MECHANISMS OF TACROLIMUS (FK-506) TRANSPLANTATION Xing Yu Liu (Linda Liu): Karllan Chen (Karen Chen): Rehma Amir: Josephine Ho: Sept 30, 2015 PHM142 Fall.

M E C H A N I S M S O F TAC R O L I M U S ( F K- 5 0 6 )

TRANSPLANTATION

Xing Yu Liu (Linda Liu): Karllan Chen (Karen Chen):Rehma Amir: Josephine Ho: Sept 30, 2015

PHM142 Fall 2015 Instructor: Dr. Jeffrey Henderson

WHAT IS TRANSPLANTATION?

• Transplantation is the act of transferring organs, tissues, or cells from one donor site to another on the same body or from one body (living, brain dead, or dead via circulatory death) to another• Autotransplantation vs. allotransplantation

• Transplantation can be done with organs, tissues, or cells• Organs: heart, kidney, liver, lung, pancreas, intestine, thymus

• The most commonly transplanted organ: kidney

• Tissues: bones, tendons, cornea, skin, heart valves, nerves, veins• The number of cornea transplants is 20x the number of kidney

transplants

THE BARRIER TO TRANSPLANTATION

• Matching process: undergo blood tests to determine your blood type (A, B, AB, or O) and your human leukocyte antigen (HLA) (on the surface of your WBC)…• 6 antigens - the more antigens you have that match

those of the donor, the greater the chance of a successful transplant

• …there is still a possibility that the immune system will reject the organ as a disease-causing microbe

• The most formidable barrier to transplantation as a routine medical treatment is our immune system

IMMUNOBIOLOGY OF REJECTION

• The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens (MHC) • Human leukocyte antigens (HLA)

IMMUNOBIOLOGY OF REJECTION

• T cells are activated by MHC molecules which signals that a foreign substance is present

• T cells then produce cytokines that travels through a signal transduction pathway that ultimately facilitate immune responses that causes rejection of a transplant

WHAT IS THE SOLUTION?

•TACROLIMUS (FK-506 or

fujimycin)

• C44H60NO12

• Macrolide lactone• Immunosuppressive drug (reduce activity of immune system)

NORMAL T-CELL PATHWAY

TACROLIMUS ACTION ON T-CELL PATHWAY

TACROLIMUS ACTION ON T-CELL PATHWAY

TACROLIMUS ACTION ON T-CELL PATHWAY

TACROLIMUS MECHANISM ON ACTION OF MAPK PATHWAY

CYCLOSPORINE ACTION ON T-CELL ACTIVATION

TACROLIMUS VS. CYCLOSPORINE

Cyclosporine• Available since 1980s• Cyclosporine less effective immunosuppresant but

lower rates of diabetes in post-transplantation patient

Tacrolimus• Introduced in the 1990s• Tacrolimus users have higher rates of developing

diabetes after organ transplant• Requires lower dosages of steroid after treatment –

beneficial to younger patients

TACROLIMUS AVAILABILITY

• Brand Name: Prograf• Made by Astellas• IV Injection: 5mg/mL (dil. To 0.004mg/mL to 0.2mg/mL in

0.9% NaCl before use)• Oral capsules: 0.5mg, 1mg, 5mg – taken twice daily• Dose to be taken depends on type of transplantation

Images: http://www.astellas.com/hk/en/base/img/Prograf-box-0.5mg-w-drug450.gifhttp://www.astellas.com/hk/en/base/img/Prograf-box-1mg-w-drug450.gifhttp://www.astellas.com/hk/en/base/img/Prograf-box-5mg-w-drug450.gif

TACROLIMUS…TOPICAL OINTMENT?

• Also used to treat atopic dermatitis (atopic eczema)

• Brand Name: Protopic (0.03% and 0.1% ointment)• Used in non-immunocompromised patients

Images: http://www.drugs.com/pro/protopic.html

TACROLIMUS – CLOSER LOOK

MACROLIDE LACTONE

A

B

C

SUMMARY

• Transplantation is the act of transferring organs, tissues, or cells from one donor site to another on the same body or from one body (living, brain dead, or dead via circulatory death) to another

• The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens (MHC) • Human leukocyte antigens (HLA)

• Tacrolimus (C44H69NO12) is a 23 membered macrolide lactone

• Immunosuppressant- reduce the activity of patient’s immune system

• Administered by IV initially, then orally (Prograf), dosage depends on type of transplant and monitoring patient response

• Tacrolimus acts on host T cells and ultimately inhibits transcription of lymphokine genes (ex. IL-2) via 2 pathways (ie. T-cell pathway and the MAPK pathway)

• Tacrolimus is a more effective drug than cyclosporine and requires lower doses of steroid post-treatment therefore more beneficial for younger patients

SUMMARY: TACROLIMUS T-CELL PATHWAY

REFERENCES

• Contie, V. (2011, March 9). NIH News in Health. Retrieved September 21, 2015.• Kundert, D. (2010, November 3). Organ Transplants: What You Need to Know (W. Steffan, Ed.).

Retrieved September 21, 2015.• Lehman, A. (2005, March 15). Organ Rejection Cartoons and Comics. Retrieved September 21,

2015, from https://www.cartoonstock.com/directory/o/organ_rejection.asp • Reed, C. (2013, February 2). Immunology of Transplant Rejection. Retrieved September 21, 2015.• PATIENT INFORMATION. (2012, August 3). Retrieved September 21, 2015, from

http://tajpharma.com/tacrolimus-metabolism-pharmacological-index.htm• Stepkowski, S. (2000, June 21). Mechanism of action of cyclosporine or tacrolimus (FK506).

Retrieved September 22, 2015, from http://journals.cambridge.org/fulltext_content/ERM/ERM2_04/S1462399400001769sup004.htm

• Martins, L. (2004, May 1). Cyclosporine versus tacrolimus in kidney transplantation: Are there differences in nephrotoxicity? Retrieved September 20, 2015, from http://www.ncbi.nlm.nih.gov/pubmed/15194300