Immunomodulatory Drugs (IMiDs), Lenalidomide and Pomalidomide, Suppress Th1-Inducing Capacity of Dendritic Cells but Enhance Th2-Mediated Allergic Response
Authors: Ito Tomoki , Vien Phan Thi Xuan , Inaba Muneo , Yoshimura Hideaki , Hotta Masaaki , Nakanishi Takahisa , Fujita Shinya , Nakaya Aya , Satake Atsushi , Ishii Kazuyoshi , Nomura Shosaku 
Published: October 2019

Abstract
Background: Analogs of thalidomide, lenalidomide (LEN) and pomalidomide (POM), are novel anti-multiple myeloma (MM) drugs (so-called Immunomodulatory Drugs; IMiDs). LEN has been reported to enhance function of effector immune cells such as T cells and NK cells and to induce selective reduction of regulatory T cells. Meanwhile, LEN and POM treatments lead to relatively high rate onset of itchy skin with rash like allergic reaction. However, cellular and molecular mechanisms underlying their immunomodulatory effects still remain largely unclear. Although there is evidence indicating the immunomodulatory actions of LEN on mouse conventional dendritic cells (DCs), there are few reports showing their effects on human DC subsets. DCs are pivotal in orchestrating both innate and acquire immunity as the center of the immune regulatory system, and series of analyses have clarified a functional plasticity of DCs to induce Th1 or Th2 response. Therefore, we focused on the effects of LEN and POM on the function of human myeloid DCs (mDCs), which are the major regulators to induce Th1 or Th2 responses and play a pathogenic role in allergy by their dysregulated Th2-inducing function (Ito T. J Exp Med 2005; 202: 1213).
Methods: Using cell sorting, flow cytometry, real-time PCR, and ELISA methods, function and signaling were analyzed in blood human CD11+ mDCs from healthy adult volunteers. Sera were obtained from 24 MM patients with before and after LEN therapy. Written informed consent was obtained for all patients. This study was approved by the Institutional Review Board of Kansai Medical University.
Results: We found that both agents at clinical in vivo plasma concentration of 0.1 µM to 1 µM did not affect the mDC survival and their CD86 and OX40-ligand expression in response to toll-like receptor (TLR)-ligands (LPS, poly IC, or R848) and Th2-inducing cytokine, thymic stromal lymphopoietin (TSLP) for 24 h culture. Either LEN or POM inhibited dose-dependently mDC-derived Th1-associated cytokines, IL-12 in response to R848 (1 µM LEN; 5.2 % of cont. and 0.3 µM POM; 12 % of cont.), IFN-λ in response to poly IC (1 µM LEN; 5.4 % of cont. and 0.3 µM POM; 10 % of cont.), and TNFα in response to R848 (1 µM LEN; 36 % of cont. and 0.3 µM POM; 17 % of cont.), but enhanced IL-10 production in response to R848 (1 µM LEN; 4.8-fold increase and 0.3 µM POM; 7.5-fold increase). When mDCs were stimulated with TSLP, both agents significantly enhanced the production of Th2-recruiting chemokine CCL17/TARC (1 µM LEN; 2.4 fold increase and 0.3 µM POM; 3.9 fold increase), which functions as chemoattractant for memory Th2 cells and contribute to aggravation of allergic inflammation. These capacities of POM were stronger than those of LEN. In addition, we revealed that, in response to LPS or R848, both LEN and POM downregulated not only IRF4 mRNA in human mDCs as in LEN-treated myeloma cells, but also STAT4 mRNA, which is important for DC-mediated Th1 response and IL-12 production. In mDCs treated with TSLP, both agents were found to upregulate STAT6 mRNA, which is responsible for TSLP-mediated CCL17 secretion (Arima K. Sci Signal2010;3:ra4). Clinically, serum CCL17/TARC levels are associated with the disease activity of atopic dermatitis and sensitively reflect short-term changes in skin conditions. We also found, in MM patients, serum CCL17 levels at the onset of LEN-associated rash during 4 weeks (n=9; 1271 ± 376 pg/ml) were significantly higher (p <0.001) compared to those without rash in LEN treatment (n=15; 476 ± 236 pg/ml) and those before treatment (296 ± 172 pg/ml).
Conclusion: Our data suggest that the IMiDs, while suppress the Th1-inducing capacity of DCs, rather lead to enhance allergic response at DC phase through modulation of signaling pathways in this stream of action. Thus, IMiDs could have the potential to shift DC-mediated response from Th1 to Th2, and our findings provide a plausible explanation for pathogenesis of IMiD-associated rash in the treatment for MM.

Disclosures
Ito: Celgene corporation: Honoraria; GSK: Patents & Royalties.