Transplantation Immunology - med.cmu.ac.th · Transplantation Immunology ชุมพล สกลวสันต์ พ.บ. เกียรตินิยมอันดับ 1
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Transplantation Immunology
ชุมพล สกลวสันต์ พ.บ. เกียรตินิยมอันดับ 1 วว. อายุรศาสตร์
Transplantation
The process of taking cells, tissues, or
organs called a graft, from one individual and placing them into a (usually) different individual.
Donor : the individual who provides the graft.
Recipient or host : the individual who receives the graft.
Autologous graft
Syngeneic graft (syngraft)
Allogeneic graft (homograft)
Xenogeneic graft
(heterologous graft, heterograft)
Types
(graft rejection)
Graft Rejection
The genetics of graft rejection.
Transplantation (Histocompatibility) Antigens
Major histocompatibility complex
(MHC) molecules :
human MHC = human leukocyte antigen (HLA)
MHC class I molecules : almost all nucleated cells
MHC class II molecules : APCs, endothelium of
renal arteries and glomeruli
Minor histocompatibility antigens : H-Y
molecule
Induction of Immune Responses
Against Transplants
Antigens that serve as the targets of rejection : alloantigens and xenoantigens
The antibodies and T cells that react against these antigens are said to be alloreactive and xenoreactive, respectively.
Allorecognition Indirect : T cells of a graft recipient recognize
intact, unprocessed MHC molecules in the graft
Direct : recipient’s MHC molecules present allogenic graft MHC proteins to recipient T cells
The frequency of T cells that
recognize a single allogeneic MHC
molecule is 100 to 1000 times
greater than the frequency of T cells
specific for any microbial peptide displayed by self MHC molecules
Activation of Alloreactive T cells and Rejection of Allografts
Donor APCs migrate to regional
lymph nodes and are recognized by
the recipient’s T cells
Alloreactive T cells in the recipient
may be activated by both pathways,
and they migrate into the graft and cause graft rejection
Allograft Rejection Different immune effectors cause graft
rejection by different mechanisms
Alloreactive CD4+ T cells : recruit and activate macrophages DTH response
Alloreactive CTLs : lyse graft endothelial and parenchymal cells directly
Alloantibodies : bind to endothelium, activate the complement system, and injure graft blood vessels
Allograft Rejection
Hyperacute rejection Acute rejection
acute vascular rejection acute cellular rejection
Chronic rejection
Hyperacute Rejection
Occurs within minutes to hours of transplantation
Pre-existing IgM (natural) antibodies against
ABO blood group antigens - the early days, not really a problem anymore
alloantigen, such as foreign MHC molecules, or alloantigen expressed on vascular endothelial cells
past blood transfusion
multiple pregnancies
previous transplantation
Hyperacute Graft Rejection1
Hyperacute Graft Rejection2
Hyperacute Graft Rejection3
Acute Rejection1
Begins several days to a few weeks after
transplantation
Acute antibody-mediated rejection
Necrosis of cells of the graft blood vessels
(vasculitis)
Mediated by alloantibodies against endothelial cell
alloantigens and complement activation
Acute Rejection2
Acute cellular rejection
Necrosis of parenchymal cells with lymphocyte and macrophage infiltrates
Effector mechanisms :
CTLs
inflammatory cells recruited and activated by cytokines produced by activated CD4+ helper T cells and CTLs
Acute Rejection
Chronic Rejection Occurs over months or years
Fibrosis with loss of normal organ structures
Mechanisms a response to chronic ischemia caused by
injury to blood vessels
wound healing following the cellular necrosis
a form of chronic DTH
Chronic Rejection
Reduce the immunogenicity of allografts
ABO blood typing to avoid hyperacute rejection
tissue (HLA) typing and crossmatching
Induce donor-specific tolerance, e.g.,
blood transfusion
costimulatory blockade
Prevention and Treatment of Allograft Rejection1
Influence of MHC matching on graft survival.
Prevention and Treatment of Allograft Rejection2 Immunosuppression
drugs that inhibit T cell signaling pathways, e.g., cyclosporine, FK506 (tacrolimus)
toxins that kill proliferating T cells, e.g., mycophenolate mofetil
antibodies that deplete or inhibit T cells, e.g., anti-TCR, anti-IL-2R
anti-inflammatory agents, e.g., corticosteroid
costimulatory blockade, e.g., CTLA4-Ig
Mechanisms of action of immunosuppressive drugs
Xenogeneic Transplantation
Primates have
natural IgM antibody
to carbohydrate on
cells of distant
species (e.g. pig)
Human (Homo sapiens)
Xenogeneic
graft
Chimpanzee (Pan troglodytes)
Concordant
species
Pig (Sus domesticus)
Discordant species - Produce α-linked
galactose on blood group
H-antigen (instead of
fucose in primate)
- More severe xenograft
rejection Xenogenic graft rejection due
to hyperacute rejection
Graft-versus-host Disease (GVHD) Occurs in bone marrow recipients
May develop when solid organs that contain significant numbers of T cells are transplanted, such as the small bowel, lung, or liver
Initiated by T cell recognition of host alloantigens
The effector cells are less well defined : NK cells, CD8+ CTLs, cytokines
Bone Marrow Transplantation and Graft-versus-host Disease
Acute GVHD Epithelial cell necrosis :
Skin
Liver
The gastrointestinal tract
Characterized by skin rash, jaundice and diarrhea
Acute GVH
Acute GVH
Chronic GVHD Characterized by fibrosis and
atrophy
Represent the fibrosis of wound
healing
Secondary to acute GVHD
A response to ischemia caused by vascular injury
Chronic GVH
Chronic GVH
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