Transplantation Immunology Flashcards
● Lifesaving treatment for end- stage organ failure,
cancers, autoimmune diseases, immune deficiencies, and a variety of other diseases.
Transplantation
DEFINITION
The transfer of cells or tissues from one individual to another or from one site
to another in the same individual.
TRANSPLANTATION
TRANSPLANTATION
DEFINITION
The _______between the donor and host is the most important factor that determines whether a transplant will be successful.
genetic match
The closer the genetic match between
the donor and recipient in terms of_______, the_____ the risk of rejection.
However, even with a good HLA match, rejection can occur due to________, which are encoded by genes outside the
MHC.
HLA types, lower
minor histocompatibility antigens (mHAs)
HLA SYSTEM/MHC
• Composed of:
• Class I: (3)
Expressed on all nucleated cells
• Presents to CD8+ T cells (Cytotoxic T cells)
Class II: (3)
Expressed on antigen-presenting cells
• Presents to CD4+ T cells (Helper T cells)
HLA-A, HLA-B, and HLA-C
HLA-DR, HLA-DQ, and HLA-DP
HLA SYSTEM/MHC
Short arm of chromosome 6 in MHC.
Inherited
as haplotypes from parental
chromosomes
_____HLA identical
_____HLA haploidentical
_____HLA nonidentical
_____Recombination
25%
50%
25%
<1%
• these are expressed on the
surface of almost all nucleated cells and exhibit significant diversity among individuals.
HLA SYSTEM/MHC
HLA antigen
• Largest immunologic barrier to successful allogeneic organ transplantation.
HLA SYSTEM/MHC
• Largest immunologic barrier to successful allogeneic organ transplantation.
HLA SYSTEM/MHC
(___________), meaning there are numerous possible variations or alleles for each gene.
Allelic polymorphism
• Non-HLA proteins that demonstrate variation in the amino acid sequence between individuals and are able to
trigger an immune response
in a transplant recipient
MINOR HISTOCOMPATIBILITY
COMPLEX (mHAs)
X-linked and Autosomal inheritance
“slower” rejection pace”
MINOR HISTOCOMPATIBILITY
COMPLEX (mHAs)
CD4 or CD8 T cells recognize the variant protein in an MHC-restricted fashion and mediate the immune response.
This response is analogous to the
reaction to a microbial antigen.
mHAs
• a cell surface protein that is involved in gamma or delta T-cell responses.
• Polymorphic (_____allelic variants)
MHC CLASS I-RELATED CHAIN A (MICA) ANTIGENS
> 50
• Expression
Expressed on: endothelial cells, keratinocytes, fibroblasts, epithelial cells, dendritic cells, and monocytes
MHC CLASS I-RELATED CHAIN A (MICA) ANTIGENS
Not expressed on: T or B lymphocytes.
MICA
• The only blood group system that affects clinical transplantation.
• Can cause_______ rejection (occurs within minutes to hours)
ABO BLOOD GROUP ANTIGENS
hyperacute
• ……develop in individuals lacking the corresponding blood group antigens.
As such, recipient-donor pairs must be
______to avoid this adverse outcome.
Anti-A or anti-B antibodies
ABO identical or compatible
ABO Blood group
Remedy:
plasma exchange and intravenous immunoglobulin administration
• (KIRs)
KILLER IMMUNOGLOBULIN-LIKE
RECEPTORS
• Regulate the activity of NK lymphocytes
The KIRs contain activating and inhibitory receptors that vary in number and type on any individual NK cell.
• KILLER IMMUNOGLOBULIN-LIKE
RECEPTORS (KIRs)
• Normally:
Interaction between the MHC protein and the no reaction inhibitory KIR maintains the NK cells in a quiescent state.
If an NK cell encounters a cell with absent or decreased HLA class I expression, inhibitory receptors are not engaged, and a loss of negative regulatory activity occurs, resulting in…
NK cell activation
• Stem cell donors have been selected for recipients who lack a corresponding class I MHC protein for the donor’s inhibitory KIR type.
• This results in alloreactivity by NK cells that repopulate the recipient
after transplant.
These alloreactive NK cells have been shown to mediate a graft-versus-
leukemia (GVL) reaction and prevent relapse after transplantation for certain types of hematologic malignancies.
• When a recipient receives a transplant, their immune system may recognize the donor’s HLAs as foreign, initiating an immune response that can lead to graft rejection.
ALLORECOGNITION
• Types of graft:
: the transfer of tissue from one area of the body to another of the same individual.
: the transfer of cells or tissues between individuals of the same species who are genetically identical, for example, identical twins.
: the transfer of cells or tissue between two genetically disparate individuals of the same species. Most transplants fall into this category.
: the transfer of tissue between two individuals of different species.
• Autograft
• Syngeneic graft (isograft)
• Allograft
• Xenograft
ALLORECOGNITION
• Two main pathways of allorecognition:
Direct
Indirect
• Recipient T cells directly recognize intact foreign MHC molecules on donor cells.
• Direct allorecognition:
• This involves the uptake, processing, and presentation of foreign HLA proteins by the recipient’s antigen-presenting cells (APCs) to recipient T cells, leading to the production of antibodies and cell-mediated responses against the graft.
• Indirect allorecognition:
• The effector responses against transplanted allogeneic tissue include:
• Direct cytotoxicity
• Delayed-type hypersensitivity responses
• Antibody-mediated mechanisms
TYPES OF TRANSPLANT REJECTION
HYPERACUTE REJECTION
ACUTE
CHRONIC
TYPES OF TRANSPLANT REJECTION
• HYPERACUTE REJECTION
• Timing:
• Occurs _______after vascular supply is established.
• Mechanism:
• Mediated by ______reacting with donor vascular endothelium.
• Target antigens: ABO, HLA, and specific endothelial antigens.
• Causes of Preformed Antibodies: (3)
• Pathophysiology:
Antibody binding activates ____ and ____ cascades
• Results in (3)
minutes to hours
preformed antibodies
• Blood transfusions
• Prior transplantation
• Maternal exposure to paternal fetal antigens during pregnancy
complement and clotting cascades.
thrombus formation, ischemia, and necrosis.
• Rare in Clinical Practice due to preventive measures:
• ABO compatibility matching
• Pre-transplant HLA antibody screening
• Crossmatch tests to confirm the absence of donor HLA-specific antibodies
HYPERACUTE REJECTION
• Accelerated Rejection
Hyperacute
ACCELERATED REJECTION
• Timing: Occurs over______ in patients with very low levels of donor-specific antibodies pre-transplant
.
• Similar Features: Involves intravascular thrombosis and necrosis, like hyperacute rejection.
several days
ACUTE REJECTION
Timing: Occurs_____ after transplantation.
days to months
2 types of acute rejection
Cellular alloresponse
Antibody mediated response
Mechanism:
Parenchymal and vascular injury.
Cellular infiltrates: Predominantly CD8+ T cells, along with CD4+ T cells and
macrophages.
CELLULAR ALLORESPONSE (ACR)
Cellular alloresponse
• Role of Cells:
_______: Cytotoxic reactions to MHC-expressing cells.
_______: Cytokine production and induction of delayed-type
hypersensitivity (DTH).
CD8+ T cells
CD4+ cells
Mechanism:
• Antibodies bind to vessel walls, activating complement.
• Results in transmural necrosis and inflammation (different from thrombosis in hyperacute rejection).
ANTIBODY-MEDIATED RESPONSE (AMR)
• Diagnostic Criteria:
Histological findings characteristic of AR.
C4d deposition in peritubular capillaries.
Detection of donor-specific HLA antibodies.
Antibody mediated response
Months or Years
• Progressive graft arteriosclerosis with fibrosis, scarring, and narrowing of vessel lumen due to smooth muscle proliferation.
• Leading cause of graft loss after the first year post-transplant; difficult to treat.
CHRONIC REJECTION
• Immunologic Component:
• Delayed-type hypersensitivity to foreign HLA proteins.
• This reaction is driven by the indirect pathway of allorecognition
Chronic rejection
Cytokine and Growth Factor Effects:
• Secreted by endothelial cells, smooth muscle cells, and macrophages activated by IFN-y.
Stimulate smooth muscle cell accumulation in graft vasculature.
Chronic rejection
• Immune response by graft lymphoid cells against the host’s
histocompatibility antigens.
GRAFT-VERSUS-HOST DISEASE (GVHD)
GRAFT-VERSUS-HOST DISEASE (GVHD)
• Common Transplants Involved:
• Hematopoietic stem cell (HSC) transplants (most common)
• Lung and liver transplants (less common)
• Donor T cells in the graft attack the host/recipient.
• Targets: Host HLA proteins (mismatched transplants) or minor histocompatibility antigens (mHAs) (matched transplants).
GVHD
• Beneficial Effects of Donor T Cells:
• Promote engraftment and immunity reconstitution.
• Mediate graft-versus-leukemia (GVL) effect.
• Acute GVHD
• Timing: Occurs within the first____ days post-transplant.
• Affected Organs: Skin, gastrointestinal tract, liver.
100
• Pathophysiology:
• Cytokine release due to donor cell activation by mismatched MHC proteins.
• Tissue destruction via infiltration of donor T cells.
• Risk Factors:
• Donor-recipient match status and other clinical variables.
Acute GVHD
• Chronic GVHD
• Timing: Beyond____ days post-transplant.
• Characteristics: Resembles______
• Affected Areas: Skin, eyes, mouth, and mucosal surfaces.
100
autoimmune disease.
