Transplantation Immunology III

Question 1

Prevention of allograft rejection

Answer 1

1. Matching donor and recipient HLA → requires donor and recipient HLA to be identified (tissue typing)
   — BUT not enough donors
2. Pre-transplant HLA antibody testing → testing the serum of the recipient for antibodies against donor HLA
   — BUT only addresses issues associated with pre-existing DSA/ (hyper)acute AMR
   — DOES NOT prevent development of NEW antibodies to the transplant
3. Immunosuppressive drugs
   — best solution currently..

Question 2

Different Immunosppressive Drugs

Answer 2

1. Induction therapy
   - Administered pre-transplant or in the peri-transplant period
2. Maintenance therapy
   - Basal immunosuppressive drugs given continuously long term
3. Rescue therapy
   - Therapies given during rejection episodes

Question 3

Mechanism of Immunosuppression

Answer 3

Inhibits undesirable immunologic activity by:

• Depletion of cells involved in the immune response
• Inhibition of pathways required for the induction of an immune response
• Blocking of receptors required for the induction of an immune response

Question 4

Types of Immunosuppressive Drugs

Answer 4

1. Glucocorticosteroids
2. Small molecule drugs
   — Maintenance therapy
   — Act intracellularly
   — Inhibit pathways downstream of cell activation
3. Protein based/biologic drugs
   — Induction and rescue therapy
   — Act extracellularly
   — Receptor-ligand or antibodies

Question 5

Glucocorticosteroid examplees

Answer 5

• Prednisone (maintenance therapy)
• Methylprednisolone (rescue therapy)

Question 6

Glucocorticosteroids mechanism

Answer 6

• Broad immunosuppressive and anti-inflammatory effects
• Interact with glucocorticosteroid receptors (GRs), found on most body cells = drug internalized by the cell
  = Down-regulation of co-stimulatory & adhesion molecules, inflammatory cytokines (ie. IL-12)
  = Up-regulation of anti-inflammatory cytokines (ie. IL-10)

Question 7

Small Molecule Drugs example + mechanisms

Answer 7

1. Calcineurin inhibitors (cyclosporine, tacrolimus)
   — inhibit growth factor production = decreased B and T cell activity
2. Purine synthesis inhibitors (mycophenolate mofetil—MMF)
   — inhibit DNA synthesis = decreased B and T cell clonal expansion
3. Mammalian target of rapamycin (mTOR) inhibitors
   — inhibits mTOR = decreased response to growth factor = decreased B and T cell clonal expansion

Question 8

Define Trough Level

Answer 8

The lowest concentration reached by a drug before next dose is administered
- variable between patients

NOTE: Trough level used to measure small molecule drugs

Question 9

Protein-based/ biological drugs Examples

Answer 9

1. Depleting antibodies
2. Non-depleting antibodies

Question 10

Depleting Antibodies examples

Answer 10

1. rabbit polyclonal antibodies-thymocyte globulin
   — deplete T or NK cells that express marker
   — induction therapy
2. Alemtuzumab (Campath)
   — monoclonal antibodies to CD52 on LYMPHOCYTES
   — Induction therapy
3. Rituximab
   — monoclonal antibodies to CD20 on B cells NOT PLASMA CELLS
   - Desensitization/ rescue therapy

NOTE: protein-based/ biological drugs

Question 11

WIP Non-Depleting Antibodies examples

Answer 11

1. Basiliximab
   — antibody to CD25 = decreased T cell activation
   — induction therapy
2. CTLA-4 Immunoglobulin
   — Fc fragment of a human IgG1 Ig linked to extracellular domain of CTLA-4 = blocks signal 2 = improper T cell activation
   — maintenance therapy

Question 12

Pros vs Cons: Protein-based/ biological drugs

Answer 12

Pros:
- High specificity, particularly monoclonal abs and fusion proteins
- Low toxicity, at least from the agent itself
- Long half-life in circulation – same as IgG molecules (~3 weeks)

Cons:
- Some interfere with antibody detection assays and/or flow cytometry XM
- Cost $$$$

Question 13

Antibody Removal methods

Answer 13

1. Plasmapheresis
   - filters the blood and removes harmful antibodies
2. IVIg
   - pooled IgG from plasma of >1000 donors
   - contains HLA antibodies
   = inhibit Ab production, complement, immune cell activation

NOTE: IVIg often administered together so body doesn’t overproduce antibodies which are being removed from plasmapheresis

Question 14

Novel Drug examples

Answer 14

1. Protease Inhibitor (Bortezomib)
   — small molecule
   — over-production of of misfolded plasma proteins = apoptosis of active plasma cells
   — rescue therapy
2. Humanized monoclonal anti-C5 (Eculizumab)
   — neutralizes C5 in classical and alternative pathway = prevents complement activation
   — rescue therapy

Question 15

Interference of IVIG on HLA testing

Answer 15

Pooled IVIg contains HLA antibodies from female donors
— after IVIg, patient must wait 3 months before HLA testing

Question 16

Define Transplantation Tolerance

Answer 16

Absence of a destructive immune response to an
allograft in an otherwise competent immune system
(Ie. no immunosuppression)

Question 17

Differentiate Central vs Peripheral Tolerance

Answer 17

1. Central Tolerance
   — established while lymphocytes are developing in Thymus (elimination of T cells that have high affinity for self-peptide: MHC) and Bone Marrow (elimination of B cells with high affinity for self molecules)
2. Peripheral Tolerance
   — acquired by mature lymphocytes in the peripheral tissues

Question 18

Challenges for Transplantation Tolerance

Answer 18

• ‘Default setting’ of the immune system is to eliminate everything that is foreign
• There are many different graft antigens
• The alloimmune response involve different cells/pathways/mechanisms
• Other infections and diseases

Question 19

T or F: Mouse tolerance translates similarity to humans

Answer 19

FALSE; Evidence of tolerance in mouse models MAY NOT translate similarity to human tolerance

Question 20

Define Chimerism

Answer 20

Both donor and recipient hematopoietic stem cells co-exist in the recipient’s bone marrow