Transplantation and immunosuppressive drugs Flashcards
What is transplantation?
- Insertion of biological material into an organism, where the immune system have evolved to remove anything it regards as non-self
- Non-self -> e.g. viral, bacterial infection or malignant tumour
Donor/recipient relationships
State + describe the 4 types of donor/recipient relationships
- Autologous: Transfer of BM from one part of individual to another part of the same individual
- Syngeneic: Transfer from donor to recipient
- A + S: Genetically identical - no immunlogical problems
- Allogenic: Donor + Recipient - Same species + genetically different
- Xenogeneic: Different species
Importance of MHC matching
Why do immune responses (rejection) to transplant occurs?
- Genetic differences between Donor + Recipient
- Key one is differences in antigens forming MHC
- MHC = Major histocompatibility complex -> histocompatibility = tissue compatibility
What epitopes are important on the donor MHC and how can differences be determined?
- B cell + T cell - NGS required for differences in HLA of D + R
- An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells
- The epitope is the specific piece of the antigen to which an antibody binds.
- The part of an antibody that binds to the epitope is called a paratope
In transplants, what components could be considered foreign/non-self?
- MHC protein/HLA allele, peptide -> identified via TCR, T-cell or AB binding VD
Describe the different scenarios of direct + indirect T-cell activation when responding to transplanted material? VD
- Allo-recognition - occur via specific epitope
- Recipient cell -> Self HLA + self peptide -> No T-cell act.
- Self HLA + non- self peptide - T-cell act. - Indirect AR
- Donor cell - Matched HLA + peptide -> No T-cell act.
- Unmatched HLA + peptide - T-cell Act. - Direct AR
Describe the relationship between HLA mismatch + graft survival and what is used to match?
- Increased mismatch -> Decreased survival
- Match 4/6 MHC II loci -> Decreased likelihood of future transplant + problems
Describe the difference in using live + dead donors?
- Recipients have disease -> degree of IF
- Dead -> organs likely to be inflamed -> due to ischemia
- Live -> success -> Decreased sensitive to MHC mismatch
Rejection mechanisms
State the 3 types of graft rejection?
- Hyperacute
- Acute
- Chronic
Hyperacute rejection
Describe general features about hyperacute rejection?
- Within few hours of transplant
- Most common for highly vascularised organs (kidney)
- Requires pre-existing AB - against donor ABO blood group antigens (expressed on endothelial cells of blood vessels) or MHC-| proteins
- AB to MHC -> arise via pregnancy, blood transfusion or previous transplants
How can ABs lead to damage in transplanted tissue?
Binding of AB to non-self MHC/HBO antigen -> recognition of Fc region -> complement activation, AB dependent cellular cytotoxicity (Fc receptor on NK cells), phagocytosis (FCR on macrophages) -> Mechanisms for transplant material detection
Describe how tissue damage occurs via hyperacute rejection? VD
- ABs bind endothelial cells -> complement fixation -> Accumulation of innate immune cells -> Endothelial damage, platelet accumulation, thrombi development -> tissue death + failure of transplanted tissue
Describe acute rejection?
MHC mismatch (DA) -> IF of transplated organ -> activation of organ resident dendritic cells -> DC migrate to secondary lymphoid tissue -> activation of circulating effector T cells + macrophages -> recognition of MHC -> increased IF -> destroy transplant DA -> Direct allorecognition
Describe chronic rejection and process of damage?
- Can occur months or years after transplant
- AlloABs bind antigen + endothelial cell of transplant organ -> recruitment of IF cells to blood vessel walls -> blood vessel walls thickened, lumina narrowed - decreased blood supply -> correlates with presence of AB to MHC-I
Describe how chronic rejection occurs and process causing T cell development?
Indirect allorecognition of foreign MHC/HLA -> Donor-derived cells die - Membrane fragments containing donor MHC taken up by host DC -> Donor MHC is processed into peptides presented by host MHC -> T cell + AB responses is generated to the peptide derived from processed donor MHC
Transplanting immune cells - Haematopoietic stem cell transfer (HSCT)
Describe Hematopoietic stem cell transfer (HSCT)
- Source is blood + autologous -> HSCs find way to bone marrow after infusion + regenerate there -> crypreserved with little damage
Graft vs host disease + leukemia
What is GVHD?
- Graft verses host disease
- When transplanted tissue has immune cells -> risk of donor immune cells attacking host
- Lethal
- Best approach is prevention -> removal of T cells from transplant or function suppression -> Decreased GVHD
What is GVL?
- Graft verses leukemia response
- mismatch + donor leukocytes - remove original leukemia -> development of GVL prevents disease relapse
Immunosuppression in transplant medicine - Immunosuppression
Describe the purpose of immunosuppression and the phases involved within its treatment?
- Maintains non-autologous transplant
- Phases of treatment: induction, maintenance + rescue
- Need to be maintained indefinately
State 3 functions of immunosuppressants for transplant with examples?
- General immune inhibitors: corticosteroids
- Cytotoxic: kill proliferating lymphocytes -> mycophenolic acid, cyclophosphamide, methotrexate
- Inhibit T-cell activation: cyclosporin, tacrolimus, rapamycin
IS methods- Cyclosporin
Describe the use of cyclosporin as an immunosuppressant method?
- Blocks T cell proliferation + differentiation
- Next generation therapies less toxic
- Effective at decreased doses
Combination immunosuppressive regimes
State a combination immunosuppressive regime stating drug examples?
- Steroids (prednisolone), cytotoxic (mycophenolate motefil), Immunosuppressive specific for T cells -> cyclosporin A, FK506
Immunosuppressive therapy monitoring
Describe a typical immunosuppressive regime?
- Induction
- AB induction therapy - Lymphocyte depleting Anti-thymocyte globulins (ATG) >, basiliximab > alemtuzumab.
- Triple drug regimen -> calcineurin inhibitor, antiproliferative agent + corticosteroid -> Tacrolimus, mycophenolate mofetil + prednisone
- Maintenance: Triple drug regimen at lower doses
Rescue: T - cell mediated rejection -> treated with ATG + steroids (methylprednisolone) - B-cell mediated rejection -> intravenous immunoglobin or anti- CD20 AB + steroids
Does immunosuppressive therapy monitoring exist?
- No IS
- Prevents transplant rejection + maintaining other immune response -> transplant patients = Increased susceptability to infection + malignancy -> IS drug toxicity = organ failure (cyclosporin nephrotoxicity in kidney transplant)
