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Review
. 1992;12(4):303-13.
doi: 10.3109/08916939209148473.

FK 506 and autoimmune disease: perspective and prospects

A W Thomson  1 , T E Starzl
Affiliations
Review

FK 506 and autoimmune disease: perspective and prospects

A W Thomson et al. Autoimmunity. 1992.
No abstract available

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Figures

Figure 1
Figure 1
Structures of the immunosuppressive macrolides FK 506 and Rapamycin showing the FKBP binding domain and the effector element of each molecule.
Figure 2
Figure 2
Within the T lymphocyte, FK 506-FKBP or CsA-cyclophilin complexes bind with high affinity to calcineurin-calmodulin to form a pentameric complex which interferes with Ca++-dependent signalling pathways. Complexes of RAPA-FKBP do not bind to calcineurin. Recent observations indicate that calcineurin (a protein phosphatase) is the target of the FK 506-FKBP and CsA-cyclophilin complexes. CaM=calmodulin; CNA=calcineurin A; CNB=calcineurin B; CYP=cyclophilin; FKBP=FK 506 binding protein.
Figure 3
Figure 3
Influence of FK 506 on signal transduction within T cells. The crucial event in T-cell activation stimulated by antigen plus IL-1 would appear to be activation of the phospholipase which splits phosphatidyl inositol diphosphate into the reactive products diacylglycerol and inositol triphosphate. The increased intracellular calcium concentration activates a number of different enzyme systems which lead to new synthesis of RNA, protein and IL-2. FK 506 blocks translocation of the pre-existing cytoplasmic component (B) of the nuclear protein NF-AT at the nucleus by acting either on a Ca++ signalling pathway or on translocation following the action of this pathway (arrows). Both components of NF-AT are required for DNA binding and activation of the IL-2 gene. TCR=T cell receptor; DAG=diacylglycerol; PLC=phospholipase C, PKC=protein kinase C; A=induced nuclear component of NF-AT; B=existing cytoplasmic component of NF-AT.
Figure 4
Figure 4
Differential effects of the immunosuppressive macrolides FK 506 and RAPA on T-cell activation and proliferation. FK 506 (and CsA) inhibit pre-transcriptional events in CD4+ T cell activation, resulting in suppression of production of IL-2 and other cytokines. In contrast, RAPA does not impair IL-2 production, IL-2R expression or ligand binding to IL-2R but blocks the response of T-cells to IL-2 and other cytokines (IL-4, IL-6). TCR=T cell receptor; LKR=lymphokine receptor.
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References

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