Danielle M Miller

Harvard Medical School, Boston, Massachusetts, United States

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Publications (5)34.13 Total impact

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    ABSTRACT: Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T-cell immunosuppressant medications. Imiquimod is a topical immune response modifier and Toll-like receptor 7 (TLR7) agonist that induces the immunological destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells, but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunological memory are ultimately T-cell-mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod before excision contained dense T-cell infiltrates associated with tumor cell apoptosis and histological evidence of tumor regression. Effector T cells from treated SCC produced more IFN-gamma, granzyme, and perforin and less IL-10 and transforming growth factor-beta (TGF-beta) than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-gamma, perforin, or granzyme, suggesting that these latter effects arise from the recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.
    Journal of Investigative Dermatology 07/2009; 129(11):2676-85. · 6.19 Impact Factor
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    ABSTRACT: Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized clinically by loosely hanging skin folds. There is often preceding cutaneous inflammatory eruption (ie, urticaria, eczema, erythema multiforme), and there is frequently internal organ involvement of the gastrointestinal, urogenital, pulmonary, and cardiovascular systems. Histologically, there are degenerative changes in the dermal elastic fibers. Of the few reports on this rare disorder, authors have speculated about an immune-mediated destruction of elastic fibers, and monoclonal gammopathies, such as multiple myeloma or heavy chain deposition disease, have a recognized association with CL. We report an unusual case of rapidly progressing acquired CL associated with leukocytoclastic vasculitis, IgA myeloma, and an immune complex-mediated glomerulonephritis. Light microscopy of the lax skin revealed complete absence of elastic fibers in areas of vasculitis.
    Journal of the American Academy of Dermatology 07/2009; 60(6):1052-7. · 4.91 Impact Factor
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    ABSTRACT: Paraneoplastic signs are an important clue to diagnosing an associated malignancy. We report an unusual variant of the sign of Leser-Trélat in a patient with a low-grade B-cell lymphoproliferative disorder and intertriginous skin spicules with histologic morphology of minute seborrheic keratoses.
    Journal of the American Academy of Dermatology 06/2009; 60(5):852-5. · 4.91 Impact Factor
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    ABSTRACT: Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)(+) T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA(+) CD8(+) T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3(+) regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-beta. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-beta by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.
    Journal of Experimental Medicine 10/2008; 205(10):2221-34. · 13.21 Impact Factor
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    ABSTRACT: Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma in the World Health Organization classification. Although the majority of cases are of B-cell lineage, cases of IVL with a T-cell phenotype and, rarely, histiocytic and natural killer (NK)-cell phenotypes have been reported. We report a case of T-cell IVL with a cytotoxic phenotype. A 62-year-old male presented with erythematous patches and plaques on the lower extremities, and a biopsy revealed IVL with an activated cytotoxic phenotype (CD56(+), perforin+, granzyme B+, TIA-1+, CD3epsilon(+), CD20(-), CD4(-), CD8(-), CD5(-), and T-cell receptor [TCR] betaF1(-)), consistent with either NK-cell or T-cell origin. TCR gene analysis showed a monoclonal T-cell population, supporting the diagnosis of a T-cell IVL. Although the patient's skin lesions were refractory to combination chemotherapy and salvage chemotherapy regimens, there has been no evidence of disease progression in 24 months of follow-up.
    Journal of the American Academy of Dermatology 03/2008; 58(2):290-4. · 4.91 Impact Factor