Kevin D. Cooper

Dysfunctional Blood and Target Tissue CD4+CD25high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation

The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4+ T lymphocyte subpopulation in peripheral blood, phenotypically CD25high, CTLA-4+, Foxp3high (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4+ responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4+CD25high Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo.

Non-Sunscreen Photoprotection: Antioxidants Add Value to a Sunscreen

The association between ultraviolet radiation (UVR) exposure and both skin cancer and photo-aging is well documented. In addition to the conventional organic-chemical and physical-mineral type sunscreens, other non-sunscreen protective strategies have been developed. These include topically applied botanical extracts and other antioxidants as well as topical DNA repair enzymes. Standard terms of photoprotection such as sun protection factor (SPF) do not accurately reflect the photoprotection benefits of these materials. For example, in spite of minimal SPF, tea extract containing polyphenols such as (-)-epigallocatechin-3-gallate (EGCG) has been shown to protect against UV-induced DNA damage and immune suppression, in part through its ability to reduce oxidative stress and inhibit NF-kB. The addition of botanical antioxidants and vitamins C and E to a broad-spectrum sunscreen may further decrease UV-induced damage compared with sunscreen alone. These agents have been shown to enhance protection against UV-induced epidermal thickening, overexpression of MMP-1and MMP-9, and depletion of CD1a(+) Langerhans cells. Non-sunscreen materials such as botanical extracts, antioxidants, and DNA repair enzymes can contribute value when applied topically to human skin in vivo.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 56-59; doi:10.1038/jidsymp.2009.14.

UVA II Exposure of Human Skin Results in Decreased Immunization Capacity, Increased Induction of Tolerance and a Unique Pattern of Epidermal Antigen-Presenting Cell Alteration

Abstract— The risks incurred from increased exposure to UVA II (320‐340 nm) (i.e. during sunscreen use and extended outdoor exposure, tanning parlors) are not well understood. Therefore, we explored the effects of UVA II on skin immune responses in humans. After a single local exposure (4 minimum erythemal dose [MED]) using a xenon arc lamp filtered with a narrow bandpass filter (335 ± 5 nm full width at half maximum), individuals were contact‐sensitized with dinitrochlorobenzene (DNCB) through a UVA II exposure site or through normal skin. UVA II induced a marked decrease in the magnitude of skin immune responses (P < 0.0001). The UVA II group had only 29% successful sensitizations, as compared to 83% in the control group. The percentage of individuals who remained tolerant to DNCB after two sensitizations was 23.6% for the UVA II‐exposed group, as compared to 3.8% in the controls (P= 0.006). UVA II also uniquely altered the type of antigen‐presenting cells present in the epidermis. Human leukocyte antigen (HLA)‐DR+ cells in control epidermal cell suspensions (C‐EC) comprised a single, homogeneous population of Langerhans cells (LC) with the phenotype: CD1ahi DRmid CD11b− CD36− (1.5 ± 0.3% of EC). UVA II irradiation reduced the number of such LC to 0.6 ± 0.2% of EC. Although cells expressing the macrophage phenotype: CD1a DRhi CD11b+ CD36+ were increased in UVA II skin, relative to C‐EC, these comprised only 10.1 ± 6.1% of the DR+ cells, which is less than that after UVB exposure. Also distinct from UVB, a third population was found in UVA II‐EC, which exhibited a novel phenotype: CD1a+ DR+ CD36+ CDllb+; these comprised 11.1 ± 6.9% of the DR+ UVA II‐EC.

Positive treatment effects of ustekinumab in psoriasis: analysis of lesional and systemic parameters.

Ustekinumab, a human anti‐interleukin (IL)‐12/IL‐23p40 monoclonal antibody has demonstrated significant efficacy in patients with moderate‐to‐severe psoriasis. Skin lesion biopsies, cell surface markers on peripheral blood lymphocytes, and ex vivo T‐helper (Th)1/Th2 cytokine responses from peripheral blood mononuclear cells (PBMC) from patients receiving ustekinumab 45 or 90u2003mg, or placebo were evaluated at baseline and week 12. Inflammatory serum protein levels were measured at baseline, week 2 and week 12. At week 12, median epidermal thickness decreased from 312.1 to 132.7u2003μm, and median levels of cellular proliferation (Ki67) and T‐cell infiltration (CD3) decreased by 84.3% and 70.7%, respectively, in the combined ustekinumab group (all Pu2003≤u20030.002). Serum levels of tumor necrosis factor (TNF)‐α, C‐C motif ligand 27 (CCL27) and other inflammatory cytokines remained unchanged. Minimal variation in the percentage of T cells expressing cutaneous lymphocyte antigen (CLA) was observed following ustekinumab treatment, with no significant variation in the percentage of cells expressing CD45RA, CD45RO, CD25, human leukocyte antigen‐DR (HLA‐DR), and C‐X‐C motif receptor 3 (CXCR3). No apparent effect on the magnitude of Th1/Th2 responses to external stimuli in PBMC was observed following placebo or ustekinumab treatment. Ustekinumab improves histological psoriasis measures, with minimal impact on the systemic immune system.

Cutaneous hypersensitivity to Candida albicans in idiopathic vulvodynia

We have observed that the majority of our vulvodynia patients give a previous history of vaginal candidiasis that was treated but was followed by symptoms of chronic vulvodynia. 27 vulvodynia patients were patch‐tested to a standard series of contact allergens, a customized vulvar series and commensal organisms including ultraviolet‐killed Candida albicans. Comparison tests for the commensal organism were made to a group of 13 female atopic dermatitis patients and to 19 female dermatitis patients without a history of childhood flexural dermatitis who were undergoing patch test evaluation in our clinic. Patients reporting vulvodynia were significantly (Pu2003<u20030.05) more likely to react to C. albicans than the dermatitis comparison group. Interestingly, lower concentrations of C. albicans caused more positive patch tests than higher concentrations. Our findings suggest that previous C. albicans infection may predispose patients to a subsequent hypersensitivity response to C. albicans that is expressed only in areas of high cutaneous peripheral fibre density. Low levels of C. albicans may also be required to elicit this response as high levels of C. albicans may actually result in decreased cutaneous inflammation and decreased intensity of C. albicans patch test responses.

Cell‐Mediated Immunosuppressive Mechanisms Induced by UV Radiation

Soon after UV exposure, mast cells degranulate, possibly because of the release of the mediators and cytokines from the epidermis, and there are subsequent vascular changes and cellular infiltration. Within a few hours, the soluble mediator milieu of UV-exposed skin becomes exceedingly complex and replete with interactions. Leukocytes newly entering the skin, as well as those already in the skin, must respond to these inflammatory signals. Altered antigen presentation and immune suppression likely derive from alterations induced in the APC that comprise the post-UV leukocyte population of the skin. Many of these mechanisms may explain the effectiveness of phototherapy in atopic dermatitis and psoriasis.

Photodynamic therapy in dermatology: current concepts in the treatment of skin cancer.

Photodynamic therapy is a treatment modality that is developing rapidly and increasing in utilization within various medical specialties, including dermatology. This technique requires the presence of a photosensitizer, light energy and molecular oxygen to selectively destroy pathologic cells. A thorough understanding of photobiology and tissue optics is necessary to correctly and effectively utilize photodynamic therapy in dermatology. Photodynamic therapy has been approved by the US Food and Drug Administration to treat actinic keratoses. In Europe, photodynamic therapy is currently being used in the treatment of actinic keratoses and basal cell carcinoma. Other off-label uses of photodynamic therapy have included cutaneous lesions of Bowen’s disease, psoriasis, cutaneous T-cell lymphoma and acne. Most recently, photodynamic therapy has been employed in photorejuvenation. The advantages of photodynamic therapy include the capacity for noninvasive targeted therapy via topical application of the drug and local irradiation of involved areas, as well as the ability to generate excellent cosmetic results with minimal discomfort. This review summarizes the fundamentals of photodynamic therapy and its role in the treatment of cutaneous disorders, particularly skin malignancies.

Review of extracorporeal photopheresis in early‐stage (IA, IB, and IIA) cutaneous T‐cell lymphoma

Background: Extracorporeal photopheresis (ECP) has been used for nearly 20 years for the treatment of cutaneous T‐cell lymphoma (CTCL). A substantial body of literature reports that this form of photoimmunotherapy improves or stabilizes the course of disease in a subset of patients across all stages. However, current clinical approach usually reserves ECP for patients who do not respond to other treatments or for patients with late‐stage disease or Sézary syndrome (SS).

IL-1 and IL-1 receptor antagonist regulation during keratinocyte cell cycle and differentiation in normal and psoriatic epidermis

Abstract Changes in the levels of IL-1 (IL-1α, IL-1β, and its receptor antagonist, IL-1RA) occur upon keratinocyte differentiation in vitro and are associated in vivo with abnormal differentiated and hyperproliferative states of psoriatic keratinocytes. A flow cytometric procedure, capable of detecting changes in the intracellular levels of IL-1, was used to determine whether intracellular IL-1/IL-1RA levels in psoriatic and normal keratinocytes alter during in vivo differentiation and the cell cycle. Increases in the IL-1RA levels and IL-1α levels were observed as both normal and psoriatic keratinocytes differentiated from basal stem cells (β 1 integrin + , small size) into transient amplifying cells (TAC; β 1 integrin + , large size). Upon further differentiation (β 1 integrin – , large size) both IL-1RA and IL-1α levels dropped. However, while psoriatic IL-1β levels increased as cells differentiated into TACs, little change occurred in the IL-1β levels of normal keratinocytes during differentiation. Changes in IL-1/IL-1RA levels were also detected as keratinocytes progressed through the cell cycle. Within the basal stem cell population of both normal and psoriatic keratinocytes, the IL-1α and IL-1RA levels increased between G0/G1 and S but not between S and G2/M. However, psoriatic basal keratinocyte IL-1β levels differed from those of normal keratinocytes by showing no increase between S and G2/M. The IL-1/IL-1RA levels of normal TAC increased throughout the cell cycle. However, in psoriatic TAC, a slight decrease in IL-1α and IL-1RA levels was observed between G0/G1 and S followed by a delayed increase between S and G2/M. IL-1β levels in psoriatic TAC varied little throughout the cell cycle. Thus, we were able to detect precisely the regulation of IL-1/IL-1RA intracellular levels during the keratinocyte cell cycle and differentiation, showing notably decreased IL-1β upregulation in psoriatic keratinocytes progressing through the cell cycle.

The sensitivity of medicare data for identifying incident cases of invasive melanoma (United States)

Background: The completeness of Medicare claims for identifying patients with melanoma for purposes of conducting population-based studies of melanoma is unknown. Methods: Using a linked Surveillance, Epidemiology, and End Result (SEER) tumor registry-Medicare database, the sensitivity of Medicare claims for identifying 5372 patients age ≥65 years diagnosed with invasive melanoma between 1992 and 1996 was determined. Sensitivity was calculated as the proportion of incident cases of melanoma reported by SEER that was also captured by Medicare claim diagnostic codes. Results: The overall sensitivity of combined Part A and Part B Medicare for incident cases of melanoma was 90.1%. Part B Medicare and Part A Medicare alone had 89.5% and 16.5% sensitivity respectively. Sensitivity was lower for patients with unrecorded Breslow depth and for patients with unstaged or distant stage melanoma. Conclusions: Medicare Part B claims have a high sensitivity for detecting melanoma incidence; Medicare Part A has low sensitivity. This sharply contrasts with published studies of other cancers, for whom Part A rather than Part B Medicare captures the predominant portion of incident cases. Medicare Part B or combined Part A and Part B administrative data is a potentially valuable resource for population-based melanoma research in the elderly. Further research characterizing the specificity and predictive value of Medicare data is needed to assess the potential implications of false positive melanoma diagnostic codes.