Background/Purpose:

Tofacitinib, an oral Janus Kinase (JAK) inhibitor, has gathered attention in treatment of Rheumatoid arthritis (RA). Although JAKs are well known for its importance in lymphocyte development and expressed in monocyte lineage cells, the effect of tofacitinib on the maturation and function of human dendritic cells (DCs) remains unknown. 

Methods:

Human monocyte-derived DCs were generated with granulocyte macrophage colony-stimulating factor and IL-4. DCs were matured with lipopolysaccharide (LPS) in the presence of tofacitinib in vitro for 48 hours and cytokine production, cell survival and surface markers were assessed by flow cytometry. After washout of tofacitinib, DCs were co-cultured with CD4+CD45RA+ naive T cells purified from healthy donor, and allogeneic-mixed lymphocyte reaction (aMLR) performed to evaluate T-cell stimulatory capacity.

Results:

When DCs were stimulated with LPS, expression of CD80, CD86 and HLA-DR were strongly induced. However, the addition of tofacitinib to DCs reduced expression of CD80 and CD86, but not HLA-DR, indicating that maturation was disturbed. Tofacitinib also inhibited the production of TNF-α　(6217ng/ml to 4964ng/ml), IL-6　(43640ng/ml to 33027ng/ml) and IL-1β　(22ng/ml to 13ng/ml) at 300nM, and the inhibitory effect was in a dose dependent manner. On the contrary, the production of TGF-β from DCs was not affected. Notably, tofacitinib increased the levels of indoleamine 2, 3-dioxygenase (IDO), an immunomodulatory enzyme in DCs. Co-culture of tofacitinib-treated DCs with allogeneic naive T cells resulted in reduction of T-cell proliferation and IFN-γ production. However, CD4+CD25+FoxP3+ regulatory T cell population was not affected.

Conclusion:

In addition to the previously known effect of tofacitinib on acquired immunity, our results indicate that tofacitinib could affect the innate immunity. Importantly, tofacitinib attenuated the LPS-induced upregulation of costimulatory molecules during DC maturation.  This resulted in a decreased allo-reactive T cell response. Moreover, tofacitinib suppressed inflammatory cytokine production and induced IDO expression. Taken together, these data provide novel potential mechanisms of action of tofacitinib, the restoration of immunoregulation as well as anti-inflammation, in patients with rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/action-of-tofacitinib-via-human-dendritic-cells/