Lec 16- Transplantation Flashcards
Transplantation
- Transplantation is the grafting of organs or tissues from one individual to another
- This is the only treatment for most end-stage organ failure
- In the UK last year: 4,655 organ transplants were carried out ->6,500 people need a transplant
- Last year 500 people died waiting for a transplant
- Lack of organs available is a serious issue but the major barrier is our immune system
Milestones in transplantation
1906-First successful transplantation- (cornea- immunologically privileged site)
1908- Proof of concept- kidney transplanted between cats
1935- First human kidney transplant (Russia) Failed due to mismatched tissue
1940s- WW2- massive advances in transplantation technology:
+Lots of injured airmen with terrible burn
+Peter medawar (Noble prize)
+Genetic component to rejection
+Successful manipulation of animals to accept transplant tissue
Milestone in transplantation
1954- 1st successful transplant performed in Boston (identical twins)
1962- First lung in uni of colarado; First lung transplant the patient survived only a few days
1967: Dr Christian Barnard performs first heart transplant but patient only lives for 1st 18 days- improvements in immunosuppressants lead to first liver transplant
1968- 1st combined hearth and liver transplant in UK
1983- 1st combined heart and lung transplant in UK
1994-1st living donor liver transplant in UK; First living donor lung lobe transplant in UK
2018: opt-out scheme for whole UK
Donor source
-Most transplants are cadaveric (Dead donors)
+Disadvantage: long waiting time
- Increases in living donor transplant in the UK- 1 in 4 kidney transplants are now from living
- For either source of donated organ, still high of rejection. The immune system is just doing tis job
Rejection
- Rate of rejection- depends on
1) Tissue type -Skin rejected faster the kidney, liver is well tolerated
2) Number of transplants -2nd grafts rejected faster
3) Rejection mechanism -Ab mediated
Types of graft
1) AUTOGRAFT(generally well accepted)- Self tissue transferred from one body site to another in the same individual
2) ISOGRAFT (generally accepted)-Tissue transferred between genetically identical individuals (Twins)
3) ALLOGRAFT (often rejected)- Tissue transferred between genetically different members of the same species
4) XENOGRAFT (VIGOROUSLY REJECTED)-Tissue transferred between different species (e.g.Baboon heart into human recipient)
Different alloreactions lead to rejections
- When a kidney is transplanted the recipient T cells attack the transplant = transplant rejection
- When bone marrow is transplanted the T cells in the transplant attack the recipient tissue= Graft-versus-host disease
Transplant rejection is an immune response Host vs Graft disease (HvGD)
The letter refers to Ags
1) Donor= A and Recipient= A *outcome= accepted
2) Donor= B and Recipient= A *Outcome= rejected
3) Donor= B; Recipient= AxB *Outcome= accepted
4) Donor=AxB; Recipient= B *Outcome= Rejected
Graft vs host disease (GvHD)
- Allogenic (transplant from genetically different member of the same species) bone marrow transplant contains mature and memory T cells
- T cells circulate in blood to secondary lymphoid tissue. Alloreactive cells interact with dendritic cells and proliferate
- Effector CD4 and CD8 T cells enter tissues inflamed by the conditioning regimen and cause further tissue damage
- Transplantation of immunocompetent cells
- GvHD can be lethal
What happening at the cellular level
- The immune response to a graft is stronger than the to a pathogen- due to the number of cells (there is far more cells in a heart than in infection)
- T cells are key player
+experimental evidence from animal studies
- But to understand these data we need to go back to a fundamental concept
- Immunological memory
Adaptive immunity improves with age
1) Primary immune response
- First encounter with a pathogen (or transplanted tissue)
+Langer lag time +Less specific response
2)Secondary immune response- second and subsequent infections with the same pathogen (transplant)
+Faster response
+More specific response
+Principle of vaccination
Immunological memory results in the more rapid elimination of pathogens, more rapid destruction of 2nd graft
-Skin graft to syngeneic recipient: MHCa ->
MHCa -Skin graft to allogenic recipient MHCa -> MHCb= Graft is rejected rapidly (Around 10 days)
- Second skin graft from same donor to same recipient: MHCa -> MHCb= Graft shows accelerated rejection (around 6 days)
- This is identical to multiple infections by the same pathogen
Adoptive transfer experiments
- The evidence for T cells in graft rejection
- Adoptive transfer experiments
- First skin graft on mouse -> first set rejection -> second skin graft strain A mouse= second set rejection
- We we extract T cells after 1st rejection and place them in a different mouse then give them a skin graft we will see second set rejection striaght away, rapid rejection to allograft
What is happening at the cellular level
-The immune response to graft is stronger then that to a pathogen
+Many T cells will recognise the graft as non-self
+Viral infection: 1:100,000 T cells respond
+Non-self graft tissue: 1:100 T cells respond (1000x more response to graft than virus)
-T cells are MHC restricted (all has to be MHC mediated) so..
+T cells can respond to non-self peptides in self MHC: Indirect allorecognition
+T cells can respond to non-self peptides in non-self MHC: Direct allorecognition
Pathways of allorecognition
1) Direct allorecognition -
T cells (CD4, 8) recognise Non-self MHC directly on donor DC 2) Indirect allorecognition
-T cells recognise non-self Ag on receipts DC
Hyper-acture graft rejection
- normal kidney frat into a patient into patient with defective kidney and pre-existing Ab against donor Ag’s
- Abs against donor Ag’s bind vascular endothelium of graft initiating an inflammatory response which occludes blood vessels
- Graft becomes engorged and purple coloured because of haemorrhage
- Pre-existing recipient alloAbs
+Sensitised to donor MHC-previous transplants, blood transfusion
- Rejection occurs in minutes
- Abs bind Ags on graft endothelial cells
- Classical complement cascade activated (inflammatory response= vascular leakage)
- Neutrophils attracted to site (release of lytic enzymes= cells damage)
- Blood clotting cascade initiated (blood coagulation= vessel blockage)
Acute graft rejection
- Type IV hypersensitivity
- Mediated by activated allospecific effector T cells
- Donor leukocytes involvement- direct allorecognition- non self peptide in non-self MHC of donor APC
- Stimulates a strong immune response
- Kidney graft with dendritic cells
- Dendritic cells migrate to spleen where they activate effector T cells
- Effector T cells migrate to graph via blood -Graft destroyed by effector T cells
Indirect allorecognition drives chronic rejection
Allogenic (non-self) HLA class I are processed and presented by self APC
- This activates self Th cells
- These will activate naive B cells- release of anti-alloHLA (Human Leukocyte Ags) alloAbs
- Endothelial cells in the graft express alloHLA Ags
- Binding of the anti-alloHLA Abs to the alloHLA Ags results in impaired function (autoimmune mechanism)
ABO and Rh Ag matching prevents type II hypersensitivity in blood transfusions
- RBC- no class I MHC, No MHC class II expression.
- BUT RBC do express ABO and Rh alloAg’s
- Preformed Abs in the transplant patients serum can bind surface Ag’s on the cells- RBC lysis
- Histocompatibility matching prior to transplantation prevents this reaction
- Cross match testing of matched blood prior to transfusion will the reveal whether any other Abs in the patients serum react with the donor RBC
HLA expression analysis
- Mix blood with panel of Abs to different HLA Ags
- Agglutination reaction (Blue) indicates Ag expression
- Who would be the better donor for this recipient
- You want the recipient and donor reactions to be on the same panels
The mixed lymphocyte reaction measure T cell responses
- Mixed lymphocyte reaction
1) Measure T cell proliferation
2) Measure T cell cytotoxicity - Incubate irradiated donor cells (yellow) with recipient lymphocytes (blue)
- If recipient cells recognise donor as non-Self, they will respond by proliferation
- CD4: MHC class II miss match and cell death
- CD8: MHC class I mismatch
- This test indicates the presence of alloreactive T cells- acute/chronic rejection
Cytotoxic drugs
Azathioprine
- Pro-drug for 6-Mercaptopurine
- Inhibit DNA replication
- Prevents replication of alloAg-stimulated T cells
- And every other dividing cell (bone marrow, intestine) Cyclophosphamide
- Chemical weapon from WW2- many toxic effects Methotrexate
- Inhibits replication, useful in inhibiting GvHD in bone marrow transplants
T cell modifiers
- Cyclosporin-A isolated from fungus
- Tacrolimus (FK506)- isolated from bacteria
- Rapamycin- isolated from bacteria on easter island
- Inhibit T cell activation but also suppress B cell/granulocyte activation
- No effets on proliferating cells (good news for the intestine) BUT fairly toxic to the kidneys
- Combination therapy
