Transplantation Objectives

Question 1

Autograft –>

Answer 1

grafts from self (i.e skin graft)

Question 2

Isograft/homograft –>

Answer 2

grafts between identical twins

Question 3

Allograft –>

Answer 3

Transplant between members of the same species

Question 4

Xenograft –>

Answer 4

grafts across species

Question 5

What is graft rejection?

Answer 5

because a graft is foreign, the host’s immune system will attempt to eliminate this intruder.

hyperacute (delayed hyperacute), acute, chronic based on the time over which the rejection process develops and the treatment options available

Question 6

Explain hyperacute graft rejection

Answer 6

Preformed antibodies (patient immunized) against antigens on the donor tissue 
Results in complement activation, endothelial damage and inflammation and thrombosis

tx: graft removal

Question 7

Explain a hyperacute graft rejection when a xenograft is used

Answer 7

existence of natural antibodies in man to carbs presented on the transplanted pig organs

Question 8

Explain Acute graft rejection

Answer 8

Most common type of allograft rejection occurring in the early period post transplantation (weeks)

recognition by, and activation of, naive T cells on parenchymal and endothelial cells.

causing immune cell infiltration and/or inflammation.

tx: immunosuppressive therapy

Question 9

Explain chronic graft rejection

Answer 9

rejection occurring weeks, months, or years after transplantation

release of non specific growth factor like mediators (fibroblast or endothelial growth factor) which causes hyperproliferation of connective tissue and mesenchymal cells

tx: immunosuppressive therapy

Question 10

Many immune cells are activated in graft rejection. Despite this, therapies aimed at acceptance of a graft are primarily based on inhibition of CD4+ Th1 cells. Why?

Answer 10

During a graft rejection chemokines and cytokines are secreted by the graft (Donor) cells and enter circulation.

These cytokines either alter vascular permeability or express adhesion molecules/activate them to high affinity on circulating leukocytes.

This leads to extravasation of T cells, monocytes and neutrophils into the graft where Class II MHC alloreactive CD4+ T cells are activatived and differentiate primarily to Th1 cells.

Question 11

what is Graft versus host disease (GVHD)

Answer 11

Donor CD4+ and CD8+ T cell activation via Class I and Class II MHC presentation by recipient cells

Immunosuppressed recipient cannot initiate counterattack –> Donor T cells initiate rejection in host tissue

Common with bone marrow, intestinal and liver transplant

Question 12

what are some symptoms/presentation with GVHD?

Answer 12

Chronic inflammatory attacks on various tissues results in altered permeability, cell and fluid migration

Skin sloughing, diarrhea, inflammation of lungs, kidneys and liver.

Question 13

What are some treatment options for patients with GVHD?

Answer 13

Removal of all donor T cells and infusion of IL-3 and GM-CSF before transplant, immunosuppression

Question 14

Explain the defect in G vs. L ( graft versus leukemia effect)

Answer 14

Same T cell reaction as GVHD except specifically directed at recipient leukemia cells

Occurs with bone marrow transplant in leukemia patients

Graft vs. Minor Histocompatibility

Question 15

Are there any treatments for G vs. L?

Answer 15

nope

Question 16

What is the problem with intestinal transplants (GVHD)(Crohn’s disease rx)

Answer 16

CMV virus infection common in acute rejection –> since immunosuppressed= serum Ig levels normal but T cell activity reduced
symptoms are weeping rash, cramps, and fever

Question 17

Corneal transplants, prognosis

Answer 17

Patients survive without immunosuppressive drugs, because the foreign antigens expressed by the graft are not seen by host cells

Question 18

Heart transplants, prognosis

Answer 18

88% of patients survive at least a year post transplant.

problem? high incidence of atherosclerotic disease in recipients occurring in years following transplant

Question 19

Liver transplant, prognosis

Answer 19

resistant to rejection once any early acute rejection episodes pass, and long term graft survival is similar
80% of patients survive at least a year

Question 20

Kidney transplant, prognosis

Answer 20

90% after one year.

required to take immunosuppressive drugs for the rest of their lives

Question 21

pancreas transplant, prognosis

Answer 21

patients survive optimally if given into the portal vein

Question 22

Bone transplant, prognosis

Answer 22

provide an inert scaffold for patients to bridge the time to replace allogenic tissue with host bone matrix.

Question 23

What are three potential problems of immunosuppression for transplant patients?

Answer 23

1) increased risk for infection
2) increased risk for malignancy
3) cardiovascular risks may also be increases with some of the immunosuppression drugs

Question 24

In the absence of immunosuppression what happens?

Answer 24

transplanted tissue will be rejected by the host

Question 25

what is the mechanism of action for Cyclosporin A and FK506?

Answer 25

block the transcription and production of IL-2 by CD4+ Th1 cells. They bind calcineurin in the cytoplasm, and interfere with delivery of the IL-2 gene activating stimulus to the nucleus.

Question 26

what is the mechanism of action for Anti-CD3 antibodies?

Answer 26

Depletes T cells by binding to CD3 and promoting phagocytosis or complement-mediated lysis (used to treat acute rejection)

Question 27

what is the mechanism of action of the Anti-CD40L?

Answer 27

inhibits macrophage and endothelial activation by blocking T cell CD40 ligand binding to CD40

Question 28

what is the mechanism of action of the CTLA-4-lg?

Answer 28

Inhibits T cell activation by blocking B7 costimulator binding to T cell CD28

Question 29

what is the mechanism of action of the Anti IL-2 receptor (CD25) antibody?

Answer 29

Inhibits T cell proliferation by blocking IL2 binding and depletes activated T cells that express CD25
No IL-2 –> no cell proliferation
No pCTL—> CTL reaction –> no clonal expansion

Question 30

optimal survival of organs in a transplant depends on what?

Answer 30

minimizing immune recognition of the graft by minimizing the genetic disparity (MHC) between donor and recipient..
Total Histocompatibility matching is the ideal scenario for clinical transplantation

Question 31

Genetic differences where contribute to immunological rejection of a graft.

Answer 31

genetic differences at any HLA locus

thus the fewer the number of mismatched loci the greater the likelihood that the graft will be accepted.