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