Download Chapter 17 Transplantation

Chapter 17 Transplantation
General Features
- graft rejection: rejection of recipient’s tissue by donor’s immune system
- due to genetic differences in MHC (major & minor)
- polymorphism: many different forms of MHC in population
- each person has six different types of class I MHC and class II MHC (codominant
expression)
- successful organ transplantation depends on: 1. MHC matching; 2.
immunsuppressive therapy
Classification of Grafts According to Their Source
- isografts: grafts between identical twins
- autografts: grafts within same individual
- allografts: grafts between members of the same species
- xenografts: grafts across species
Iso (or auto) grafts
- no need for immunosuppression
- no Graft vs. Host Disease (no rejection)
Allografts
- match MHC
- immunosuppression
Xenografts
- porcine heart grafts
- concern with risk of retroviral species crossing species to human
Classification of Graft Rejection
Hyperacute rejection
- minutes to hours
- preformed antibody mediated
- Individuals at high risk: multiparous women, previous graft rejection
- Xenograft  natural antibodies to carbs on pig organs
- Complement activation, stimulation of coagulation cascade, thrombosis & rapid
graft failure
- Tx: graft removal
Delayed accelerated rejection
- 1-3 days post transplant
- antibody/complement-mediated activation of graft endothelium
Acute rejection
- most common type of allograft rejection
- weeks
- T cell mediated
- If rejection is suspected a tissue biopsy is performed looking for immune cell
infiltration and/or inflammation
- Tx: increase immunosuppressive therapy  increased risk of infection,
malignancy, and drug toxicity
- Type 1 cytokine production (DTH)
Chronic rejection
- weeks/months/years
- fibroblast growth factor; endothelial growth factor  fibrosis and
hyperproliferation of connective tissue
- does not respond to treatment
- type 2 cytokine production
Genetics of Transplantation
Major histocompatibility complex
- HLA in humans (MHC in mice)
- The fewer the number of mismatched loci, the greater the likelihood that the graft
will be accepted
Minor histocompatibility complex
- differ between individuals
- can lead to graft rejection that is as strong as those occurring with MHC
differences
- currently we can’t measure MiHC and matching for MHC does not imply
matching of MHC
Major histocompatibility typing in organ transplantation
- matching MHC between donor and recipient
- methods for determining compatibility between donor and recipient are
serological, mixed lymphocyte reaction, and molecular techniques
Serological techniques
- looking for a negative reaction
- if HLA antibody recognizes the RBC there will be lysis by complement and a dye
is used to detect lysis = positive reaction
- Disadvantage: does not necessarily indicate compatibility
Mixed lymphocyte reaction (MLR)
- measures CD4+ T cell activation because these cells are key players in graft
rejection
-
cells from donor and recipient are cultured together. Proliferation of recipient
CD4+ T cells only occurs when they see a class II MHC difference on donor cells
proliferation is measured by radioactive isotype
Disadvantage: requires 72-96 hrs
Molecular techniques
- RFLP  DNA fragments compared after specific enzyme digestion
- Number of disparities does not predict the severity of rejection between
donor/recipient
- PCR (amplify MHCI and MHCII to compare alleles)
Immunology of Graft Rejection
- mediated by activation of CD4+ or CD8+ T cells, macrophages, neutrophils, and
the vascular endothelium
- early after transplantation, ischemia-reperfusion damage induces chemokine &
cytokine secretion by donor graft cells
- increase in vascular permeability and alters expression of adhesion molecules on
leukocytes and endothelium
- several days later, monocytes, neutrophils, CD4+ and CD8+ T cells infiltrate the
graft
- monocytes  macs by IFN (also enhances phagocytosis by macs)
- macrophages and neutrophils secrete toxic products that lead to tissue damage
- CD4+ T cells differentiate to Th1 cells secreting type 1 cytokines
- CTL matures and leads to cell lysis of graft
Graft invasion by CD4+ T cells
- when T cells leave the circulation and enter a graft, alloantigen on APC is
recognized by T cell (DIRECT recognition)
- recipient APC with self-MHC class II presents alloantigen  INDIRECT
recognition (particularly for CD4+ T cells)
Antigenic stimuli that activate CD4+ T cells
- higher frequency of T cells activated after allostimulation
- review Direct and indirect recognition
Role of CD4+ T cells in graft rejection
- IFN stimulates monocytes, macrophages, and NKs
- IL-2 aids in differentiation of a pCTL to a CTL
- IL-4, IL-5 growth/differentiation of B cells
Role of macrophages in graft rejection
- secrete cytokines and chemokines that enhance the inflammatory response
- activated macs  IL-12  activation of NKs, differentiation of CD4+ T cells to
Th1
- IL-1, TNF  increase expression of adhesion molecules, fever
Role of vascular endothelial cells
- Mac derived TNF, IL-1, IL-8 induce expression and higher affinity of integrins on
endothelial cells and leukocytes
- Leukocytes that enter the tissue secrete metalloproteinases which break the
basement membrane resulting in increased extravasation of additional leukocytes
Role of CD8+ T cells in graft rejection
- DIRECT recognition of graft  donor cell with alloMHCI is recognized by
recipient’s CD8+ T cell
- INDIRECT allo-recognition in CD8+ T cells
Role of B cells
- preformed antibodies have role in hyperacute rejection  complement destruction
of graft
- xenoantibody against 1,3 galactosyl linkage of porcine carbohydrate antigens 
IC formed on blood vessel wall  activation of the classical pathway 
complement activation on endothelial cells lining graft blood vessels, activation
of the coagulation cascade, thrombosis, and graft loss
Tissue Differences in Clinical Transplantation
- Corneal transplant  immunologically privileged site, don’t require
immunosuppression
- Heart transplants  high incidence of atherosclerosis in the years following
successful transplantation
- Liver transplants  resistant to rejection once any early acute rejection episodes
pass, and long term survival is similar for both well-matched and unmatched
tissues
- Kidney transplant  immunosuppressive therapy for life
- Pancreas transplants  islet grafts
- Bone transplants  avascular  no problem with immune rejection
- Bone marrow transplants  graft versus host disease
Graft Versus Host Disease
- donor T cells reject host tissue
- donor CD8+ and/or CD4+ T cells are activated when they interact with host cells
expressing class I and/or class II MHC
- skin sloughing, diarrhea, inflammation of the lungs, liver and kidneys
- deplete donor T cells and give patients IL-3, GM-CSF to speed up restoration of
the lymphohematopoietic system from donor stem cells
- treatment for leukemia or lymphoma
- graft vs leukemia effect
Immunosuppression in Transplantation
Nonspecific immunosuppression
- cyclosporine A and FK506  block production of IL-2
- rapamycin  synergistic with cyclosporine
- prednisone  suppress activation of macs and release of INF  inhibit antigen
presentation
- azathioprine  blocks cell division and clonal expansion of activated cells
- anti-CD3 antibodies  suppress activity of all T cells
- anti-CD4 antibody
Specific immunosuppression (tolerance)
- deliberate infusion of donor cells in addition to organ allograft which led to
prolonged survival of the graft