Effects of cyclosporin A, FK 506, and mycalamide A on the activation of murine CD4⁺ T cells by the murine B7 antigen

Abstract

The murine B7 (mB7) protein is a potent co-stimulatory molecule for the activation of murine CD4+ T cells. We have previously shown that stable mB7-transfected Chinese hamster ovary (CHO) cells synergize with either anti-CD3 monoclonal antibodies (mAb) or concanavalin A to stimulate T cell activation. In addition, mB7 can synergize with phorbol 12-myristate 13-acetate (PMA) to induce T cell activation in an alternative pathway. In the present report we describe the effects of three immunosuppressive drugs, cyclosporin A (CsA), FK 506, and mycalamide A on mB7-mediated T cell activation. The immunophilin ligands CsA and FK 506 block activation of murine CD4+ T cells by the combination of anti-CD3 mAb and CHO-mB7 cells but do not affect activation by CHO-mB7 cells and PMA. These results support the relevance of pharmacological studies of immunosuppressive compounds in the murine model prior to their application in man. In contrast to the effects of CsA and FK 506, mycalamide A blocks activation of murine CD4+ T cells by anti-CD3 mAb and mB7 as well as activation by mB7 and PMA. On a molar basis, mycalamide A appears to be at least 10-fold more potent than FK 506 which is 100-fold more potent than CsA. Because of its effects on multiple activation pathways and because of its potency, mycalamide A could have considerable therapeutic potential.

Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus (SLE) patients

“…As expected [31], this proliferative response was not affected by treatment with CsA. Taken together, our data strongly suggest that the restoration of T cell-associated defects observed in SLE T cells is specifically mediated by the triggering of the CD28 molecule.…”

“…Namely, that CD28-mediated activation of T cells requires PTK activity [28,29] and that it is resistant to CsA [30,31]. Data obtained after exploring PTK activity are shown in Fig.…”

Activation of CD4+ T lymphocytes form interleukin 2-deficient mice by costimulatory B7 molecules.

“…Two members of the B7 family, B7-1 (CD80) (3-5) and B7-2 (CD86) (6)(7)(8), have been cloned, and a third member, B7-3, has been postulated (9). In the case of CD4+ T lymphocytes, transfected cell lines that express B7-1 or B7-2 as well as B7-Ig fusion proteins can synergize with anti-CD3-, lectin-, or antigen-stimulated T-cell activation (6)(7)(8)(10)(11)(12)(13)(14)(15). Engagement of the CD28 receptor by B7 molecules results in the production of cytokines such as interleukin 2 (IL-2) (10) and interleukin 4 (IL-4) (13), in the cell-surface expression of cytokine receptors (15) …”

“…In the case of CD4+ T lymphocytes, transfected cell lines that express B7-1 or B7-2 as well as B7-Ig fusion proteins can synergize with anti-CD3-, lectin-, or antigen-stimulated T-cell activation (6)(7)(8)(10)(11)(12)(13)(14)(15). Engagement of the CD28 receptor by B7 molecules results in the production of cytokines such as interleukin 2 (IL-2) (10) and interleukin 4 (IL-4) (13), in the cell-surface expression of cytokine receptors (15), and in the expression of the bcl-xL survival gene (16). Thus, costimulation with B7 molecules can promote growth of primary T cells by a multitude of mechanisms, although it is still unclear whether B7-1 and B7-2 induce identical or different gene effector programs (17).…”

Studies toward the Asymmetric Synthesis of the Right Part of the Mycalamides

“…The reaction was quenched with H 2 O (20 mL) and extracted with ether (4 × 20 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 The solvent was removed under reduced pressure, and the crude oil was purified by flash column chromatography (EtOAc/hexane, 1:1) to afford the expected diol (0.557 g, 100%) as a colorless oil 6,112.4,98.1,96.5,79.6,76.0,74.2,61.0,56.4,55.7,41.4,24.5,22.5;IR (neat) NMO (352 mg,3.00 mmol) and activated molecular sieves (0.5 g) in CH 2 Cl 2 (10 mL) was added a catalytic amount of TPAP (8.0 mg, 0.023 mmol) in one portion at room temperature. The resulting deep blue solution was stirred at room temperature for 18 h. Upon consumption of the starting material, the reaction mixture was filtered through a pad of silica gel, which was then washed with CH 2 Cl 2 .…”