Dendritic cells (DCs) show a remarkable functional plasticity in the recognition of Aspergillus fumigatus and orchestrate the antifungal immune resistance in the lungs. Here, we show that thymosin alpha 1, a naturally occurring thymic peptide, induces functional maturation and interleukin-12 production by fungus-pulsed DCs through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway. This occurs by signaling through the myeloid differentiation factor 88-dependent pathway, involving distinct Toll-like receptors. In vivo, the synthetic peptide activates T-helper (Th) cell 1-dependent antifungal immunity, accelerates myeloid cell recovery, and protects highly susceptible mice that received hematopoietic transplants from aspergillosis. By revealing the unexpected activity of an old molecule, our finding provides the rationale for its therapeutic utility and qualify the synthetic peptide as a candidate adjuvant promoting the coordinated activation of the innate and adaptive Th immunity to the fungus.

IntroductionThe induction of tolerance is central to the maintenance of immune homeostasis. Not only are dendritic cells (DCs) key elements in the development of immunity, but they also participate in the generation and maintenance of immune tolerance. Many studies have demonstrated a pivotal role for the enzyme indoleamine 2,3-dioxygenase (IDO) in immune regulation during infection, pregnancy, autoimmunity, transplantation, and neoplasia. 1,2 IDO is widely expressed in a variety of human tissues as well as in macrophages and DCs and is induced in inflammatory states via type I or type II IFN signaling. Through localized tryptophan deficiency combined with the release of proapoptotic kynurenines, DCs exert an IDO-dependent homeostatic control over the proliferation and survival of peripheral T cells and promote antigen-specific tolerance. 3,4 Murine plasmacytoid DCs (pDCs), which produce and respond to type I IFNs, have been credited with a unique ability to express functional IDO, implying an important role for these cells in the maintenance of peripheral tolerance. 5 DCs are now being exploited to improve vaccine efficacy. 6 Pathogen-pulsed DCs act, indeed, as a potent fungal vaccine in experimental hematopoietic stem cell transplantation (HSCT). 7 Protection is associated with myeloid and T-cell recovery, the activation of CD4 ϩ T-helper type 1 (Th1) lymphocytes, and the concomitant production of IL-10. This cytokine is required for the induction of regulatory T (Treg) cells, which have important functions in immune homeostasis including the onset of transplantation tolerance, inhibition of inflammation, and prevention of graft-versus-host disease (GVHD) lethality and leukemia relapse. [8][9][10] As tolerance is also one major requirement of a successful immune response to fungi, 11-13 tolerogenic DCs, including pDCs, may be pivotal in the generation of some form of dominant regulation that ultimately controls inflammation, pathogen immunity, and tolerance in transplant recipients. 14 Thymosin ␣1 (T␣1) is a naturally occurring thymic peptide 15 that promotes activation and cytokine production in human and murine mature DCs by signaling through Toll-like receptors (TLRs), including TLR9. 16 By influencing the balance of IL-12-and IL-10-producing DCs, T␣1 acts as an immune regulator capable of inducing protective immunity to Aspergillus fumigatus. 16 TLR9 stimulation can also lead to IDO activation via mechanisms including autocrine type I IFN signaling 17,18 and can promote pDC-mediated generation of CD4 ϩ CD25 ϩ cells, 19 which are an essential component of the IDO-dependent protective immunity to fungi. [11][12][13] We hypothesized that T␣1 could affect the balance of immunity and tolerance by DCs and the generation of Treg cells. We assessed here the effects of T␣1 on deriving DCs from bone marrow (murine) or peripheral blood (human) L.R. and P.P. devised the study, critically evaluated the data at regular intervals, and drafted the paper. L.R. takes responsibility for integrity of the work as a whole. K.P....

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The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.