Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the ...skin-draining lymph nodes (LNs). In mice, Langerin–CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin–CD11b- migDCs). Here, we build on the observation that Langerin–CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin–CD11b- Flt3L-responsive DCs are largely CD24(+) and CX3CR1low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin–CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin– CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment.
The active ubiquitin E3 ligase GRAIL is crucial in the induction of CD4 T cell anergy. Here we show that GRAIL is associated with and regulated by two isoforms of the ubiquitin-specific protease ...otubain 1. In lethally irradiated mice reconstituted with bone marrow cells from T cell receptor-transgenic mice retrovirally transduced to express the genes encoding these proteases, otubain 1-expressing cells contained negligible amounts of endogenous GRAIL, proliferated well and produced large amounts of interleukin 2 after antigenic stimulation. In contrast, cells expressing the alternatively spliced isoform, otubain 1 alternative reading frame 1, contained large amounts of endogenous GRAIL and were functionally anergic, and they proliferated poorly and produced undetectable interleukin 2 when stimulated in a similar way. Thus, these two proteins have opposing epistatic functions in controlling the stability of GRAIL expression and the resultant anergy phenotype in T cells.
Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the ...skin-draining lymph nodes (LNs). In mice, Langerin-CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b- migDCs). Here, we build on the observation that Langerin-CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b- Flt3L-responsive DCs are largely CD24(+) and CX3CR1(low) and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin- CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment.
Abstract 4124
Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSC), early progenitor cells, immature thymocytes, and steady ...state dendritic cells and induces the proliferation, differentiation, development and mobilization of these cells in the bone marrow, peripheral blood, and lymphoid organs. Given its potential as a stem cell mobilizer and immunotherapeutic, the safety and biologic activity of recombinant human (rh) Flt3L were originally demonstrated in clinical studies conducted by Immunex Inc, but development had been halted. CDX-301 is a soluble, rhFlt3L composed of the identical amino acid sequence and comparable biologic activity as the Immunex product. A Phase 1 trial was initiated to assess the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301. Using a standard 3+3 dose-escalating design, 18 healthy volunteers (HV) (51% male, median age = 32 years) received 5 daily subcutaneous injections of CDX-301 (at a dose of 1, 3, 10, 25 or 75 mcg/kg) followed by 28-day observation. All HV completed dosing and CDX-301 was well tolerated. Dose-escalation proceeded through the 25 mcg/kg dose level with no DLT (n=3 in each cohort). In the 75 mcg/kg cohort, one HV with a remote history of community acquired pneumonia developed community acquired pneumonia on study day 12; the event responded rapidly to antibiotic treatment and fully recovered within 2 weeks, but was considered a dose-limiting toxicity given the temporal association with CDX-301 administration. The cohort was expanded to a total of six HV, and no additional infections or DLT were reported. Transient Grade 1 lymphadenopathy was observed in 3 HV across multiple dose levels. No anti-CDX-301 antibodies were detected through end of study day 34 in any HV. White blood cell count (WBC) and monocytes increased in all HV; peak levels were observed around Day 10 and generally returned to baseline by Day 34. At doses above 3 mcg/kg, there was no clear dose response; mean maximum % change from baseline for the HV receiving 10 – 75 mcg/kg = 111% (range: 55–224%) for WBC and 800% (range: 450–1167%) for monocytes.
Display omitted
In-depth phenotypic and/or functional analysis of hematopoietic stem cells and dendritic cell subsets are planned. Data from this current Phase 1 trial are consistent with previous studies showing that rhFlt3L can safely and effectively mobilize hematopoietic cell populations. Two additional cohorts will receive extended dosing (25 mcg/kg dose; 7 & 10 day durations) to further define an optimal dosing regimen for planned trials of CDX-301 in allogeneic hematopoietic stem cell transplantation (HSCT) and immunotherapy.
Riggs:CelldexTherapeutics: Employment, Equity Ownership. Green:Celldex: Employment, Equity Ownership. Yellin:CelldexTherapeutics: Employment, Equity Ownership. Davis:CelldexTherapeutics: Employment, Equity Ownership. Keler:CelldexTherapeutics: Employment, Equity Ownership.
BackgroundDendritic cells (DC) are gatekeepers of immunity, critical to both an initiate immune response upon infection and promote tolerance to self-antigens.MethodsWe have just established that DC ...subsets in the skin that constitutively migrate into LNs can individually and collectively temper an on-going immune response. Tissue DC originating in skin share a unique transcriptome signature geared towards immune dampening when compared to their lymphoid counterparts in both mouse and human.ResultsHere we demonstrate expression of unique core skin DC transcripts are closely associated with increased clinical aggressiveness of BCC in humans and the stratify stage 4 melanoma outcomes. In mice, loss of signature genes in DC, which include but are not limited to PD-L1/PD-L2, lead to enhanced antigen-specific immunity, decreased tumor growth, and improved anti-tumor vaccine priming to melanoma skin cancer by distinguishable molecular control of T cell effector function and clonal proliferation.ConclusionsThese data suggest core skin DC signatures regulate the immune-epithelial interface.
Multiple apocrine hidrocystomas Anandasabapathy, Niroshana; Soldano, Anthony C
Dermatology online journal,
2008-May-15, Volume:
14, Issue:
5
Journal Article
Peer reviewed
A 83-year-old woman presented with a 7-year history of translucent papules that were scattered diffusely over her nose, peri-orbital region, and cheeks. These lesions were exacerbated by heat and ...exercise. Histopathologic examination of a biopsy specimen from the cheek showed a thin-walled cyst lined by a flattened bi-layered epithelium that exhibited decapitation secretion in the upper part of the epidermis. A diagnosis of multiple apocrine hidrocystomas was made based on the clinical and histopathologic findings, and the patient is currently considering treatment options. These include electrodesiccation, excision, trichloracetic acid, carbon-dioxide laser, and 1450-nm diode laser.
We recently described a novel way to isolate populations of antigen-reactive CD4+ T cells with a wide range of reactivity to a specific antigen, using immunization with a fixed dose of nominal ...antigen and FACS® sorting by CD4high expression. Phenotypic, FACS®, functional, antibody inhibition, and major histocompatibility complex–peptide tetramer analyses, as well as T cell receptor Vβ sequence analyses, of the antigen-specific CD4high T cell populations demonstrated that a diverse sperm whale myoglobin 110–121–reactive CD4+ T cell repertoire was activated at the beginning (day 3 after immunization) of the immune response. Within 6 d of immunization, lower affinity clones were lost from the responding population, leaving an expanded population of oligoclonal, intermediate affinity (and residual high affinity) T cells. This T cell subset persisted for at least 4 wk after immunization and dominated the secondary immune response. These data provide evidence that CD4+ T cell repertoire selection occurs early in the immune response in vivo and suggest that persistence and expansion of a population of oligoclonal, intermediate affinity T cells is involved in CD4+ T cell memory.
Amalgam tattoo Tran, Hien T; Anandasabapathy, Niroshana; Soldano, Anthony C
Dermatology online journal,
2008-May-15, Volume:
14, Issue:
5
Journal Article
Peer reviewed
A 53-year-old woman with a history of melanoma status-post excision two years prior presented with a 4-month history of 4, dark-brown macules on the inferior surface of her tongue. A biopsy specimen ...showed a squamous mucosa with chronic submucosal inflammation and brown pigment. The clinical and histopathologic findings were consistent with a diagnosis of amalgam tattoo. Amalgam tattoos are common, oral pigmented lesions that clinically present as isolated, blue, grey, or black macules on the gingivae, the buccal and alveolar mucosae, the palate, and/or the tongue. They are due to deposition of a mixture of silver, tin, mercury, copper, and zinc, which are components of an amalgam filling, into the oral soft tissues. Amalgam tattoos can either be treated surgically or with a Q-switched ruby laser. In the case of our patient with the history of melanoma, her oral lesions proved not to be the more dire diagnosis of malignant melanoma.
A 46-year-old man presented with a 1-year history of asymptomatic papules on the right arm, without an antecedent event. Initial clinical and histopathologic features were consistent with a ...pseudolymphoma without gene rearrangements, and the patient was treated with intralesional glucocorticoids. Four months later, the patient developed additional papules and plaques on the right arm, and, at this time, clinical and histopathologic features were most consistent with a T-cell-rich, large B-cell lymphoma, with monoclonal immunoglobulin light chain gene rearrangement. Systemic evaluation showed no evidence of extracutaneous involvement. The transformation of a pseudolymphoma into a large B-cell lymphoma is a rare event. This patient's subtype, diffuse large B-cell lymphoma-other, carries an intermediate prognosis when compared to the more aggressive leg subtype and more indolent folliculocentric subtype. Potential therapeutic options include local radiotherapy, chemotherapy, and rituximab.
PDF
