains)

Offspring can accept graft from either parent

Neither parent can accept graft from offspring

Ch. 17

slide9

Outbred populations:

Chance of match between (full) siblings

is about 25%

How to determine if donor and recipient are

compatible?

Blood groups must match

blood group antigens are also found on

endothelium of blood vessels (part of

donor tissue)

Microcytotoxicity test

Ch. 17

slide10

p. 429

Ch. 17

slide13

p. 430

Ch. 17

slide14

Identity at MHC Class I and Class II is not the

whole story

MHC differences may be recognized directly

by T cells (alloreactivity)

Other antigens must be presented

Ch. 17

slide15

Mechanisms of graft rejection

Sensitization

Dendritic cells in graft may act as APCs

Host effector cells can migrate

Donor cells can migrate to periphery and present

graft antigens there

Other cells may act as APCs

Ch. 17

slide16

Varies with the graft

Effector cells are usually produced in the

lymphoid tissue and then circulate back

to graft

Skin- vasculature restored gradually

Kidney or heart- immediately

Some sites (e.g., eye) do not encounter immune

cells

Ch. 17

slide17

p. 432

Ch. 17

slide18

p. 453

Ch. 17

slide19

Clinical aspects of graft rejection

Hyperacute- within 24 hours

graft is never vascularized

preexisting antibodies (complement)

Crossmatching to prevent this

Acute- within a few weeks

TH cell activation

Chronic- a long time later

humoral and cell-mediated

an intractable problem

Ch. 17

slide20

Immunosuppressive therapy

Most drugs are nonspecific

Other rapidly-dividing cells are affected

(epithelial cells, bone marrow cells)

Mitotic inhibitors- azothiaprine, methotrexate

Corticosteroids- anti-inflammatory

More specific inhibitors

cyclosporin A, FK506- inhibit T cell

activation

Rapamycin- blocks TH proliferation

Ch. 17

slide21

Cyclosporin A was the breakthrough

Other drugs are newer

less toxic to kidneys

effective at lower doses

TLI- total lymphoid irradiation

recipient’s lymphoid tissues are irradiated

before grafting

bone marrow is not; repopulating cells seem

to be more tolerant

Ch. 17

slide22

p. 436

Ch. 17

slide23

Immune therapy

Monoclonal antibodies that block T cell response

To surface proteins

high-affinity IL-2 receptor

TCR-CD3 or accessory molecules

adhesion molecules

looking for anergy

To cytokines

To co-stimulatory signal

might target activated T cells more

specifically (TH and APC)

Ch. 17

slide24

p. 438

Ch. 17

slide26

p. 439

Ch. 17

slide27

p. 440

Ch. 17

slide28

Clinical cases

  • Kidney
  • most common; easier surgically than some
  • the donor survives
  • Transplant recipients are sensitized to further
  • transplants

Ch. 17

slide29

II. Bone marrow

Recipient is immunosuppressed before graft

Graft-vs-host disease is common (50-70%)

TNF- is a major player

Possible treatments

immunosuppression

donor T cell depletion (partial; some

activity needed against host T cells)

Ch. 17

slide30

III. Heart

surgery is quite successful

MHC matching is often not feasible;

massive immunosuppression

transplants seem to be prone to

coronary disease

IV. Lungs sometimes go with heart

transplants are still rare

V. Liver- parts have been grafted successfully

resistant to antibody mediated toxicity

but not GVHD

relatively difficult surgery

Ch. 17

slide31

VI. Pancreas- functional parts (islet cells)

still rare

VII. Skin- usually autologous

burn victims- tissue bank donors have been

used.

immunosuppression is a problem because

a burn patient is vulnerable to infection

Ch. 17

slide32

p. 443

Ch. 17

slide33

VIII. Immunologically privileged sites

Some areas not infiltrated by immune cells

cornea, brain, uterus, testes

thymus?

What about sequestering donor tissue from host

immune system?

e.g., islet cells in semipermeable membranes

worked in mice

Ch. 17

slide34

VIII. Xenotransplantation- promising but

controversial

Better to meet the demand?

Nonhuman primates- have not been particularly

successful, and not that common anyway

Transgenic pigs

organs are similar size and structure

are being engineered to have human antigens

and/or immunosuppressive capacities

can be bred in large numbers and under

controlled conditions

Ch. 17

slide35

Drawbacks

success of graft is not proven

appropriate use of these animals?

risk of spreading zoonoses (animal-borne

diseases) to human recipients?

development of new pathogens?

should we be doing this?

Ch. 17

slide36

Why is the fetus not rejected?

  • “Protected” site
  • Local immunosuppression
  • uterine epithelium and trophoblast* secrete
  • cytokines that suppresses TH1
  • placenta secretes a substance that depletes
  • tryptophan: T cell starvation?
  • tolerance of paternal MHC antigens?
  • *Outer layer of placenta; does not express MHC
    • Class I and Class II antigens

Ch. 17