Lecture 24 Transplantation Immunology Flashcards
autograft
transplant from one anatomical location to another on the same person
isograft
transplant from one individual who is syngeneic to the donor (identical twin) HISTOCOMPATIBLE
allograft
transplant from one individual to a genetically dissimilar individual HISTOINCOMPATIBLE
alloantigens
antigens that differ between members of the same species
xenograft
graft between donor and recipient from different species; HISTOINCOMPATIBLE
Bone Marrow and HSC transplantation
allogeneic and autologous
Which type of transplants would you expect to see rejection?
allograft and xenograft because they are HISTOINCOMPATIBLE
Allogeneic bone marrow transplant runs a risk for
graft vs host disease
Colony stimulating factors include
granulocyte-monocyte-CSF or IL-13
Autologous bone marrow transplant
HSC or bone marrow from same individual following CD34, cryopreservation, ablative therapy followed by reintroduction of frozen HSC
First-set rejection
first graft from a histoincompatible donor leads to rejection in 2 weeks
Second-set rejection (immunological memory)
second graft from the same donor will be completely rejected within a week
which type of individuals would not reject an allograft
athymic - T cell plays a large role in rejection
Hyperacute rejection
within hours, pre-formed antibodies to incompatible MHC or blood group antigens and activation of complement causes a reaction
Hyperacute rejection is mediated by
present antibodies binding to tissue inducing complement and recruitment of phagocytic cells, platelet activation -> thrombosis -> hemorrhage -> necrosis
Pre-formed antibodies may be present as a result of
ABO incompatibility, previous incompatible transfusion, pre void blood transfusion from related donor, pregnancy
Manifestations of hyperacute rejection
fever, leukocytosis, loss of function of organ
Therapy for hyperacute rejection
NONE
Acute rejection
within days, non-sensitized patients’ T cell-mediated immunity recognizes mismatch of HLA types
Acute rejection is complete by
14 days, may be shorter in sensitized patients
Acute rejection occurs when
there is a mismatch or incomplete match in HLA types
Histological definition of acute rejection
infiltration of lymphocytes and monocytic macrophages
destruction of cells in acute rejection occurs by
cytotoxic T cells, phagocytosis and presentation of transplant antigen to help T cells
Therapy for acute rejection
immunsuppressive therapy (antibodies against T lymphocytes, corticosteroids, or other drugs)
Histological definition of chronic rejection
lymphoid proliferation and formation of lymphoid follicles, fibrotic changes
Chronic rejection
over months or years, CD4+ cell activation along with macrophage activation, cytotoxic T cell activation, antibody produced against allograft antigens, classical complement, and ADCC cause loss of function of organ
Therapy for chronic rejection
none, damage has been done
Graft vs host disease
transplantation of donor lymphocytes or precursors genetically dissimilar can ATTACK RECIPIENT’s tissue
To avoid Graft vs host disease
immunocompetent lymphocytes from donor and recipient must be immune compromised
Manifestations of Graft vs host disease
rash, hepato-slpenomagaly, lymphadenopathy, diarrhea, anemia, weight loss, wasting
Graft-versus-leukemia effect
donor T cells recognize minor histocompatibility or tumor-specific antigens and attack and kill leukemic cells, reducing the reoccurrence
Major Histocompatibility Complex (MHC)
primary immunological importance in graft acceptance or rejection
transplantation agents
MHC
HLA
products of the MHC gene complex
MHC class I is composed of
several closely linked genes or loci known as A, B, C
MHC class II is composed of
several closely linked genes or loci known as DP, DQ, and DR
HLA class I are expessed on
All nucleated cells
HLA class II are expressed on
a subset of hematopoietic cells (dendritic cells) and thymocytes
HLA class II can be induced by what cytokine
INF-gamma
Haplotype of MHC
combination of 6 alleles (one for each A, B, C, DP, DQ, and DR
Genotype of MHC
2 haplotypes, 1 from each parent = 12 alleles expressed
Use of HLA alleles for
MHC genetic polymorphisms is the basics for forensics, paternity testing, DNA ancestry, tissue typing
MHC is inherited as
a block of genes from each parent, because they are so closely linked
The most potent transplant antigen is
MHC Class II HLA-DR
The key initiating event in allograft rejection is
direct activation of the recipient’s CD4+ T cells by NONSELF HLA Class II molecules from donor
Direct recognition
recognition of nonself HLA molecules does not require processed foreign peptides, instead CD4 recognized non-self HLA alone
In direct recognition, because CD4 TCR does not need HLA + peptide for recognition, the body mounts a
much broader immune response (5% of all T cells respond)
indirect recognition
receipient’s APC processes donor antigens and presents them to T cells
Which locus is associated with the longest graph survival
HLA-DR
Activation of CD4+ cells via
recognition of foreign HLA class II (with or without peptide) occurs
Activation of CD8+ T cells via
direct activation by nonself HLA class I UT require the assistance of CD4+ T cells via IL-2 production
Important cytokines in allograft rejection are predominantly
Th1, hence graft rejection reflects a type 1 immune reponse
IFN-gamma role in allograft rejection
accumulation and activation of macrophages and increased HLA Class II expression, cytolytic response
IFN-gamma and IFN-alpha/beta and TNF-alpha and beta role in allograft rejection
increase HLA class I expression and result in cytolysis of transplanted cells
TNF-beta role in allograft rejection
cytotoxic to graft cells
Tissues that are highly dependent on HLA matching for survival
bone marrow and kidney
Tissues that are moderately dependent on HLA matching for survival
heart and liver
Tissues that are not dependent on HLA matching for survival
cornea
What is the reason for graft rejection when 2 individuals are HLA-matched
Minor histocompatibility antigens
reaction due to minor histocompatibility antigens is
not as rapid, but patients must still be under immunosuppressive therapy to prevent graft rejection
Testing for histocompatibility
blood typing and cross-match (ABO mismatch = hyperacute rejection), genotyping HLA by PCR
Genotpying HLA alleles by PCR
HLA sequence-based typing (HLA-SBT), PCR, DNA sequencing, comparison to known allele sequences
Prevention of allograft rejection
all medications are not antigen-specific, but rather induce generalized immune suppression
Tissue typing (lymphocytotoxicity)
antibodies against known HLA sequence-marker is added to cells, cells stained indicate +HLA marker
Mixed Leukocyte Reaction (1 way)
known LIVING donor available, highly sensitivite for major and minor HC, mix recipient and donor cells together (inactivate 1) if T cell reconizes other as foreign then cells divide and incorporate thymidine in DNA. If not foreign, no proliferation and no uptake
Corticosteroids
inhibit T cell cytokine production and HLA expression (-ones)
Antimetabolites
azathioprine and mercaptopurine - inhiibit lymphocyte proliferation - purine agonist; cyclophosphamide and chlorambucil - DNA alkylating agents; methotrexate - folic acid antagonist
azathioprine
inhibit lymphocyte proliferation - purine agonist
mercaptopurine
inhibit lymphocyte proliferation - purine agonist
cyclophosphamide
DNA alkylating agents
chlorambucil
DNA alkylating agents
methotrexate
folic acid antagonist
Blocking agents
antibodies against CD-3, IL-2 receptor, B7 ligands
Antibody against CD-3
blocks T cell activation
Antibody against IL-2R
receptor on T cells
Antibody against B7 ligands
blocks effects of co-stimulating molecules
Cyclosporine
inhibits T cell cytokine production by interfering with gene transcription
FK506 and rapamycin
similar to cyclosporine - inhibits T cell cytokine production by interfering with gene transcription
