Differential inhibition of primary versus preactivated T cells by pimecrolimus but not by tacrolimus in vitro.
BACKGROUND
Recent studies in murine models of allergic contact dermatitis have shown that systemic treatment with pimecrolimus in contrast to tacrolimus did not inhibit the sensitization phase, whereas both compounds equivalently suppressed the inflammatory response in sensitized animals. This finding indicated a differential sensitivity of antigen-naïve and primed T cells towards pimecrolimus and tacrolimus.


METHODS
T cells obtained from healthy and allergic donors were subjected to primary and secondary stimulation by allogeneic or staphylococcal superantigen-presenting dendritic cells (DC). Human skin-derived, allergen-specific T cell clones from an atopic dermatitis patient were activated by anti-CD3 antibodies or by specific allergen-presenting DC. The inhibition of T cell proliferation and cytokine release by graded doses of calcineurin inhibitors was evaluated.


RESULTS
Primary stimulation of T cells was inhibited by pimecrolimus with an approximately 8-fold lower potency as compared with tacrolimus. In contrast, the secondary response of ex vivo expanded T cells activated by allogeneic or staphylococcal superantigen-presenting DC was inhibited by both compounds with equivalent potency. Likewise, both drugs showed very similar potency to inhibit the proliferation and cytokine synthesis from antigen- stimulated T cell clones and the induction of cytokines in Jurkat T cells.


CONCLUSIONS
These data indicate that pimecrolimus has a selectivity for antigen-primed memory T cells not seen with tacrolimus.
Kalthoff
Frank S
FS
Novartis Institutes for Biomedical Research, Vienna, Austria. frank.kalthoff@novartis.com
Winiski
Anthony
A
Fichtinger
Petra
P
Schwendinger
Brigitte
B
Wang
Shirley
S
Weishaeupl
Cordula
C
Stuetz
Anton
A
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; C117268:pimecrolimus; D016559:Tacrolimus