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)
What are three classes of immunosuppressants for transplants?
→General immune inhibitors (e.g. corticosteroids)
→Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic acid, cyclophosphamide, methotrexate)
→Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
What is cyclosporin?
→Immunosuppresant - enables transplants to survive longer in recipients
→Blocks T cell proliferation and differentiation
What is involved in combination immunosuppressive regimes?
→Steroids – e.g. prednisolone
→(2) Cytotoxic – e.g. mycophenolate motefil
→(3) Immunosuppressive specific for T cells – e.g. cyclosporin A, FK506
What type of immunosuppression regime can be used during the induction phase?
→Antibody induction therapy - lymphocyte depleting e.g. anti-thymocyte globulins (ATG) which bind to many targets on T cells, preventing proliferation and activation of T cells
→Triple drug regimen
What is involved in triple drug regimen?
→a calcineurin inhibitor, an antiproliferative agent, and corticosteroid used at high doses
eg. Tacrolimus, mycophenolate mofetil, and prednisone is the most common regimen
What is involved in the maintenance stage of immunosuppression regime?
→Triple drug regimen at lower doses- tapering off dose as time goes on as risk of transplant rejection decreases
→No antibody regimen (unlike induction)
How is Tcell mediated rejection treated?
→ATG and high dose corticosteroids (eg, methylprednisolone 250-1000 mg per dose)
How is Bcell mediated rejection treated?
→Intravenous immunoglobulin or anti-CD20 antibody and high dose corticosteroids.
What are different types of immunosppressants?
→calcineurin inhibitors- inhibit IL-2 production
→antiproliferative- inhibit Tcell and Bcell proliferation
→corticosteroids- general anti-inflammatory and anti-immuneresponses
→mTOR inhibitors- blocks Tcell activation
→Monoclonal antibodies- costimulation blockers
→IL-2 receptor antagonist
→antithymocyte globulins- inhibits and deplete Tcell
What can immunosuppressive drug toxicity lead to and give an example?
→organ failure
→ E.g. cyclosporin induces nephrotoxicity in kidney transplants
Why is FMT (faecal material transplant) used in immunosuppressed patients?
→ To change gut/intestinal microbiome to promote effective anti-cancer immune responses in cancer patients who do not respond to cancer immune therapy
Example of autologous transplantation in humans
Skin graft
Example of syngeneic transplantation in humans
Transport of biological material from one identical twin to another identical twin
Examples of when we undergo xenogeneic transplantation in humans
Heart valve transplantation using porcine or bovine valves
How diverse is HLA
Most diverse - 1000s of genes of HLA found in chromosome 6
How many HLA alleles?
HLA-A; HLA-B; HLA-C
How many alleles in total of HLA?
6= 2 alleles from each gene as one allele from mother and second from father
What are the epitopes that can be recognised by recipients immune system
These epitopes are present on donor MHC which are present in transplanted tissue or organ
- b-cell epitopes derived from donor MHC
- t-cell epitopes derived from donor MHC
How many epitopes are reactive in a transplantation setting?
100s only although there are 1000s of HLA alleles
How to ascertain the differences between the HLA of donor and the recipient?
Next generation sequencing - used to see difference not just in the alleles but the epitopes themselves which may be reactive
What do t-cells recognise
Non-self: viruses, bacteria, tumour, transplants via HLA
How does body recognise foreign peptides?
CD8-TCR interacts with HLA class 1 molecule and the epitopes it is expressing CD4-TCR interacts with HLA-2 and the epitopes in its binding groove
What do T cells recognise?
Short peptide fragments presented to them by MHC-1/MHC-2
Differences between MHC-1 AND MHC-2?
1: binds to fragments of intracellular proteins; seen by TCR on Cytotoxic CD8 cells
2: binds to fragments of proteins which have been taken up by endocytosis; seen by TCR on CD4 helper cells
What is the role of CD4+ helper T cells?
Provides info about the nature of the infection through the presentation of epitopes on HLA-2 and production of cytokines, can activate B cell responses, activate cytotoxic T cell responses or inhibit these responses by reducing regulatory T cell responses depending on whether the helper T cells produce cytokines such as IL-2, IFN-gamma or IL-10.
What is the role of cytotoxic CD8+ T cells
Involved in the lysis of cells which are presenting epitopes on their HLA-1 molecules to which the T cell is specific to the epitope. These T cells can kill virally infected cells, cancer cells or transplanted cells that they recognise as foreign.
What are helper T cells needed for?
Production of antibody (via B cells) and cytotoxic T cell responses
What does a TCR of a T cell interact with?
Peptide presented on HLA molecule and the HLA molecule itself
What is allo-recognition?
When T cells are activated to respond to transplanted material - can be both direct or indirect
How does indirect allo-recognition come to be?
When non-self peptide is derived from donated transplant- may occur if there is partial matching between donor and recipient HLA’s so one of the HLA that does match could present a non-self peptide derived from HLA that does not match thus recognised as foreign by recipients immune system and so T cell activation
What is direct allo- recognition?
Unmatched donor HLA presenting non-self epitope (protein) thus may cause antibody or TCR binding.
For hyperactive rejection what is required for it to occur?
- Pre-existing antibodies - ABO blood group antigens or MHC-1 proteins
ABO antigens expressed on endothelial cells of blood vessels
Are ABO blood group antigens recognised as non-self?
YES
What are the 3 mechanisms used to defend against viral infections or tumour cells but also used to detect transplanted tissue?
- Complement activation
- If NK cells recognise the Fc Receptors: antibody dependent cellular cytotoxicity
- if macrophages recognise Fc receptors: phagocytosis
What is acute rejection?
- inflammation in transplanted organ results in activation of organs’ dendritic cells.
- the dendritic cells induce a T cell response which develops as a result of MHC mismatch
What is chronic rejection?
→ can occur months or years after the transplant
→alloantibodies bind to antigens on the endothelial cells of the transplant organ
→recruit other immune effector cells such as macrophages and cytotoxic T cells which induce damage and reduce blood supply to organ
→ blood vessel walls thickened, lumina narrowed - loss of blood supply
→ correlates with presence of antibodies to MHC-1 of the transplanted organ
is chronic rejection due to indirect or direct allorecognition of foreign MHC/HLA?
INDIRECT
What is Haematopoietic Stem Cell Transfer (HSCT)
→Transplantation of immune cells
→Peviously known as bone marrow transplantation but source is often blood
→autologous
→can be cryopreserved with little damage
What do HSCs do when they are infused into patient?
→find their way to bone marrow and regenerate
→In BM, HSCs can produce common precursors for lymphocytes
When HSCs are in the BM, which cells can they thus produce?
→common lymphoid progenitors → T cells and B cells → activated effector T cells and plasma cells (capable of producing antibodies)
→common myeloid progenitor → granulocyte/macrophage progenitors → granulocytes/polymorphonuclear lymphocytes: neutrophils, eosinophils, basophils, monocytes and immature dendritic cells
→ mature cells: mast cells, macrophages, dendritic cells
→erythroblast → erythrocyte
Why is immunosuppression important?
→ to maintain non-autologous (allogenic) transplant
What are the 3 phases of treatment in immunosuppression?
→ induction
→ maintenance
→ rescue phase
Disadvantages of cyclosporin?
→cytotoxic
→side effects
thus next-gen therapies have been developed:
→less cytotoxic
→effective at lower doses
What is the rescue phase?
→When transplant rejection occurs
→treatments used depends on nature of rejection (TCMR and BCMR)
What are transplant patients more susceptible with?
→ chronic infection e.g. cytomegalovirus
→malignancy
