Transplantation

Question 1

Define Autologous graft

Answer 1

A graft transplanted from an individual to the same individual.

Ex; bone marrow or blood harvested and saved for future use

Question 2

define Syngeneic grafts

Answer 2

or syngraft is a transplant between two genetically identical individuals (i.e identical twins)

Question 3

Define allogeneic graft

Answer 3

transplanted between two genetically dissimilar individuals of the same species

Most common form of transplant

Question 4

Define Xenogeneic graft

Answer 4

Aka xenograft is a transplant between members of two different species. (pigs etc.)

Question 5

Define Orthotopic transplant

Answer 5

graft placed in its normal anatomic location

Question 6

Define Heterotopic transplant

Answer 6

Placed in an anatomically different sites.

Question 7

Describe the mechanisms of privileged sites

Answer 7

• -> extracellular fluid bathes these tissues and doesn’t leave through conventional lymphatics
• -> TGF-beta is produced at these sites (inhibitory cytokine)
• -> Fas ligand –> reacts with Fas on lymphocytes to induce apoptosis

Question 8

Describe incidences when privileged sites are disrupted

Answer 8

antigens at these sites can be targeted:

• • Sympathetic ophthalmia –> one eye is damaged by trauma and autoimmune response to eye proteins threatens the undamaged eye
• —– Immunosuppressive therapy required to prevent destruction of undamaged eye. removal of damaged eye may be required

Question 9

What are the three laws that govern transplantation

Answer 9

1) Transplants between identical twins are never rejected
2) transplants between genetically dissimilar individuals are almost always rejected (without immunosuppression)
3) grafts derived from children will be rejected by either parent. Children would express antigens that either parent sees as foreign.

Question 10

What are antigens perceived as foreign

Answer 10

Class I and class II MHC proteins are perceived as foreign because:

• Expression = polymorphic –> all express particular set of “self” MHC
• Education of thymocytes –> other MHC proteins perceived as foreign
• Probability that two random individuals express same MHC proteins is extremely small

Question 11

Describe Hyperacute Rejection*

Answer 11

Takes place within minutes of attaching the graft to the recipient’s blood supply

• -> mediated by pre-existing antibodies
• -> E.G Anti-ABO blood group antibodies (give you the wrong blood)
• -> Essentially untreatable, but uncommon

Question 12

Describe Acute Rejection

Answer 12

Takes place within 1 month of transplantation

Two basic types:

• • Acute humoral rejection: Antibody and complement-medaited lysis of graft tissue –> Necrosis of the blood vessel walls
• • Acute cellular rejection: cell-mediated lysis of grafts tissue by CTL’s NK cells and or macrophages

**Treated with increased immunosuppression, e.g. high does of steroid therapy or anti-T cell antibodies

Question 13

Describe Chronic Rejection

Answer 13

May occurs months or years after transplantation

• -> mechanism unknown: May involved antibody-mediated injury (DTH rxn)
• -> fibrosis and deposition of collagen are characteristic with accelerated arteriosclerosis resulting in vascular occlusion
• -> unresponsive to increased immunosuppression.

Question 14

Define Alloreactivity (direct alloantigen recognition)

Answer 14

Recognition of foreign MHC proteins by the TCR due to polymorphic amino acids of foreign MHC proteins mimicking conformation of BOTH self MHC and foreign peptide

• -> same TCR can recognize self MHC + foreign peptide conformations as well as foreign MHC proteins
• -> 20% of T cells can be alloreactive toward a set of foreign MHC proteins, therefore alloreactivity is felt to be the most important mechanism for T-helper cell activation

Question 15

Define Indirect alloantigen presentation

Answer 15

Recipient APC's could present foreign MHC peptides in conjunction with self class II MHC proteins to activate T-helper cells:
--> Does occur, but cannot be primary mechanism for T-helper cell activation, since CTL's could not lyse the foreign MHC class I-bearing graft cells (since they could NOT recognize non-self class I MHC)

Question 16

Define the mechanism of Allorecognition

Answer 16

1) The self MHC - restricted T cell recognizes a structure formed by both the allgogeneic MHC molecule and the bound peptide
2) The self MHC - restricted T cell recognizes the allogeneic MHC molecule whose structure resembles a self MHC –> foreign peptide complex

Question 17

Define the steps of activation of alloreactivity

Answer 17

Step 1: Direct (using donor dendritic cells) and indirect (using recipient dendritic cells) presentation of alloantigens stimulate CD4+ alloreactive T cells (from the recipient to become activated
Step 2: Alloreactive CD4+ T helper cells provide IL-2 and IFN-gamma to alloreactive CD8+ T cells to produce CTL’s that can lyse graft cells, alloreactive B cells to produce anti-graft antibodies

Question 18

Describe strategies of preventing Rejection

Answer 18

1) Reduce graft immunogenicity by selecting most compatible graft:
2) Immunosupression is used to ward of graft rejection
- -> corticosteroids - lyse immature thymocytes, block release of cytokine and inhibit leukocyte migration
- -> cyclosporine = drug of choice for immunosuppression (more effective against primary immune response)
3) depletion of passenger leukocytes from graft can eliminate or delay graft rejection

Question 19

Describe Graft Vs Host disease

Answer 19

Differentiates bone marrow transplantation from all other types:

• -> Acute GVHD - quickly following bone marrow transplantation and involved epithelial cell necrosis of the skin liver and GI tract (fatal in severe cases)
• -> Chronic GVHD - Fibrosis in organs causing dysfunction. Fatal if severely affects critical organs

Question 20

How do you prevent Graft vs Host disease

Answer 20

Anti-CD3 monoclonal antibodies (with complement) –> leads to a decrease incidence of GVHD, but reduces chance of engraftment

–> Graft-versus-leukemia effect = helps prevent recurrence of cancer because the GVHD reaction removes minimal residual disease

Question 21

Describe Fetal Immunology

Answer 21

Maternal-fetal interaction mimics alloreactivity and graft rejection, i.e. fetus is a naturally occuring allografts

Question 22

Describe the mechanism of fetal immunology

Answer 22

1) Trophoblast cells don’t express paternal MHC proteins. in addition, HLA-G (MHC class I-like protein) keeps NK cells from becoming activated by the trophoblast cells that express no MHC proteins
2) Trophoblast cells may secrete INHIBITORY cytokines such as TGF-Beta
3) Tryptophan is broken down at the fetal-maternal interface by the enzyme indolamine 2,3-dioxygenase. Tryptophan-starved T lymphocytes react poorly to antigen