Transplantation and immunosuppressive drugs

Question 1

What is transplantation?

Answer 1

• 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

Question 2

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

Answer 2

• 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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

• 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

Question 5

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

Answer 5

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

Question 6

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

Answer 6

• 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

Question 7

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

Answer 7

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

Question 8

Describe the difference in using live + dead donors?

Answer 8

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

Question 9

Rejection mechanisms
State the 3 types of graft rejection?

Answer 9

• Hyperacute
• Acute
• Chronic

Question 10

Hyperacute rejection
Describe general features about hyperacute rejection?

Answer 10

• 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

Question 11

How can ABs lead to damage in transplanted tissue?

Answer 11

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

Question 12

Describe how tissue damage occurs via hyperacute rejection? VD

Answer 12

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

Question 13

Describe acute rejection?

Answer 13

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

Question 14

Describe chronic rejection and process of damage?

Answer 14

• 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

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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

Question 17

Graft vs host disease + leukemia
What is GVHD?

Answer 17

• 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

Question 18

What is GVL?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

State 3 functions of immunosuppressants for transplant with examples?

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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

Question 23

Immunosuppressive therapy monitoring
Describe a typical immunosuppressive regime?

Answer 23

• 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

Question 24

Does immunosuppressive therapy monitoring exist?

Answer 24

• 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)

Question 25

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

Answer 25

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