Transplantation

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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.
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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

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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

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Liver Transplantation
Cornea Transplantation
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Kidney Transplantation
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Rules of transplantation
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• 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

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Immunologically privileged tissue

• Corneal or cartilage grafts---covered with
  Sialomucin which masks the MHC
• Testes express Fas ligand

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Clinical Transplantation
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Xenograftspigs and baboons have been tissue and
organ donors for human transplants
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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.

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Indications

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

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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

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MLR (mixed lymphocyte reaction test)Co-culture
of blood cells from donor and recipientMore
proliferation More mismatch
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Immune mechanisms

• Skin is transplanted to genetically different
  organisms

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Graft
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Rules of rejection
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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
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Hyperacute Rejection
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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.

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Acute rejection
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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

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Chronic rejection
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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

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Indirect recognition donor APC shed MHC that
activate immune system that then reacts to
transplanted organ
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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

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2 types of alloreactions
Also, there is GVL (Leukemia) effect against
recipients leukemic or tumor cells
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Diseases for which bone marrow transplantation is
a therapy (BMT)
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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
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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.

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GVH disease in humans
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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.

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SITES OF ACTION OF MAJOR IMMUNOSUPPRESSIVE DRUGS
OKT3
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Effects of corticosteroids
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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.
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Cyclosporine A and FK506 inactivate calcineurin
(a calcium binding protein), which is required
for T, B and granulocyte activation
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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?
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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

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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-?
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T -regulatory cell function
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Why is fetus not rejected by the mother?
C/D
A/B
A/C, A/D, B/C, B/D
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Fetus as an allograft
Strain A
Strain B
mate
Immunize with fathers Ags
fetus survives
Skin graft rejected
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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