Strategies for manipulating T-helper cell lymphokine secretions to prompt immunosuppression

Lymphokines produced by T-helper 1 (Th1) and Th2 cells are mutually inhibitory and/or self stimulatory and this may be exploited to inactivate or downregulate the subset of choice in order to achieve controlled and specific immunosuppression. Attempts to specifically activate normal human Th precursor cells into the Th2 subset are reported. Cholera toxin and forskolin increased intracellular cyclic AMP levels, but this had no discriminatory effect on Th1 and Th2 secretions. Primary activation with calcium ionophores, alone or in combination with phorbol esters, high concentrations of anti-CD3 monoclonal antibody and selective inhibition IL-2 synthesis with cyclosporin A or FK506 were unable to skew lymphokine production, away from vigorous IL-2 synthesis, to IL-4 predominance. However, it was possible to selectively activate the Th2 component in unprimed, normal human T-lympocytes by primary stimulation in mixed lymphocyte culture in the presence of IL-2 and high concentrations of IL-4, followed by restimulation. Ex vivo activation of these cells may have clinical significance in situations where suppression of Th1-like responses or IFN-( synthesis is desirable for example, in autoimmunity and transplant rejection.