Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.

The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex.

Polyaromatic hydrocarbons are ubiquitous environmental chemicals that are important mutagens and carcinogens. The purpose of this study was to determine whether genes within the major histocompatibility complex (MHC) influence their biological activities. Cell-mediated immunity to dimethylbenz(a)anthracene (DMBA) was investigated in congenic strains of mice. On three different backgrounds, H-2(k) and H-2(a) haplotype mice developed significantly greater contact-hypersensitivity responses to DMBA than H-2(b), H-2(d), and H-2(s) mice. In B10.A(R1) mice, which are Kk and Id, a vigorous contact-hypersensitivity response was present, indicating that the response was governed by class I, rather than class II, MHC genes. C3H/HeN (H-2(k)) and C3H.SW (H-2(s)) strains were also compared for the development of skin tumors and the persistence of DMBA-DNA adducts. When subjected to a DMBA initiation, phorbol 12-tetradecanoate 13-acetate (TPA)-promotion skin-tumorigenesis protocol, C3H/HeN mice, (which develop cell-mediated immunity to DMBA) were found to have significantly fewer tumors than C3H.SW mice (a strain that failed to develop a cell-mediated immune response to DMBA). DMBA-DNA adducts were removed more rapidly in C3H/HeN than in C3H.SW mice. The results indicate that genes within the MHC play an important role in several of the biological activities of carcinogenic polyaromatic hydrocarbons. The observations are consistent with the hypothesis that cell-mediated immunity to chemical carcinogens serves to protect individuals by removing mutant cells before they can evolve into clinically apparent neoplasms.

A comparative analysis of silicon phthalocyanine photosensitizers for in vivo photodynamic therapy of RIF-1 tumors in C3H mice.

Photofrin photodynamic therapy (PDT) has recently received FDA approval for the palliative treatment of totally and partially obstructing esophageal malignancies. However, there is a need for new PDT photosensitizers because Photofrin has a number of undesirable features. The purpose of this study was to evaluate the efficacy of four amine-bearing silicon phthalocyanines--Pc4, Pc10, Pc12 and Pc18--as potential PDT photosensitizers. Equimolar concentrations of these Pc were found to be highly effective at causing the regression of RIF-1 tumors transplanted to C3H/HeN mice. The amount of Pc4 necessary to cause an equivalent amount of tumor regression in this model system was substantially less than the amount of Photofrin. The cutaneous phototoxicity of the silicon Pc photosensitizer was assessed by the utilization of the murine ear-swelling model. When C3H mice were exposed to 167 J/cm2 of polychromatic visible light from a UVB-filtered solar simulator, which emitted UV radiation and visible light above 320 nm, the Pc produced little, if any, cutaneous photosensitivity. These results indicate that Pc4, Pc10, Pc12 and Pc18 are at least as effective as Photofrin in PDT protocols, while at the same time addressing many of the drawbacks of Photofrin.

Genetic variation in low-dose UV-induced suppression of contact hypersensitivity and in the skin photocarcinogenesis response.

Two of the major cutaneous consequences of ultraviolet (UV) radiation exposure are immunosuppression and the development of skin cancer. This study examined whether these effects are genetically determined. Suppression of contact hypersensitivity by local, low-dose UV radiation was examined in what have been termed "UV-susceptible" and "UV-resistant" strains of mice. C3H/HeJ mice ("UV resistant") were resistant to the adverse effects of low-dose UV radiation when normal doses of hapten were applied to UV-irradiated skin; however, they were sensitive when the amount of hapten used for sensitization was reduced. A similar effect was observed in BALB/c mice ("UV resistant") and when the hapten was dimethylbenz(a)anthracene, thus indicating that the genetic variation was not strain or hapten specific. Despite the fact that some strains were sensitive and some were resistant to low-dose UV radiation when high doses of hapten were employed, all strains initially sensitized to hapten through UV-irradiated skin were found to be unresponsive when rechallenged on normal skin, no matter what the initial sensitizing dose of hapten was. To determine whether other biologic effects of UV also exhibited genetic variation, C3H/HeN and C3H/HeJ mice were compared for susceptibility to UVB-induced skin cancer formation. C3H/HeJ mice developed significantly more tumors than C3H/HeN mice when subjected to a single dose of UV radiation followed by repeated exposure to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. These studies provide strong evidence that genetic factors influence individual susceptibility to the biologic effects of UV radiation.

ICAM-1 mRNA levels and relative transcription rates are decreased by UV irradiation of monocytes.

We have previously demonstrated that in vitro exposure of antigen-presenting cells to UVB radiation inhibits their ability to activate T cells through selective effects on the expression of the adhesion molecule ICAM-1 (intercellular adhesion molecule-1). Intercellular adhesion molecule-1 is an important costimulatory molecule provided by antigen-presenting cells for T-cell activation. Using human peripheral blood monocytes and the U937 human monocytoid cell line as model antigen-presenting cells, we investigated the effect of UV radiation on the mRNA steady-state levels for human ICAM-1 by northern blot analysis and relative transcription rates of ICAM-1-specific mRNA by nuclear run-on assay (NRO). Northern blot analysis demonstrated a decreased level of ICAM-1 mRNA at 4 h postradiation relative to glyceraldehyde-3-dehydrogenase mRNA. The NRO analysis demonstrated a greater than 35% decrease of newly synthesized specific mRNA at 4 h postirradiation. The results demonstrate a transcriptionally based mechanism for the diminution of both mRNA and translatable mRNA specific for ICAM-1 regulation in UV-treated antigen-presenting cells.

In situ expression of a B7-like adhesion molecule on keratinocytes from human epidermis.

The B7 adhesion molecule, a member of the immunoglobulin superfamily, has previously been identified primarily on cells of hematopoietic origin. Because B7 has been shown to facilitate interactions with T cells and because cells of the epidermis are proficient at binding and activating T lymphocytes, studies were performed to determine whether B7 was expressed in human epidermis. A subpopulation of brightly staining B7-positive cells was observed in situ in normal human epidermis. Flow-cytometric examination of epidermal cell suspensions that had been cultured for 24 h or longer demonstrated that between 10 and 40% of cells expressed B7 or a closely related antigen. Immunoelectron microscopy, double-staining procedures, and examination of epidermal suspensions depleted of Langerhans cells all confirmed that the B7-positive cells were keratinocytes. These studies identify human epidermal keratinocytes, a non-hematopoietic cell population, as a cell type capable of expressing a B7-like adhesion molecule.