Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can effectively target tumors, but until now the pathways that govern their differentiation have been poorly understood. We demonstrate that CD134 (OX40) costimulation programs naive self- and virus-reactive CD4 T cells to undergo in vivo differentiation into cytotoxic Th1 effectors. CD137 (4-1BB) costimulation maximized clonal expansion and IL-2 was necessary for cytotoxic Th1 differentiation. Importantly, the T-box transcription factor Eomesodermin (Eomes) was critical for inducing the cytotoxic marker granzyme B. CD134 plus CD137 dual costimulation also imprinted a cytotoxic phenotype on bystanding CD4 T cells. Thus, the present study identifies for the first time a specific costimulatory pathway and an intracellular mechanism relying on Eomes that induces both antigen-specific and bystander cytotoxic CD4 Th1 cells. This mechanism might be therapeutically useful since CD134 plus CD137 dual costimulation induced CD4 T cell-dependent tumoricidal function in a mouse melanoma model.

Background and Purpose: Reduced nitric oxide (NO) bioavailability, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vasoocclusion, and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyzes synthesis of cyclic guanosine monophosphate (cGMP) in response to NO. cGMP amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate tumor necrosis factor alpha (TNFα)-induced inflammation in wild-type C57BL/6 mice and in "humanized" mouse models of SCD. Experimental Approach: The effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. Key Results: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFa-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte/endothelial cell interactions, improved blood flow, and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat-than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-hour urine excretion, plasma levels of cystatin C, and urinary excretion of N-acetyl-beta-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. Conclusion and Implications:Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion, and kidney injury in mouse models of SCD and systemic inflammation.

Angiomyolipoma (AML) is classified as perivascular epithelioid cell neoplasm (PEComas) and is commonly seen in the kidney. AML is a solid mesenchymal neoplasm rarely encountered at the extrarenal site. Extrarenal AML is infrequently seen in the female genital tract. Four cases of AML of the cervix have been reported in the literature to our knowledge. We report a case of a 44-year-old female patient who presented with complaints of “lower abdominal pressure” and a history of post-coital bleeding and human papillomavirus (HPV) infection. A cyst in the uterine cervix was found incidentally on computerized tomography (CT) scan of the abdomen and pelvis. The patient underwent a loop electrosurgical excision procedure. The histologic and immunohistochemical features of the cervical biopsy favored the diagnosis of AML. The patient underwent a laparoscopic hysterectomy with bilateral salpingectomy. Grossly, a 4 cm white soft-to-firm mass was identified within the anterior lip of the cervix. Microscopy of the mass showed smooth muscle proliferation with prominent blood vessels, and scant mature adipose tissue trapped in between the smooth muscle bundles. Immunohistochemical stains showed smooth muscle actin (SMA) and desmin highlighting the smooth muscle component of AML. The histology and immunohistochemistry of the cervical mass in the surgical specimen were identical to the biopsy specimen and a diagnosis of AML was made.

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