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Transplantation

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Title: Transplantation


1
Transplantation
The transfer of living cells, tissues, or organs
from a donor to a recipient, with the intention
of maintaining the functional integrity of the
transplanted material in the recipient.
2
Background
  • Blood Transfusion
  • First attempts were unsuccesful (MISMATCH)
  • Discovery of blood groups (Red cell antigens)
  • A-B Landsteiner 1900
  • Rh Levine, Stetson 1939
  • Succesful transfusion TRANSPLANTATION
  • Alexis Carel experimental kidney transplantation
  • 1912 Nobel prize
  • 1935 human kidney transplant in Russia -
    rejection
  • P.B. Medawar (1945) skin grafts
  • Self skin accepted
  • Relative not accepted ! ? What is the
    difference ?
  • ? Immunologic mechanism
  • A. Mitchison (1950)
  • Lymphocytes are responsible for rejection

3
Background
  • Peter Gorer (1935)
  • Identification of 4 group of genes for RBC
  • Gorer and Gorge Snell (1950)
  • Group II antigens are responsible for rejection
  • ? histocompatibility genes
  • Nobel prize 1980 George Snell
  • 1954 Succesful kidney transplant between
    identical twins in Boston Peter Bent Brigham
    Hospital

4
Liver Transplantation
Cornea Transplantation
5
Kidney Transplantation
6
Rules of transplantation
7
  • Hearts, kidneys, livers, lungs,
    corneas, pancreases, skin,
    and
    bone marrow are transplanted
  • Successful transplants lie in genetics
  • Types of transplantation are defined by the
    relationship between the donor and recipient
  • Autograft from one person to self
  • Isograft from identical twin
  • Allograft members of same species
  • Xenograft from another species

8
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9
Immunologically privileged tissue
  • Corneal or cartilage grafts---covered with
    Sialomucin which masks the MHC
  • Testes express Fas ligand

10
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11
Clinical Transplantation
12
Xenograftspigs and baboons have been tissue and
organ donors for human transplants
13
Xenogenic Transplantation
  • gt50,000 people that need organs die while waiting
    for a donor
  • Studies are underway involving nonhuman organs
  • Attention has been focused on the pig but the
    problem is the existence of natural or preformed
    antibodies to carbohydrate moieties expressed in
    the grafts endothelial cells and as a consequence
    activation of the complement cascade occurs
    rapidly and hyperacute rejection ensues
  • Concern has given to debate about the safe use of
    xenografts and animal tissues that the tissues
    might harbor germs
  • Potential solutions
  • Transgenic pigs expressing human DAF, which
    prevents complement reaction
  • Transgenic pigs that dont express the reactive
    antigens.
  • Advantage
  • MHC molecules of different species are so
    different from those of humans that human T cells
    can not recognize them. So T-cell mediated
    rejection is mild.

14
Indications
  • Acute and chronic leukemias
  • Aplastic anemia
  • Congenital immunodeficiency diseases
  • Lymphomas
  • Metabolic disease of childhood
  • Myelodisplasia
  • Thalassemia

15
Tests before transplantation
  • Tests for compatibility
  • HLA (HLA-A, HLA-B and HLA-DR )
  • and ABO
  • Screening for Presence of Preformed
  • Antibodies to allogeneic HLA
  • Tests for pathogens
  • Human Immunodeficiency Virus (HIV-1/2),
  • Hepatitis B (HbsAg)
  • Hepatitis C (HCV).
  • Also CMV, HTLV-1, syphilis, Epstein-Barr virus,
    and HTLV-2

16
MLR (mixed lymphocyte reaction test)Co-culture
of blood cells from donor and recipientMore
proliferation More mismatch
17
Immune mechanisms
  • Skin is transplanted to genetically different
    organisms

18
Graft
19
Rules of rejection
20
Hyperacute Rejection
  • Occurs within a few minutes to a few hours
  • Result of destruction of the transplant by
    performed antibodies (cytoxic antibodies) to ABO
    antigens (and/or MHC class I/II molecules)
    expressed by Endothelial cells
  • Generated because of previous transplants, blood
    transfusions, and Multiple pregnancies
  • Antibodies activate the complement system then
    platelet activation and deposition causing
    hemorrhaging and swelling

Graft failure
21
Hyperacute Rejection
22
Acute Rejection
  • Seen in recipient that has not been previously
    sensitized to the transplant
  • Mediated by T cells and is a result of their
    direct recognition of alloantigens (HLA
    different) expressed by the donor
  • After transplantation, donor-derived dendritic
    cells migrate to the recipient spleen and
    activate recipient T cells, which mediate graft
    rejection (Vascular and parenchymal injury).
  • Very common in mismatched tissue or insufficient
    immunosuppressive treatment
  • Reduced by immunosuppressive therapy and anti-T
    cell antibodies
  • Accelerated Acute rejection (within days) is
    mediated by sensitized (memory) T cells induced
    by previous grafts or exposure.

23
Acute rejection
24
Chronic rejection
  • Caused by both antibody and cell-mediated
    immunity
  • May occur months to years down the road in
    allograft transplants after normal function has
    been assumed
  • Important to point out rate, extent, and
    underlying mechanisms of rejection that vary
    depending on tissue and site
  • The recipients circulation, lymphatic drainage,
    expression of MHC antigens and other factors
    determine the rejection rate
  • Inflammation, smooth muscle proliferation,
    fibrosis, Tissue ischemia
  • localized tissue anemia due to obstruction of the
    inflow of arterial blood
  • Occurs in most solid organ transplants
  • Heart, Kidney, Lung, Liver

25
Chronic rejection
26
Role of MHC molecules
  • T cells are reacting directly with the donor
    APCs expressing allogeneic MHC in combination
    with peptide. These donor APCs also have
    costimulatory activity to generate the second
    signal for the second reaction to occur
  • Dendritic cells are more potent than macrophages
    in presenting alloantigen to T cells.
  • CD4 and CD8 IL-2, IFN-a,ß,? , TNF-a,ß
  • Minor H antigens are encoded by genes outside the
    MHC

27
Indirect recognition donor APC shed MHC that
activate immune system that then reacts to
transplanted organ
28
Complications
  • Graft-vs,-host disease (GVHD)
  • Infections
  • Prolonged immunodeficiency
  • Disease recurrence
  • Alloimmunization with increased risk for platelet
    refractoriness and humoral transplant rejection
  • Recipient can make antibody against donor HLA
    antigen, most common
  • Transfusion-Related Acute Lung Injury
  • donor HLA antibodies react against recipient
    antigens

29
2 types of alloreactions
Also, there is GVL (Leukemia) effect against
recipients leukemic or tumor cells
30
Diseases for which bone marrow transplantation is
a therapy (BMT)
31
GVHD
  • Donor T cell response against recipient tissue
    cells
  • Prophylaxis against GVHD begins day 1 with
    immunosuppressive agents
  • Cyclosporine, methotrexate, mycophenelate
  • Acute GVHD first 3-6 months
  • Skin, GI (especially diarrhea) or obstructive
    Liver dysfunction
  • gt60 develop
  • Chronic GVHD develops 12-18 months post
    transplant
  • Autoimmune manifestations of Skin especially, as
    well as GI, Liver and Lung
  • 30-40 develop
  • Methods to overcome GVHR
  • Treat bone marrow to deplete T cells.
  • Use autologous bone marrow.
  • Use umbilical cord blood.
  • The graft must contain immunocompetent cells (T
    cells)
  • MHC mismatch
  • The recipient must be incapable of rejecting the
    graft
  • (immunodeficient after radiation/chemo therapy)

For GVHD to occur
32
Stages of GVHD
  •  Stage 1 (mild) a skin rash over less than 25
    of the body.
  • Stage 2 (moderate) a skin rash over a more than
    25 of the body accompanied by mild liver or
    stomach and intestinal disorders.
  • Stage 3 (severe) redness of the skin, similar
    to a severe sunburn, and moderate liver, stomach
    and intestinal problems.
  • Stage 4 (life-threatening) blistering, peeling
    skin, and severe liver, stomach, and intestinal
    problems.

33
GVH disease in humans
34
Prolonging Allograft Survival
  • Anti-inflammatory Agents transcription
    regulators
  • Cytotoxic Drugs DNA synthesis inhibitors
  • Agents that interfere with Cytokine production
    and signaling
  • Immunosuppressive Therapies signaling inhibitors
  • New Immunosuppressive strategies immune cell
    depletion by using of monoclonal Ab (Anti-CD3,
    Anti-CD52, Anti-IL-2, AntiCD25)
  • - These antibodies can be made in sheep or
    goats that have been immunized with human
    lymphocytes or from mouse hybridoma cells.
    Limitation These non-human antibodies can
    induce formation of antibodies to the anti-T cell
    antibodies, which reduces the effectiveness of
    anti-T cell antibodies after the first use.

35
SITES OF ACTION OF MAJOR IMMUNOSUPPRESSIVE DRUGS
OKT3
36
Effects of corticosteroids
37
Corticosteroids Prednisolone
Induces expression of many genes, one of which is
IkB-alpha that inhibits NF-Kb activation. Side
effects fluid retention, weight gain, diabetes,
loss of bone mineral, thinning of the skin.
38
Cyclosporine A and FK506 inactivate calcineurin
(a calcium binding protein), which is required
for T, B and granulocyte activation
39
Cytotoxic drugs kill dividing cells
Azathioprine inhibits DNA replication. Kills not
only lymphocytes but also all dividing cells in
the body bone marrow cells, intestinal
epithelial cells and hair follicle
cells Cyclophosphamide cross-link DNA. Side
effect includes damage to bladder. Methotrexate
prevents DNA replication by inhibiting thymidine
synthesis
Specificity issue?
40
ANTIGEN SPECIFIC TOLERANCE (VS GENERAL
IMMUNOSUPPRESSION)
  • Decreases risk of infections and secondary
    cancers
  • Enhance allospecific T regulatory cell
    stimulation
  • Monoclonal antibodies or protein blockers for
    costimulatory molecules
  • Decrease graft immunogenicity

41
Induction of tolerance Enhance allospecific T
regulatory cell activity
If T reg cells can be induced to recognize the
indirect antigen presentation, they exert a
powerful suppressive effect on both indirect and
direct CD4 and CD8 cell activity through the
secretion of IL-10 and TGF-?
42
T -regulatory cell function
43
Why is fetus not rejected by the mother?
C/D
A/B
A/C, A/D, B/C, B/D
44
Fetus as an allograft
Strain A
Strain B
mate
Immunize with fathers Ags
fetus survives
Skin graft rejected
45
Why is fetus not rejected?
  • Placenta acts as a barrier or filter.
  • It filters anti-MHC Abs.
  • Trophoblast---outermost layer of fetal
    tissue---is in direct contact with maternal
    blood.
  • Trophoblast expresses weak or no MHC or
    non-polymorph MHC.
  • HLA-G KIR ligand in NK cell
  • progesterone---hormone---immunosuppressive.
  • Placenta expresses FasL.
  • AFP immunosuppressive
  • Partial lack of professional APC like DC
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