Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology
Transplant rejection - reaction types
- Hyperacute rejection is due to deposition of neutrophils, endothelial damage, and thrombosis. It is mediated by preformed ABO natural antibodies, HLA antibodies, and complement. It occurs within minutes to hours within the first day of transplantation.
- Accelerated rejection is due to vascular disruption and hemorrhage. It is mediated by non-complement fixing antibodies, NK cells, and monocytes. It occurs over the course of 3-5 days after transplantation.
- Acute rejection is due to tubulitis (in kidney transplants), interstitial inflammation, parenchymal
cell damage, and endovasculitis. It is mediated by T cells and antibodies.
- Chronic rejection is due to intimal proliferation and vessel occlusion. It is mediated by antibodies. It takes place over months to years.
High risk groups for hyperacute and accelerated rejection:
- multiparous women
- recipients of multiple blood transfusions
Stimulation of CD4+ T cells through antigen receptor is not sufficient to initiate activation. Activation of CD4+ T lymphocytes needs co-stimulation via the APC.
T cell vs. ligand combinations for activation of CD4+ T cells
CD40L -- CD40
CD28 -- CD80 or CD86
Cyclosporine and tacrolimus interfere with activating process involving T cell receptors and costimulatory molecules CD28 and CD80 or CD86. Together with tacrolimus, cyclosporine is a calcineurin inhibitor (CNI).
Cyclosporine binds to the cytosolic protein cyclophilin (an immunophilin) of lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which normally induces the transcription of interleukin-2.
Ciclosporin (INN), cyclosporine (USAN) or cyclosporin (former BAN). Image source: Wikipedia, public domain.
Cyclosporine and FK-506 block T cell cytokine production by inhibiting activation of the NFAT transcription factor (note: different from NFkB).
Tacrolimus (FK-506 or Fujimycin, trade name Prograf) is a product of the fungus Streptomyces tsukubaensis. It is a macrolide lactone and acts by inhibiting calcineurin.
Tacrolimus. Image source: Wikipedia, public domain.
It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than cyclosporine and has less pronounced side-effects.
What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?
Acute rejection typically occurs after:
A. minutes to hours
B. 3 months
C. one week
D. after long-term follow-up
Desensitization protocols may overcome incompatibility barriers in renal transplantation, NEJM, 2011.