immunosuppression

Question 1

what is immunosuppression for

Answer 1

• suppresses organ rejection

- used treat autoimmune disease

Question 2

How are T-cells involved in immunosuppression

Answer 2

• makes IL-2 when alloantigen is detected which activates cytotoxic T cells to kill
• release IFNg which activate endothelium to make endothelin which cause vasoconstriction restriction blood flow to organ transplant leads to necrosis
• IFNg leads to production of IL-8 causes inflammation
• IFNg causes smooth cell profile-ration of smooth muscle cells + fibrosis

Question 3

NICE for immunosuppression

Answer 3

early - 2 weeks post transplant use anti CD25(basiliximab) + cyclosporin
OR tacrolimus + azathioprine reduces t-cells

intial therapy
calcineulin inhibitor + antiprofilerative + corticosteroid

maintenence= lower doses of the above

Question 4

How T-cell is activated

Answer 4

has TCR receptor which get to t-cell surface with help of CD3

TCR binds to antigen fragments presented by MHC

TCR has alpha, beta subunits used to make I-TAMs these get phosphorylated by kinases

the kinases are called fyn and lck they phosphorylate residues on CD3 of ITAMs this allows ZAP-70 enzyme to come bind

-which incresases increases IP3 this increases ca2t this activates calneu
rins

-increases DAG which increases PKC that activates MAP pathway which activate NFKB
and activates MAP kinases that activate APi

Question 5

Calcinuerin pathway

Answer 5

MHC interact TRC increase intracell Ca2t

this activates calmoudulin which activates Calcineurin

calcineurin removes phosphate from NF-AT allows NFAT to enter nucleus

NFAT enters with NFKB or API these bind to promoter to allow expression of IL-2 which is key in profileration of T-cell

Question 6

IL-2 pathway

Answer 6

works via mTOR pathway

Question 7

Cyclosporin function
(calciuneurin inhibitor)

Answer 7

binds to immunophillin (cyclophillin) CsA: CyP complex inactivates calcinuerin

prevents T-cell signalling inhibit IL-2 production - prevents T-cell profileration

Question 8

Tacromilus

calcineurin inhibitor

Answer 8

binds immunophllin FKBP complex inhibits calcineurin

Question 9

Azathioprine

anti-profilerative

Answer 9

inhibits DNA and RNA synthesis - inhibits T-cell profileration

drug low selectivity can cause bone marrow suppression

Question 10

Mycophenolate

anti-profilerative

Answer 10

inhibits purine

more selective and efficacy than azathioprine

Question 11

Sirolimus

Answer 11

-binds to FKBP nihints mTOR prevents IL-2 acting after made can be used with cyclosporin

Question 12

Corticosteroids

Answer 12

reduce T-cell and macrophage cytokines including IL-2

reduce MHC antigen expression prevents T-cell activation

Question 13

Managing rejection

Answer 13

use steroid methylprednisolone if fail use anti-lymphoctye linke anti thymocyte

Question 14

What is rabbit ant-thymocyte

Answer 14

made when t-cell from humans put in rabbit these produce anti serum which can be injected in humans to kill t-cells

Question 15

How does betalacept work

Answer 15

it has FC + CTLA4

uses CTLA4 to bind to antigen presenting cell prevents T-cell binding and getting activated by the antigen presenting cell

Question 16

future of immunosuppression

Answer 16

developing immunosuppressants that are very selective

don’t kill all immune system cell only those that respond to transplant cells

Question 17

T-cell receptors

Answer 17

• TCR
• CD28 - used to strengthen intercation with MHC
• CTLA4- inhibitor

over time CD28 can get replaced with CTLA4 if they T-cell not actiavated