Transplants and Immunoactive drugs

Question 1

hyperacute transplant rejection

Answer 1

occurs within minutes when recipient has pre-existing antibodies to donor tissue. type II rxn that activates compliment. leads to widespread thrombosis of graft vessels that causes ischemia and necrosis. graft must be removed.

Question 2

acute transplant rejection

Answer 2

occurs weeks to months of transplant.
recipient develops immunity to donor tissue. may be cell mediated or humoral. cell mediated would be due to cytotoxic T cells activated against donor MHCs. causes vasculitis of graft vessels with dense interstitial lymphocytic infiltrate.
We can suppress/prevent this with immunosuppressants.

Question 3

chronic transplant rejection: mechanism

Answer 3

complicated. irreversible.
basically, recipient T cells start to recognize donor MHC complexes as if they were their own. However, donor tissue makes different proteins, so the recipient T cells interpret this as viral infection (recipient T cells start to recognize donor antigens). Recipient T cells attack donor tissue. there are both cellular and humoral components.

Question 4

What do we see in the heart with chronic transplant rejection? What about the lungs?

Answer 4

heart: atherosclerosis
lungs: bchonchiolitis obliterans (destruction of the bronchioles)

Question 5

What is seen in chronic transplant rejection of the liver? Of the kidneys?

Answer 5

liver: vanishing bile ducts
kidney: vascular fibrosis, glomerulopathy

Question 6

What is graft vs. host disease?

Answer 6

grafted immunocompetent T cells proliferate in the immunocompromised host and start destroying recipient tissue. can cause severe organ dysfunction and may manifest as maculopapular rash, jaundice, diarrhea, or hepatosplenomegaly. Or, can be good in bone marrow transplant for leukemia (graft-vs,tumor effect)

Question 7

What is the MoA of cyclosporine?

Answer 7

calcineurin inhibitor that binds cyclophilin. cyclosporin blocks T cell activation by preventing IL-2 transcription

Question 8

What is the use and toxicities of cyclosporine?

Answer 8

used in transplant rejection, psoriasis, and RA
Main toxicity is NEPHROTOXICITY
(can also cause HTN, hyperlipidemia, hyperglcemia, tremor, gingeval hyperplasia, hirusitism)

Question 9

What is tacrolimus?

Answer 9

calcineurin inhibitor that binds FKBP. this also blocks T cell activation by prevening IL-2 transcription

Question 10

What is the use and toxicity of tacrolimus?

Answer 10

NEPHROTOXICITY. Incr. risk of DM and neurotoxicity compared to cyclosporine (less gingival hyperplasia or hirsutism).
used for transplant rejection prophylaxis.

Question 11

What is the sirolimus/rapamycin?

Answer 11

mTOR inhibitor that binds FKBP.

this blocks T cell activation and B cell differentiation by preventing IL-2 signal transduction.

Question 12

What are the uses toxicities of sirolimus?

Answer 12

used for kidney transplant rejection prophylaxis and drug eluting stents
it is non-nephrotoxic
(may cause anemia, thrombocytopenia, leukopenia, insulin resistance, hyperlipidemia)

Question 13

What is azathioprine?

Answer 13

antimetabolite precursor of 6-mercaptopurine. inhibits lymphocyte prolif by blocking nucleotide synthesis.

Question 14

Uses and toxicities of azathiopurine?

Answer 14

used for transplant rejection, RA, Crohn, glomerulonephritis, others
toxicity increased by allopurinols. they include the ‘penias:’ leukopenia, anemai, thrombocytopenia

Question 15

What is Basiliximab?

Answer 15

monoclonal ab agains IL-2 receptor. used for kidney transplant rejection prophylaxis. may see edema, HTN.

Question 16

How do glucocorticoids work?

Answer 16

inhibit NF-kB. suppress B and T cell function by decreasing the transcription of many cytokines.

Question 17

Target and use of bevacizumab?

Answer 17

anti-VEGF used for colorectal and renal cell carcinoma

Question 18

Target and use of cetuximab?

Answer 18

target: EGFR. for stage IV colorectal CA, head and neck CA

Question 19

Target and use of rituximab?

Answer 19

CD20. for B cell non-hodgkin lymphoma, RA ( with methotrexate), ITP

Question 20

target and use of trastuzumab?

Answer 20

HER2/neu. used for breast CA, gastric cancer

Question 21

Target and use if infliximab

Answer 21

TNF-alpha

used for IBD, RA, ankylosing spondylitis, psoriasis (PAIR)

Question 22

Target and use of abciximab

Answer 22

target: glcyoprotein IIB/IIIa. used as an anti-platelet agent for prevention of ischemic complications in pts undergoing percutaneous coronary intervention.