L25: Transplantation & Immunosuppressive Drugs Flashcards
What was the first transplanted material?
→cornea
What is the difference between autologous and syngeneic donor relationships?
→autologous= within same individual →syngeneic= donor with a genetically identical
What is allogenic transplant?
→Donors and recipients are from the same species but genetically different
What is xenogeneic transplant?
→Donor and recipient are different species
What are immune responses to transplant mainly due to?
→differences the antigens forming the major histocompatibility complex
Where are HLA genes found?
→chromosome 6
What may be foreign in transplants?
→both the MHC protein and the peptide in its binding groove may be foreign
What is the outcome of indirect allorecognition of self HLA and non-self peptide?
→Tcell activation
What is the outcome of direct allo-recognition of non-self HLA in a donor cell?
→Unmatched HLA + peptide = T-cell activation
What needs to be matched to reduce likelihood of problems with transplants?
→match 4/6 MHC class II loci
Compare live and dead donors
→Organs from deceased donors are also likely to be in inflamed condition due to ischemia
→Transplant success is less sensitive to MHC mismatch for live donors
What are the types of graft rejections?
→Hyperacute rejection
→Acute rejection
→Chronic rejection
When does hyperacute rejection occur?
→Within a few hours of transplant
What type of transplants commonly see hyperacute rejection?
→highly vascularised organs (e.g. kidney)
What is the blood group implicated in hyperacute rejection?
→ABO
→MHC-I
How can antibodies to MHC arise?
→pregnancy
→blood transfusion or previous transplants
How do antibodies cause damage to transplanted tissue?
→Recognition of Fc region leading to -
→Complement activation
→Antibody dependent cellular cytotoxicity -(Fc Receptors on NK cells)
→Phagocytosis- (Fc Receptors on macrophages)
Describe the process of hyperacute rejection
→Antibodies bind to endothelial cells
→complement fixation
→accumulation of innate immune cells (NK and phagocytes accumulate, phagocytose and low within the endothelial cells within the transplanted tissue )
→Endothelial damage results in platelets accumulating, thrombi develop (blood lots developing)
→which results in tissue death and failure of the transplanted tissue
What cells are activated in acute rejection?
→organ’s resident dendritic cells
Why is there a Tcell response in acute rejection?
→MHC mismatch
Describe the process of direct allorecognition of foreign MHC (acute rejection)
→Inflammation results in activation of organ’s resident dendritic cells
→DC migrate to secondary lymphoid tissue of the recipient, where they encounter circulating effector T cells of the recipient
→These T cells recognise the foreign MHC inducing a direct allorecognition
→Macrophages and CTL increase inflammation and destroy transplant
What happens in chronic rejection?
alloantibodies recruit inflammatory cells to blood vessel
→Blood vessel walls thickened, lumina narrowed – loss of blood supply
→Correlates with presence of antibodies to MHC-I
What is the main cause of chronic rejection?
→indirect allorecognition of foreign MHC
Describe the process of indirect allorecognition of foreign MHC (chronic rejection)
→Donor-derived cells die
→Membrane fragments containing donor MHC are taken up by host dendritic cells
→Donor MHC is processed into peptides which are presented by host MHC/HLA
→The recipient HLA can then induce T cell and antibody responses, generated from the peptides derived from processed donor MHC (accessible as the DC are taking up the dead cells caused by the damage initiated by the alloantibodies)
What type of transplant is haematopoietic stem cell transplant?
→autologous
Where do
transplanted HSCs regenerate?
→bone marrow
How are HSCs preserved?
→cyropreserved
What is graft vs host disease (GVHD)?
→donor immune cells attacking the host
so transplant targeting host which can be lethal
What is one way of reducing GVHD?
Prevention:
→Removing T cells from transplant
→suppressing their function via immunosuppressant medicine
When is GVHD beneficial to the host, and how?
→ Graft can identify and kill leukaemia cells - Grace vs Leukaemia response
→Graft sees leukeamia as non-self thus
→may prevent disease relapse as immune response against the tumour cells thus gets weaker.
(recipients original immune response would partially see the leukaemia as self)