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Biomedical subjects

M L Kripke

Publications and source records attributed to M L Kripke.

At least 37 records · Page 2Linked to original sources
PubMed1998

Health risks.

The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, i.e., increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). Quantitative risk estimates are available for some of the UV-B-associated effects, e.g., cataract and skin cancer; however, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. Ocular damage from UV exposures includes effects on the cornea, lens, iris, and associated epithelial and conjunctival tissues. The most common acute ocular effect of environmental ultraviolet radiation (UVR) is photokeratitis. Also known as snowblindness in skiers, this condition also occurs in other outdoor recreationists. Chronic eye conditions likely to increase with ozone depletion include cataract, squamous cell carcinoma, ocular melanoma, and a variety of corneal/conjunctival effects, e.g., pterygium and pinguecula. Suppression of local (at the site of UV exposure) and systemic (at a distant, unexposed site) immune responses to a variety of antigens has been demonstrated in both humans and animals exposed to UV-B. In experiments with animals these effects have been shown to worsen the course/outcome of some infectious diseases and cancers. There is reasonably good evidence that such immunosuppression plays a role in human carcinogenesis; however, the implications of such immunosuppression for human infectious diseases are still unknown. In light-skinned populations, exposure to solar UVR appears to be the most important environmental risk factor for basal and squamous cell carcinomas and cutaneous melanoma. Originally it was believed that total accumulated exposure to UVR was the most important environmental factor in determining risk for these tumors. Recent information now suggests that only squamous cell carcinoma risk is related to total exposure. In the cases of both basal cell carcinoma and melanoma, new information suggests that increases in risk are tied to early exposures (before about age 15), particularly those leading to severe sunburns. Testing of a number of the chlorofluorocarbon (CFC) alternatives indicates that most of these chemicals have low acute toxicity, and low to moderate chronic toxicity. Some chemicals that were originally proposed as alternatives have been dropped from consideration because these tests raised concerns about toxicity and/or manufacturing difficulties. In one instance, high accidental occupational exposure was associated with liver damage, underlining the need for care in the use of these substitutes. Recent quantitative risk estimates have been developed for cataract, melanoma, and all skin cancers combined. These estimates indicate that under the Montreal Adjustments, cataract and skin-cancer incidence will peak mid-century at additional incidences of just under 3 per 100,000 and about 7 per 100,000, respectively.

Animals↗
PubMed1998

Molecular regulation of UVB-induced cutaneous angiogenesis.

We determined whether cutaneous angiogenesis induced by exposure of mice to ultraviolet-B (UVB) radiation is associated with an imbalance between positive and negative angiogenesis-regulating molecules. Unshaved C3H/HeN mice were exposed to a single dose (15 kJ per m2) of UVB. At various times, the mice were killed, and their external ears were processed for routine histology and immunohistochemistry. Antibodies against proliferating cell nuclear antigen and bromodeoxyuridine identified dividing cells. Antibodies against CD31/ PECAM-1 identified endothelial cells, and antibodies against basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor, and interferon-beta (IFN-beta) identified angiogenesis-regulating molecules. Epidermal hyperplasia was documented by 48 h and reached a maximum on day 7 after exposure to UVB. The expression of bFGF increased by 24 h, whereas the expression of IFN-beta decreased by 72 h after exposure to UVB. The expression of vascular endothelial growth factor/vascular permeability factor increased slightly after irradiation. The altered balance between bFGF and IFN-beta was associated with increased endothelial cell proliferation (bromodeoxyuridine + CD31 + cells) within existing blood vessels, leading to telangiectasia and new blood vessels. UV-induced epidermal hyperplasia and cutaneous angiogenesis were highest in IFN-alpha/beta receptor knockout mice. These results demonstrate that in response to UVB radiation, dividing keratinocytes produce a positive angiogenic molecule (bFGF) but not a negative angiogenic molecule (IFN-beta), and that this altered balance is associated with enhanced cutaneous angiogenesis.

Animals↗
PubMed1998

p53 Mutations in hairless SKH-hr1 mouse skin tumors induced by a solar simulator.

In this study, we investigated whether the spectrum of p53 mutations in skin tumors induced in hairless SKH-hr1 mice by a solar simulator (290-400 nm) are similar to those found in skin tumors induced in C3H mice by UV radiation from unfiltered (250-400 nm) and Kodacel-filtered (290-400 nm) FS40 sunlamps. Analysis of tumor DNA for p53 mutations revealed that 14 of 16 (87.5%) SkH-hr1 skin tumors induced by the solar simulator contained mutations. Single C-->T transitions at dipyrimidine sequences located on the nontranscribed DNA strand were the most predominant type of p53 mutation. Remarkably, 52% of all p53 mutations in solar simulator-induced SKH-hr1 skin tumors occurred at codon 270, which is also a hotspot in C3H skin tumors induced by unfiltered and Kodacel-filtered FS40 sunlamps. However, T-->G transversions, which are hallmarks of UVA-induced mutations, were not detected in any of the solar simulator-induced skin tumors analyzed. These results demonstrate that the p53 mutation spectra seen in solar simulator-induced SKH-hr1 skin tumors are similar to those present in -unfiltered and Kodacel-filtered FS40 sunlamp-induced C3H skin tumors. In addition, our data indicate that the UVA present in solar simulator radiation does not play a role in the induction of p53 mutations that contribute to skin cancer development.

Animals↗
PubMed1998

Inhibition of UV-induced p53 mutations by sunscreens: implications for skin cancer prevention.

Ultraviolet (UV) radiation is a potent human carcinogen and it induces skin cancer in experimental animals. Recent studies have shown that unique mutations in the p53 tumor suppressor gene contribute to the development of human and mouse UV-induced skin cancers. Such mutations are also found in sun-damaged skin and actinic keratosis, suggesting that p53 mutations arise early during UV skin carcinogenesis. Our studies have shown that p53 mutations can be detected in UV-irradiated mouse skin months before the gross appearance of skin tumors, suggesting that p53 mutations can serve as a surrogate early biologic endpoint in skin cancer prevention studies. Indeed, application of sun protection factor 15 sunscreens to mouse skin before each UV irradiation resulted in an 88-92% reduction in the number of p53 mutations. Because p53 mutations represent an early essential step in photocarcinogenesis, these results imply that inhibition of this event may protect against skin cancer development.

Animals↗
PubMed1998

Suppression of delayed and contact hypersensitivity responses in mice have different UV dose responses.

Although acute exposure to UV radiation suppresses the induction of delayed-type (DTH) and contact (CHS) hypersensitivity in mice, it is not clear whether the photobiological mechanism(s) involved in suppressing these closely related immune reactions is the same. A careful examination of the UV dose responses and wavelength dependencies involved in suppressing CHS and DTH may provide important insights into the mechanisms involved. We compared the UV dose-response curves for suppressing four closely related immune reactions, local and systemic suppression of CHS to dinitrofluorobenzene, systemic suppression of DTH to Candida albicans and systemic suppression of DTH to alloantigen using three different UV spectra (FS40 sunlamps, Kodacel-filtered FS40 sunlamps and solar-simulated light). For each immune response studied, the amount of UVB radiation required to induce 50% immune suppression was lowest when FS40 sunlamps were used, highest with solar-simulated light and intermediate when Kodacel-filtered FS40 sunlamps were used, but the differences observed were not statistically significant. The UV dose-response curves for immune suppression differed significantly depending on the assay used, the site of antigenic sensitization and the antigen used. These findings suggest that the mechanisms by which UV radiation induces immune suppression differ for the four immunological reactions studied.

Animals↗
PubMed1997

The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers.

Exposing skin to UVB (280-320 nm) radiation suppresses contact hypersensitivity by a mechanism that involves an alteration in the activity of cutaneous antigen-presenting cells (APC). UV-induced DNA damage appears to be an important molecular trigger for this effect. The specific target cells in the skin that sustain DNA damage relevant to the immunosuppressive effect have yet to be identified. We tested the hypothesis that UV-induced DNA damage in the cutaneous APC was responsible for their impaired ability to present antigen after in vivo UV irradiation. Cutaneous APC were collected from the draining lymph nodes of UVB-irradiated, hapten-sensitized mice and incubated in vitro with liposomes containing a photolyase (Photosomes; Applied Genetics, Freeport, NY), which, upon absorption of photoreactivating light, splits UV-induced cyclobutane pyrimidine dimers. Photosome treatment followed by photoreactivating light reduced the number of dimer-containing APC, restored the in vivo antigen-presenting activity of the draining lymph node cells, and blocked the induction of suppressor T cells. Neither Photosomes nor photoreactivating light alone, nor photoreactivating light given before Photosomes, restored APC activity, and Photosome treatment did not reverse the impairment of APC function when isopsoralen plus UVA (320-400 nm) radiation was used instead of UVB. These controls indicate that the restoration of APC function matched the requirements of Photosome-mediated DNA repair for dimers and post-treatment photoreactivating light. These results provide compelling evidence that it is UV-induced DNA damage in cutaneous APC that leads to reduced immune function.

Animals↗
PubMed1997

Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens.

UV-induced mutations in the p53 tumor suppressor gene play an essential role in skin cancer development. We report here that such mutations can be detected in UV-irradiated mouse skin months before the gross appearance of skin tumors. Application of SPF-15 sunscreens to mouse skin before each UV irradiation nearly abolished the frequency of p53 mutations. These results indicate that p53 mutation is an early event in UV skin carcinogenesis and that inhibition of this event may serve as an early end point for assessing protective measures against skin cancer development.

Animals↗
PubMed1997

Immune response associated with nonmelanoma skin cancer.

It is now clear that UV radiation causes nonmelanoma skin cancer in at least two ways: by causing permanent changes in the genetic code and by preventing immunologic recognition of mutant cells. These are interacting rather than separate mechanisms. Damage to DNA results in disregulation of cellular proliferation and initiates immune suppression by stimulating the production of suppressive cytokines. These cytokines contribute to the loss of immunosurveillance. Ultraviolet radiation has both local and systemic immunosuppressive effects. Locally, it depletes and alters antigen-presenting LC at the site of UV irradiation. Systemic suppression results when Ts cells are induced, by altered LC, by inflammatory macrophages that enter the skin following UV irradiation, or by the action of cytokines. Damage to DNA appears to be one of the triggering events in inducing systemic immunosuppression via the release of immunosuppressive cytokines and mediators. Immunologic approaches to treating skin cancers so far have concentrated on nonspecifically stimulating immune cells that infiltrate these tumors, but induction of specific immune responses against these tumors with antitumor vaccines has received little attention as yet. Preventive measures include sun avoidance and the use of sunscreens to prevent DNA damage by UV light. Future strategies may employ means to reverse UV-induced immunosuppression by using anti-inflammatory agents, biologicals that accelerate DNA repair or prevent the generation of immunosuppressive cytokines, and specific immunotherapy with tumor antigens. New approaches for studying the immunology of human skin cancers are needed to accelerate progress in this field.

Animals↗
PubMed1996

Differential effects of a monoclonal antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation.

Urocanic acid (UCA) occurs naturally in the stratum corneum of the skin as the trans-isomer and, upon exposure to UVB radiation, converts to cis-UCA. It has been proposed that trans-UCA is the photoreceptor for and, following its isomerization to cis-UCA, a mediator of the suppressive effects of UVB irradiation on systemic T cell-mediated immune responses, such as contact hypersensitivity (CH) and delayed-type hypersensitivity (DTH). To address this question directly, we studied the consequence of deleting the in vivo function of cis-UCA on systemic suppression of CH and DTH, by injecting mice with a anti-cis-UCA mAb several hours before exposure to UVB radiation. We found that while DTH responses were completely restored, the anti-cis-UCA Ab had no effect on UV-induced immunosuppression of the CH response, even though suppressor cell formation was inhibited in both cases. Further, the kinetics of IL-10 expression in the skin of irradiated mice injected with the anti-cis-UCA mAb was altered and the diminished APC function of spleen-adherent cells from UVB-irradiated mice was totally reversed by the Ab. These findings suggest that cis-UCA acts as a mediator for some but not all of the systemic suppressive effects of UVB irradiation. They also suggest that cis-UCA may act indirectly via IL-10 to modulate immune function.

Adoptive Transfer↗
PubMed1996

Evidence that DNA damage triggers interleukin 10 cytokine production in UV-irradiated murine keratinocytes.

UV irradiation interferes with the induction of T cell-mediated immune responses, in part by causing cells in the skin to produce immunoregulatory cytokines. Recent evidence implicates UV-induced DNA damage as a trigger for the cascade of events leading to systemic immune suppression in vivo. However, to date, there has been no direct evidence linking DNA damage and cytokine production in UV-irradiated cells. Here we provide such evidence by showing that treatment of UV-irradiated murine keratinocytes in vitro with liposomal T4 endonuclease V, which accelerates the repair of cyclobutylpyrimidine dimers in these cells, inhibits their production of immunosuppressive cytokines, including interleukin 10. Application of these liposomes to murine skin in vivo also reduced the induction of interleukin 10 by UV irradiation, whereas liposomes containing heat-inactivated T4 endonuclease V were ineffective. These results support our hypothesis that unrepaired DNA damage in the skin activates the production of cytokines that down-regulate immune responses initiated at distant sites.

Animals↗
PubMed1996

Enhanced growth of murine melanoma in ultraviolet-irradiated skin is associated with local inhibition of immune effector mechanisms.

We have developed a model for studying the role of local immunologic mechanisms in tumor development, in which injection of K1735 melanoma cells into the UV-irradiated ears of C3H mice results in a significantly higher incidence of tumors than injection into unirradiated ears. This effect of UV irradiation is immunologically mediated. We hypothesized that UV blocks the efferent arm of the immune response, thereby facilitating tumor development within the irradiated site. We demonstrate that elicitation of a delayed type hypersensitivity response to alloantigen is diminished in UV-irradiated ears. in addition, tumor rejection is impaired in melanoma-immune mice challenged in UV-irradiated ears, even though such mice exhibit systemic immunity when challenged in a nonirradiated site. The ability of immune lymphoid cells to inhibit melanoma growth when mixed with tumor cells and injected into the ears was inhibited by prior UV irradiation of the ears, indicating that the activity of immune effector cells is abrogated in the UV-irradiated microenvironment. Analysis of lymphoid cells in growing tumors indicated that the number of CD8+ T lymphocytes was reduced in the UV-irradiated site. We conclude that efferent immune responses are impaired in UV-irradiated tissue and suggest that the impairment may involve reductions in both the number and the activity of immune effector cells. These studies illustrate that conditions in the local microenvironment during the early stages of tumor growth may profoundly influence the outcome of the host-tumor interaction.

Animals↗
PubMed1996

Localization of DNA damage and its role in altered antigen-presenting cell function in ultraviolet-irradiated mice.

Prior ultraviolet (UV) irradiation of the site of application of hapten on murine skin reduces contact sensitization, impairs the ability of dendritic cells in the draining lymph nodes (DLN) to present antigen, and leads to development of hapten-specific suppressor T lymphocytes. We tested the hypothesis that UV-induced DNA damage plays a role in the impaired antigen-presenting activity of DLN cells. First, we assessed the location and persistence of cells containing DNA damage. A monoclonal antibody specific for cyclobutyl pyrimidine dimers (CPD) was used to identify UV-damaged cells in the skin and DLN of C3H mice exposed to UV radiation. Cells containing CPD were present in the epidermis, dermis, and DLN and persisted, particularly in the dermis, for at least 4 d after UV irradiation. When fluorescein isothiocyanate (FITC) was applied to UV-exposed skin, the DLN contained cells that were Ia+, FITC+, and CPD+; such cells from mice sensitized 3 d after UV irradiation exhibited reduced antigen-presenting function in vivo. We then assessed the role of DNA damage in UV-induced modulation of antigen-presenting cell (APC) function by using a novel method of increasing DNA repair in mouse skin in vivo. Liposomes containing T4 endonuclease V (T4N5) were applied to the site of UV exposure immediately after irradiation. This treatment prevented the impairment in APC function and reduced the number of CPD+ cells in the DLN of UV-irradiated mice. Treatment of unirradiated skin with T4N5 in liposomes or treatment of UV-irradiated skin with liposomes containing heat-inactivated T4N5 did not restore immune function. These studies demonstrate that cutaneous immune cells sustain DNA damage in vivo that persists for several days, and that FITC sensitization causes the migration of these to the DLN, which exhibits impaired APC function. Further, they support the hypothesis that DNA damage is an essential initiator of one or more of the steps involved in impaired APC function after UV irradiation.

Animals↗
PubMed1996

DNA repair and cytokines in antimutagenesis and anticarcinogenesis.

UV is a complete carcinogen because it can induce skin cancer by sequential steps of initiation, promotion and progression. It produces the mutagenic DNA photoproducts that lead to activation of skin oncogenes, and also suppresses the cellular immune responses that are otherwise able to eliminate highly antigenic skin tumors. What is new is that these two steps are related because unrepaired DNA photoproducts cause the release of cytokines, producing a variety of response that contribute to tumor promotion, tumor progression, immunosuppression, and the induction of latent viruses. DNA repair enzymes are a key genoprotection mechanism not only by reversing DNA photoproducts, but also by blocking the carcinogenic cellular responses triggered by cytokines.

Cytokines↗
PubMed1996

Rôle of DNA damage in local suppression of contact hypersensitivity in mice by UV radiation.

Exposure of mice to UVB radiation down-regulates the induction of contact hypersensitivity (CHS) responses to haptens applied to the site of irradiation. Concomittantly, the activity of antigen-presenting cells (APC) in the draining lymph nodes is decreased, and T lymphocytes that suppress the induction of CHS are induced. We assessed the rôle of DNA damage in modulation of the CHS response by UV irradiation by applying liposomes containing T4 endonuclease V (T4N5) to the UV-irradiated skin. Liposomal T4N5, which increases the rate of repair of cyclobutyl pyrimidine dimers (CPD) in DNA, prevented the reduction in the CHS response, the impairement in APC function, and the induction of transferrable immune suppression. Liposomes containing heat-inactivated T4N5 did not restore immune responsiveness. In this model, hapten-bearing APC from unirradiated mice also fail to induce CHS upon injection into UV-irradiated recipients. This systemic effect of UV irradiation on APC function was also prevented by application of liposomes containing active, but not inactive, T4N5. These studies support the hypothesis that DNA damage is an essential initiator of one or more steps leading to impaired immune responsiveness after UV irradiation. They further imply that the release of cytokines that modulate APC function after UV irradiation is triggered by DNA damage.

Animals↗
PubMed1996

UVB irradiation decreases the magnitude of the Th1 response to hapten but does not increase the Th2 response.

Exposure of murine skin to low doses of ultraviolet-B (UVB) radiation before sensitization with hapten reduces the ability of antigen presenting cells (APC) in the draining lymph nodes to initiate contact hypersensitivity responses in vivo and results in the induction of hapten-specific suppressor T cells. In the present study, we tested the hypothesis that exposure of skin to UVB radiation suppresses T cell responses to hapten in vivo by altering the functions of APC, resulting in decreased stimulation of Th1 lymphocytes, which mediate contact hypersensitivity responses, and preferential activation of Th2 cells. C3H/HeN mice were exposed to either a single 2 kJ/m2 dose of UVB or to 400 J/m2 of UVB daily from FS40 sunlamps for four consecutive days and sensitized with fluorescein isothiocyanate on UV-irradiated skin. Draining lymph node cells were collected 18 h after sensitization and co-cultured with nylon wool-purified T cells from naive or fluorescein-immunized mice. Unseparated lymph node cells or sorter-purified fluorescein-bearing APC from UV-irradiated mice induced less T cell proliferation than APC from non-UV-exposed mice. Lymph node cells produced less Th1 and Th2-associated cytokines, interferon-gamma and interleukin-4, respectively, in response to APC from UV-irradiated animals compared with APC from unirradiated, fluorescein-sensitized mice. Thus, low doses of UV radiation do not result in preferential stimulation of Th2 response in lymph nodes, and results from cloned cell lines may incompletely reflect T cell responses in vivo.

Animals↗