Depletion of the Mature Cd4+8- Thymocyte Subset by Fk506 Analogs Correlates With Their Immunosuppressive and Calcineurin Inhibitory Activities

Abstract

FK506 blocks T cell activation by preventing the transcription of lymphokine genes through binding to the intracellular protein FKBP12 and formation of complex that inhibits the phosphatase activity of calcineurin. Beside exerting potent suppressive activity on cellular and humoral immune responses, in vivo treatment with FK506 in rodent models induces thymic alterations characterized by a selective reduction of mature CD4+8- cells. The potential relationship between such thymic alterations and the immunosuppressive and calcineurin inhibitory activities of FK506 has not been defined. Here, we took advantage of the availability of FK506 analogs with different immunosuppressive potencies to address this question. Intravenous daily administration of FK506 in Sprague-Dawley rats for 4 days was found to be sufficient to cause a depletion of CD4+8- thymocytes with an ED50=0.06 mg/kg/day. Under the same conditions, L-683,590 which is 2-3-fold less potent than FK506 in inhibiting T cell activation and calcineurin function gave an ED50=0.17 mg/kg/day. In contrast, the nonimmunosuppressive, calcineurin noninhibitory antagonist L-685,818, failed to deplete the CD4+8- thymocyte subset but could reverse the reducing effect of FK506 on this subset. Another analog, L-688,617, which does not completely inhibit T cell activation in vitro, also behaved as a partial agonist of CD4+8- cell depletion. Therefore, the ability of FK506 analogs to deplete the CD4+8- thymocytes subset correlates with their immunosuppressive and calcineurin inhibitory potencies. This suggests that calcineurin is involved in the intra-thymic maturation processes of CD4+8- T cells. Moreover, the short-term treatment protocol described here provides a rapid and quantitative assay to determine the immunosuppressive potency of FK506-like compounds in vivo

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

“…1 and Table I). Suppression of the Tc response and decreases in the number of CD4 ϩ CD8 Ϫ T cells in the thymus and spleen are hallmarks of CyA (43,44), and these were among the most prominent effects in the present study (Table II). Enhancement of macrophage nitrite production by DEX may seem surprising in view of reported suppression in vitro (45), but we noted that the persistence of this suppression was dependent on the concentration of DEX to which the macrophages had been exposed and on the time after exposure at which the macrophages were stimulated (28).…”

The Regulated Expression of a Diverse Set of Genes during Thymocyte Positive Selection In Vivo

“…Small molecule inhibitors of calcineurin were shown to block positive selection in organ cultures and in vivo (9,10). In addition, mice deficient for calcineurin B (11) or NFAT4 (12) are defective in this process.…”

Electrotransfer of naked DNA in the skeletal muscles of animal models of muscular dystrophies

“…This agent is a blocker of interleukin-mediated T cell activation and inhibits cellular-and humoral-specific immune responses directed against neo-antigens. [54][55][56][57][58] FK506 has been used previously to prevent the rejection of transgene products brought in recipient animals by cellular or viral vectors. [37][38][39][40][41][42][43][44] Our present results indicate that the specific immune reactions are blocked by the permanent or discontinuous administration of the FK506 immunosuppressant.…”