Transplantation and immunosuppressive drugs Flashcards

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1
Q

What is transplantation?

A
  • 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
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2
Q

Donor/recipient relationships
State + describe the 4 types of donor/recipient relationships

A
  • 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
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3
Q

Importance of MHC matching
Why do immune responses (rejection) to transplant occurs?

A
  • Genetic differences between Donor + Recipient
  • Key one is differences in antigens forming MHC
  • MHC = Major histocompatibility complex -> histocompatibility = tissue compatibility
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4
Q

What epitopes are important on the donor MHC and how can differences be determined?

A
  • 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
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5
Q

In transplants, what components could be considered foreign/non-self?

A
  • MHC protein/HLA allele, peptide -> identified via TCR, T-cell or AB binding VD
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6
Q

Describe the different scenarios of direct + indirect T-cell activation when responding to transplanted material? VD

A
  • 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
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7
Q

Describe the relationship between HLA mismatch + graft survival and what is used to match?

A
  • Increased mismatch -> Decreased survival
  • Match 4/6 MHC II loci -> Decreased likelihood of future transplant + problems
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8
Q

Describe the difference in using live + dead donors?

A
  • Recipients have disease -> degree of IF
  • Dead -> organs likely to be inflamed -> due to ischemia
  • Live -> success -> Decreased sensitive to MHC mismatch
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9
Q

Rejection mechanisms
State the 3 types of graft rejection?

A
  • Hyperacute
  • Acute
  • Chronic
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10
Q

Hyperacute rejection
Describe general features about hyperacute rejection?

A
  • 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
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11
Q

How can ABs lead to damage in transplanted tissue?

A

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

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12
Q

Describe how tissue damage occurs via hyperacute rejection? VD

A
  • ABs bind endothelial cells -> complement fixation -> Accumulation of innate immune cells -> Endothelial damage, platelet accumulation, thrombi development -> tissue death + failure of transplanted tissue
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13
Q

Describe acute rejection?

A

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

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14
Q

Describe chronic rejection and process of damage?

A
  • 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
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15
Q

Describe how chronic rejection occurs and process causing T cell development?

A

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

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16
Q

Transplanting immune cells - Haematopoietic stem cell transfer (HSCT)
Describe Hematopoietic stem cell transfer (HSCT)

A
  • Source is blood + autologous -> HSCs find way to bone marrow after infusion + regenerate there -> crypreserved with little damage
17
Q

Graft vs host disease + leukemia
What is GVHD?

A
  • 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
18
Q

What is GVL?

A
  • Graft verses leukemia response
  • mismatch + donor leukocytes - remove original leukemia -> development of GVL prevents disease relapse
19
Q

Immunosuppression in transplant medicine - Immunosuppression
Describe the purpose of immunosuppression and the phases involved within its treatment?

A
  • Maintains non-autologous transplant
  • Phases of treatment: induction, maintenance + rescue
  • Need to be maintained indefinately
20
Q

State 3 functions of immunosuppressants for transplant with examples?

A
  • General immune inhibitors: corticosteroids
  • Cytotoxic: kill proliferating lymphocytes -> mycophenolic acid, cyclophosphamide, methotrexate
  • Inhibit T-cell activation: cyclosporin, tacrolimus, rapamycin
21
Q

IS methods- Cyclosporin
Describe the use of cyclosporin as an immunosuppressant method?

A
  • Blocks T cell proliferation + differentiation
  • Next generation therapies less toxic
  • Effective at decreased doses
22
Q

Combination immunosuppressive regimes
State a combination immunosuppressive regime stating drug examples?

A
  • Steroids (prednisolone), cytotoxic (mycophenolate motefil), Immunosuppressive specific for T cells -> cyclosporin A, FK506
23
Q

Immunosuppressive therapy monitoring
Describe a typical immunosuppressive regime?

A
  • 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
24
Q

Does immunosuppressive therapy monitoring exist?

A
  • 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)
25
Q

Intestinal microbiome
Describe the role of the microbiome in immune response and how it can be involved within transplants

A
  • Regulates adaptive immune response
  • Immunosuppressive patients take faecal maternal transplant -> Increased anti-cancer immune responses -> may be implicated in transplant outcomes