Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also ...associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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•Type 2 cytokines directly activate both mouse and human sensory neurons•IL-4 enhances neuronal responsiveness to multiple pruritogens•Sensory neuron-specific deletion of IL-4Rα or JAK1 reduces chronic itch•Clinical studies demonstrate that JAK inhibitors relieve chronic itch
Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.
New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates ...CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.
•Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT.•First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.
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Highlights • This is the first trial to evaluate a selective CDK4/6 inhibitor in HNSCC. • The novel combination of palbociclib and cetuximab was feasible and safe. • The palbociclib dose recommended ...is 125 mg/day 1–21 q 28 days with cetuximab. • Measureable decreases in target lesions occurred in 56% of patients. • The disease control rate was 89% and median TTP was 112 days (upper range 224).
This case series report of mogamulizumab-associated cutaneous granulomatous drug eruption (CGDE) describes 12 patients with mycosis fungoides (MF) whose CGDE mimicked the MF but was followed by ...durable clinical MF response.
Background Mycosis fungoides (MF) is a neoplasm of skin-homing CD4+ helper T (TH ) lymphocytes with dysregulation of TH 1 and TH 2 immunity. Diagnosis of MF is challenging, as there is significant ...morphologic overlap with other dermatologic entities. Objective We investigated diagnostic utility of TH 1- and TH 2-specific markers, T-bet, and GATA-3, respectively, in MF and its reactive and neoplastic mimics. Methods Immunohistochemical staining for CD3/T-bet and CD3/GATA-3 was performed on inflammatory dermatoses (n = 56), MF (n = 37), Sezary syndrome (SS; n = 8), and cutaneous anaplastic large cell lymphoma (C-ALCL; n = 14). Results Inflammatory dermatoses showed epidermal T cells predominantly expressing GATA-3, except psoriasis, which exhibited a mixed GATA-3/T-bet staining. In contrast, neoplastic T cells in patch stage MF showed markedly increased T-bet positivity with minimal GATA-3 expression. Plaque stage MF had a mixed T-bet/GATA-3 phenotype, whereas tumor stage MF and SS exhibited diffuse GATA-3 expression. C-ALCL lacked significant staining for both markers. Limitations Sample size was relatively small. Conclusions A predominance of T-bet+ T cells in the epidermis support patch stage MF over dermatitis. A predominance of GATA-3+ T cells in the dermis support CD30+ MF with large cell transformation over C-ALCL. These stains do not allow distinction between dermatitis and cutaneous infiltrates of SS.
Hematopathology of the Skin provides an up-to-date, interdisciplinary approach to this complex field. Unparalleled in scope, this comprehensive text features a logical, consistent format heavily ...illustrated with high-quality clinical and pathological images throughout. More than 40 leading dermatopathologists, hematopathologists, and dermatologists from major academic centers in the U.S. and around the world share their expertise and personal experiences with cutaneous hematologic neoplasms, helping you arrive at an accurate, more efficient diagnosis and improve patient care.
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