Theme 10: Transplants and Immunotherapies

Question 1

What are syngeneic grafts?

Answer 1

Isografts and autografts, usually accepted due to antigenic compatibility

Question 2

What is alloreactivity?

Answer 2

Th and Tc cells recognize non-self molecules from transplants

Question 3

What is the timeline for first-set rejection?

Answer 3

Complete within 2 weeks, where memory against the graft is generated

Question 4

What is the timeline for second-set rejection?

Answer 4

Complete within less than a week

Question 5

What are paired organs?

Answer 5

Organs which we have 2 of (e.g., kidneys), which is available for living donor transplants and allows for more time to properly match MHCs

Question 6

Describe the process of histocompatibility assessment

Answer 6

1) ABO blood group must match (antigenic difference = hyperacute rejection)
2) MHC haplotype and minor histocompatibility locus is assessed (parents or siblings are first choice)
3) Cross-match test where recipient serum is checked for presence of Abs that might attack donor cells

Question 7

What is the minor histocompatibility locus?

Answer 7

Genes coding for receptors on cell surface of donated organs known to give an immunological response

Question 8

What is histocompatibility?

Answer 8

When tissues are sufficiently similar that no rejection reaction takes place (e.g., identical twins)

Question 9

What % MHC identity do you share with a parent?

Answer 9

50%, because you inherit one haplotype from each parent

Question 10

What is the rule of HLA inheritance between siblings?

Answer 10

1) There is a 25% chance of inheriting all of the same HLA as a sibling
2) There is a 25% chance of not inheriting any of the same
3) There is a 50% chance of sharing 1 haplotype with a sibling

Question 11

What is hyperacute rejection?

Answer 11

1) Immediate damage mediated by preformed antibodies that stimulate complement, resulting in complete rejection within 24 hours
2) Occurs before tissue revascularization
3) Antibodies could recognize and bind ABO or HLA and are often due to past blood transfusions/transplants and past infection (cross-reactivity)
4) Can be avoided via blood typing and cross-matching

Question 12

What is acute rejection?

Answer 12

1) Mediated by T cells, APCs, and cytokines after initial sensitization to donor alloantigens, beginning after about a week
2) Can be avoided/delayed using immunosuppressive drugs

Question 13

What are the 2 types of presentation of allogenic MHC?

Answer 13

1) Direct presentation
2) Indirect presentation

Question 14

What is direct allorecognition?

Answer 14

Donor APCs bearing foreign MHC molecules can engage directly with host T cells, independent of antigens associated

Question 15

What is indirect allorecognition?

Answer 15

Recipient APCs take up cellular debris/donor cells and display foreign MHC antigens for T cell recognition

Question 16

What is chronic rejection?

Answer 16

Occurs months or years after resolution of earlier rejection, has unknown inducers and is more resistant to standard immunosuppression

Question 17

When is tolerance to allografts favoured?

Answer 17

1) When tissues lack alloantigens (like cartilage or heart valves)
2) When preventative measures are taken (e.g., grafting first to privileged immune sites)
3) When Tregs are involved

Question 18

Describe the process of grafting cells/tissues to privileged sites

Answer 18

1) Privileged sites = hidden from immune surveillance
2) Tolerance to donor alloantigens is induced biologically prior to transfer of donor tissue to the actual site of interest
3) Called mixed hematopoietic chimerism = recipient and donor hematopoietic cells coexist

Question 19

What is ideal for immunotherapy?

Answer 19

It is ideal to have antigen-specific immunotherapy such that it inhibits reactions to the graft but maintains immune system’s ability to respond to other pathogens

Question 20

What are some general immunosuppressive therapy for transplantation?

Answer 20

1) Total lymphoid irradiation
2) Azathioprine
3) Cyclophosphamide
4) Fungal metabolites

Question 21

What is total lymphoid irradiation?

Answer 21

1) Used to treat GvHD or for bone marrow transplants
2) Recipient thymus, spleen, and lymph nodes irradiated to wipe out recipient immune cells
2) Bone marrow is transplanted into recipient and donor stem cells can engraft to form a new immune system safely

Question 22

What is azathioprine?

Answer 22

Mitotic inhibitor to diminish T and B cell populations and increase the survival of allografts

Question 23

What is cyclophosphamide?

Answer 23

Inserts into DNA helix, used to treat transplant recipients

Question 24

What are fungal metabolites?

Answer 24

Inhibit Th cell proliferation and cytokine expression to reduce activation of other effector populations involved in graft rejection

Question 25

What are some antigen-specific immunosuppressive therapy?

Answer 25

1) mAb to CD3 on T cells
2) mAb to CD25 (IL-2 receptor) to block T cell proliferation
3) mAbs against T cell markers
4) Soluble CTLA-4 fusion proteins (binds B7 to induce anergy)

Question 26

What is used to prevent fetal hemolytic disease?

Answer 26

Rhogam, when the mother is Rh- and the fetus is Rh+

Question 27

What are broad-spectrum therapies for autoimmune disease?

Answer 27

1) Strong anti-inflammatory drugs
2) Organ removal (e.g., thymus)
3) Used to reduce symptoms

Question 28

What are the side effects of anti-inflammatory drugs?

Answer 28

More susceptible to cancer and infection

Question 29

What are therapies that block steps in the inflammatory process?

Answer 29

1) Drugs that block TNF
2) IL-1 receptor antagonist
3) Chemokine/adhesion molecule blockers

Question 30

Describe the antigen-specific immunotherapy used to treat type I diabetes

Answer 30

Nanoparticles are coated with proinsulin (one of the target antigens) and a molecule that can deliver a tolerogenic signal to APCs

Question 31

What was the London Drug Trial Catastrophe?

Answer 31

A CD28 agonist was being developed for treatment of rheumatoid arthritis but ended up activation all T cells

Question 32

What are the 4 categories of anti-cancer therapies?

Answer 32

1) Chemotherapy (arrest proliferation)
2) Hormonal therapies (interfere with tumor growth)
3) Targeted therapies
4) Immunotherapies

Question 33

What are some immunotherapies for cancer?

Answer 33

1) Immunotoxins (Ab conjugated to toxic molecules)
2) Vaccines
3) Tumor-specific T cell induction
4) CAR-T
5) Manipulation of costimulatory signals (e.g., blocking inhibitory costimulators)

Question 34

How is immunodeficiency treated?

Answer 34

Mostly with antibacterials, antivirals, and replacement therapies

Question 35

What are some replacement therapies for immunodeficiency?

Answer 35

1) mAb or cytokines treatment
2) Hematopoietic stem cell transplantation (bone marrow transplants)
3) Gene therapy