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M L Kripke

Publications and source records attributed to M L Kripke.

At least 91 records · Page 5Linked to original sources
PubMed1991

Antigen-presenting activity of draining lymph node cells from mice painted with a contact allergen during ultraviolet carcinogenesis.

The induction of skin cancers in mice by chronic UV irradiation is accompanied by a decrease in the numbers of Ia+ and Thy-1+ dendritic cells in the epidermis early in the course of UV irradiation. Subsequently, the number of Ia+ cells, but not Thy-1+ cells, increases until the time of tumor development. To assess the functional significance of these changes in cutaneous immune cells, and to help define the role these cells may play in immune surveillance against skin cancers, we tested the afferent immunologic capability of the skin during the development of UV-B radiation-induced skin cancers. Afferent immune function was measured by testing the Ag-presenting capacity of draining lymph node (DLN) cells from mice sensitized epicutaneously with dinitrofluorobenzene. A reduced contact hypersensitivity response was induced in mice immunized with DLN cells from UV-irradiated mice that had been sensitized with hapten on UV-irradiated skin. This decreased reactivity was present during the entire latent period of tumor development. However, in tumor-bearing mice, the DLN cells from UV-irradiated, sensitized animals exhibited normal Ag-presenting activity. DLN cells from UV-irradiated mice sensitized on ventral, unirradiated skin exhibited normal Ag-presenting activity. The lowest amount of Ag-presenting activity in the draining lymph nodes of UV-irradiated mice correlated temporally with the lowest number of Ia+, adenosine triphosphatase+ dendritic epidermal cells in the UV-irradiated skin. At least during the early part of the tumor latent period, an increase in the number of these cells was paralleled by an increase in the Ag-presenting activity of the DLN cells. In contrast, the number of Thy-1+ dendritic epidermal cells in UV-irradiated skin did not correlate with the Ag-presenting activity. Thus, the decrease in the number of identifiable epidermal Langerhans cells early in the course of chronic UV irradiation correlated with a decrease in Ag-presenting activity after sensitization through the UV-irradiated skin. These studies demonstrate that the afferent arm of the cutaneous immune response is impaired in the site of tumor development throughout the latent period of UV carcinogenesis.

Animals↗
PubMed1991

Photoimmunology of experimental melanoma.

Increases in the incidence of cutaneous melanoma during the past few decades has drawn attention to the possible causes of this cancer. Although sunlight exposure has long been suspected of being a contributing factor, direct evidence of its participation has been difficult to obtain using epidemiological approaches. We have used murine models to investigate the possible contributions of UV radiation to the induction and pathogenesis of melanoma. Our studies demonstrate that UV radiation contributes to the induction of melanoma in a variety of ways, including an indirect, local effect on the skin. Recent evidence suggests that this indirect effect is immunologically mediated.

Animals↗
PubMed1991

Local suppression of contact hypersensitivity in mice by a new bifunctional psoralen, 4,4',5'-trimethylazapsoralen, and UVA radiation.

Although psoralens plus UVA radiation (320-400 nm) have been widely used for the treatment of dermatologic diseases, the toxic effects of these agents have led investigators to develop new photochemotherapeutic compounds. One such compound is 4,4',5'-trimethylazapsoralen (TMAP), a new bifunctional molecule. The purpose of this study was to examine the immunologic side effects of repeated treatment of C3H mice with TMAP plus UVA radiation. During this treatment, the number of ATPase+, la+, and Thy-1+ dendritic epidermal cells greatly decreased in the treated site, despite the lack of phototoxicity. The reduction in the number of detectable cutaneous immune cells was accompanied by a decrease in the induction of contact hypersensitivity to dinitrofluorobenzene applied to the treated skin, an impairment in the antigen-presenting activity of draining lymph node cells, and the presence of suppressor lymphoid cells in the spleen of unresponsive mice. Treatment with UVA radiation alone also reduced the number of ATPase+, Ia+, and Thy-1+ cells in the skin, but did not cause any detectable alterations in immune function. This implies that morphologic alterations in these cells do not necessarily indicate loss of function. Thus, although TMAP in combination with UVA radiation is not overtly phototoxic, it is highly immunosuppressive in mice.

Animals↗
PubMed1991

Activation of keratinocytes with psoralen plus UVA radiation induces the release of soluble factors that suppress delayed and contact hypersensitivity.

Exposure of mice to psoralen plus ultraviolet A (320-400 nm) radiation or midrange ultraviolet B (280-320 nm) radiation causes a systemic suppression of the immune response. Although the mechanisms involved in the induction of suppression are not entirely clear, recent studies have demonstrated that ultraviolet B--irradiated keratinocytes release soluble factors that depress delayed-type hypersensitivity to alloantigens and activate the suppressor cell pathway. The purpose of this study was to determine whether PUVA-treated keratinocytes could also cause the release of such immunosuppressive factors. Treatment of keratinocytes with psoralen and UVA radiation induced the release of a factor that depressed the delayed-type hypersensitivity reaction to alloantigen. The suppressive factor was released regardless of whether the psoralen formed monofunctional or bifunctional adducts with DNA and regardless of its phototoxicity. In addition, keratinocytes treated with psoralen and lower doses of UVA radiation released a factor that inhibited contact but not delayed-type hypersensitivity, suggesting that more than one immunosuppressive factor is released following treatment of keratinocytes with appropriate doses of psoralen and UVA radiation. Our findings provide evidence that immunosuppressive factors released from keratinocytes may play a role in the induction of systemic immune suppression following PUVA treatment. Moreover, they demonstrate that PUVA treatment, unlike UVB treatment, can cause the release of more than one immunosuppressive factor from keratinocytes.

Animals↗
PubMed1991

Supernatants from ultraviolet-irradiated keratinocytes decrease the resistance and delayed-type hypersensitivity response to Mycobacterium bovis bacillus Calmette-Guerin in mice and impair the phagocytic ability of macrophages.

We recently demonstrated that exposure of mice to a single high dose or multiple smaller doses of ultraviolet (UV) radiation decreased the induction of the delayed-type hypersensitivity (DTH) response to bacillus Calmette-Guerin (BCG) from Mycobacterium bovis injected into unexposed sites. In view of the limited ability of UV radiation to penetrate beyond the epidermis and upper layers of the dermis, it is not entirely clear how exposing the dorsal skin of mice to UV radiation causes systemic impairment of the immune response to BCG. In this study we report that mice injected with supernatants from keratinocyte cultures exposed to UV radiation in vitro impaired host resistance to BCG. Both induction and elicitation of the DTH reaction were suppressed after the intravenous injection of supernatants from UV-irradiated keratinocytes. Furthermore, these supernatants interfered with the elimination of viable bacteria from the lymphoid organs. To determine whether macrophages were the target of the UV-induced, keratinocyte-derived, suppressive cytokine, macrophages were isolated from mice injected with the suppressive cytokine or treated in vitro with the supernatants and tested for their ability to ingest and kill BCG in vitro. Injection of the suppressive factor significantly reduced the phagocytosis of BCG by the macrophages but did not alter the rate of intracellular killing. Similarly, phagocytosis was reduced when normal macrophages were treated in vitro with the suppressive factor. These findings suggest that the suppressive cytokine interferes with the elimination of bacteria in vivo by inhibiting the initial step in bacterial clearance, the uptake of the bacteria by host macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization.

These studies address the hypothesis that Ag-bearing epidermal Langerhans cells migrate to the regional lymph node during contact sensitization and function as APC. Skin from C3H mice was grafted onto BALB/c nude mice, and 7 or 14 days later, the recipients were sensitized with FITC through the grafts. APC from lymph nodes draining the site of sensitization were capable of sensitizing C3H recipients to FITC. Because sensitization is MHC restricted, only cells reaching the lymph node from the grafted skin could have induced contact hypersensitivity in C3H mice. Examination of the FITC+ draining lymph node cells by immunofluorescence and immunoelectron microscopy demonstrated that all were Ia+, most were F4/80+, and some contained Birbeck granules. These studies demonstrate that Ia+, FITC+ cells from the skin, at least some of which are Langerhans cells, leave the skin after epicutaneous sensitization with FITC and participate in the initiation of the contact hypersensitivity response within the regional lymph node.

Animals↗
PubMed1990

Alteration of the immune response to Mycobacterium bovis BCG in mice exposed chronically to low doses of UV radiation.

BALB/c mice were exposed on shaved dorsal skin to 1 minimal erythemal dose (MED) of UVB radiation (2.25 kJ/m2) from a bank of six FS-40 sunlamps three times per week. The total number of irradiations ranged from 1 to 27. At regular intervals, groups of mice were injected in the left hind foot pad with 1 x 10(6) live mycobacteria (Mycobacterium bovis BCG) 3 days after the last UVB exposure. The mice were tested 21 and 42 days after infection for a delayed type hypersensitivity (DTH) response to the purified protein derivative (PPD) of tubercle bacilli by injecting PPD into the right hind foot pad and measuring the foot pad swelling 24 hr later. The course of infection was followed by assessing the number of bacterial colony forming units in the lymph node draining the site of BCG infection and the spleen. Mice exposed from 1 to 15 times to 1 MED of UV radiation showed a significant suppression in their DTH response to PPD compared with the unirradiated mice. At the same time, the number of bacterial colony-forming units in the lymph node and spleen of the UV-irradiated mice was greater than in control mice. With continued exposure to UVB, however, the DTH response recovered to a normal level, and there was no longer an increase in the number of viable bacteria in the lymphoid organs. These results indicate that early in the course of chronic UV irradiation, mice were impaired in their ability to mount a DTH response to BCG and to clear these bacteria from their lymphoid organs; later the mice recovered from these effects of UV, with continued treatment. A dose-response study using single doses of UV radiation indicated that a dose of 2.7 kJ/m2 suppressed the DTH response by 50%. Thus, exposure of mice to a single or multiple low doses of UV radiation prior to infection can interfere with systemic immunity to mycobacteria.

Animals↗
PubMed1990

The role of suppressor factors in the regulation of immune responses by ultraviolet radiation-induced suppressor T lymphocytes. III. Isolation of a suppressor factor with the B16G monoclonal antibody.

The purpose of this study was to determine whether the ultraviolet (UV) radiation-induced systemic suppression of the immune response results from the release of soluble suppressor factors (TsF) by UV-induced suppressor T cells (UV Ts). Injecting a TsF-specific monoclonal antibody (B16G) significantly reduced the UV radiation-induced suppression of contact hypersensitivity (CHS). The transfer of spleen cells from the UV-irradiated, B16G-treated mice into normal recipients suppressed CHS in the recipients, indicating that while the suppression of CHS was reversed in the UV-irradiated, B16G-treated mice, suppressor cells were still present. Supernatants from cultures containing UV Ts were incubated on B16G-immunoadsorbent columns. The antibody-bound fraction (45- to 60-kDa, non-disulfide-linked proteins) suppressed CHS when injected into normal recipients. These results demonstrate that the B16G antibody reacts with TsF from UV Ts and suggest that B16G acts in vivo by inhibiting the activity of TsF. Thus, suppressor factors appear to play an essential role in the regulation of immune responses by UV Ts.

Animals↗
PubMed1990

Murine Thy-1+ dendritic epidermal cells induce immunologic tolerance in vivo.

To study the potential immunologic functions of murine Thy-1+ dendritic epidermal cells (Tdec), we used long term, IL-2-dependent, Tdec lines derived from the skin of C3H mice. Cells of the Tdec lines AU16 or AU4 were conjugated in vitro with the hapten FITC and injected s.c. into the footpad (ifp.) or i.v. into syngeneic recipient mice to assess their ability to induce or inhibit contact hypersensitivity (CHS). FITC-conjugated Tdec were unable to induce CHS after ifp. or i.v. injection. Furthermore, when mice were sensitized epicutaneously with FITC after the injection of FITC-conjugated Tdec, they were unable to mount a CHS response. These results indicated that hapten-conjugated Tdec are capable of inducing tolerance upon ifp. or i.v. injection. In contrast, ifp. injection of normal lymphocytes conjugated with FITC in vitro produced no impairment of the CHS response to FITC, although i.v. injection of these cells, as with that of FITC-conjugated Tdec, induced down-regulation of CHS. The immunologic tolerance induced by FITC-conjugated Tdec was Ag specific, but not H-2 restricted. Immunization with unconjugated Tdec either ifp. or i.v. did not induce tolerance, indicating that unconjugated Tdec by themselves are not suppressive. In addition, Tdec were unable to mediate a local graft-vs-host reaction in an F1 host. These results demonstrate that Tdec can induce immunologic tolerance and suggest that these cells may play a role in the down-regulation of cutaneous immune responses.

Animals↗
PubMed1990

Ultraviolet radiation-induced damage to human Langerhans cells in vivo is not reversed by ultraviolet A or visible light.

Exposure of human skin in vivo to UVB radiation induces pyrimidine dimers in DNA and alters the morphology and function of epidermal Langerhans cells. Cells in human skin have been reported to contain a photoreactivation repair mechanism that, following exposure to UVA or visible light, repairs UVB-induced pyrimidine dimers. The purpose of this study was to determine whether exposure to photoreactivating light would also reverse the UVB-induced morphologic alterations in human Langerhans cells. The skin of eight healthy volunteers was exposed to a low dose of UVB radiation (between 0.75 and 1.5 times the minimal erythema dose), and immediately thereafter exposed to photoreactivating light from either BLB fluorescent lamps (UVA radiation) or incandescent bulbs (visible light). After exposure to UVB radiation, the number of ATPase+ epidermal Langerhans cells was reduced in all subjects to between 21% and 65% of that in unirradiated skin, and the majority of the remaining cells exhibited morphologic alterations. Exposure of the UVB-irradiated skin to photoreactivating light did not reverse or reduce these effects. We conclude that UVB-induced morphologic alterations of human Langerhans cells are not subject to photoreactivation. These results imply either that pyrimidine dimers are not involved in these effects of UVB irradiation, or that photoreactivation does not occur in human Langerhans cells in situ.

Adult↗
PubMed1990

Immunosuppression by factors released from UV-irradiated epidermal cells: selective effects on the generation of contact and delayed hypersensitivity after exposure to UVA or UVB radiation.

Exposure of murine epidermal cells to UV radiation in vitro causes the release of immunoregulatory factors that mimic some of the immunosuppressive effects of in vivo UV irradiation. The purpose of this study was to investigate the spectrum of immune responses affected following i.v. injection of supernatants obtained from cultures of epidermal cells exposed in vitro to UV radiation. Treatment of primary epidermal cell cultures or transformed keratinocytes (Pam 212 cells) with UVB (280-320 nm) radiation caused the release of factors that suppressed the induction of delayed hypersensitivity to alloantigen and trinitrophenyl-modified self-antigens in syngeneic and allogeneic mice. Contrary to expectations, however, the injection of supernatants from UVB-irradiated epidermal cells had no effect on the induction of contact hypersensitivity to trinitrochlorobenzene. On the other hand, treatment of the keratinocytes with UVA radiation (320-400 nm, filtered to remove wavelengths in the UVB region) resulted in the release of a factor that suppressed contact but not delayed hypersensitivity. Neither the UVA-induced nor the UVB-induced suppressive factor inhibited the generation of an antibody response to sheep erythrocytes, indicating that, like the suppression that occurs after in vivo exposure to UV radiation, the suppression induced by factors from UV-irradiated keratinocytes is selective in nature. These data support the hypothesis that soluble keratinocyte-derived suppressive factors are involved in the induction of systemic immune suppression by UV radiation. In addition, they suggest that multiple suppressive factors, having different immunosuppressive properties, are produced by different wavelengths of UV radiation.

Animals↗
PubMed1990

The effect of photochemotherapy with 4,4',6 trimethylangelicin on murine cutaneous immune cells.

The effect of photochemotherapy with 4,4',6 trimethylangelicin (TMA), a new monofunctional furocoumarin with a high antiproliferative activity, was studied on murine dendritic epidermal cells. Female mice (C3H/HeN[MTV-]) were treated topically with the drug three times a week for 4 consecutive weeks followed each time by 1 J/cm2 of UVA radiation. At the end of the treatment almost total depletion of ATPase+, Ia+ and Thy-1+ dendritic epidermal cells was observed, associated with marked hyperpigmentation but no gross or microscopic phototoxicity. Although 4,4',6 TMA is not phototoxic in mice, it affects the cutaneous immune cells.

Animals↗
PubMed1990

Photoimmunology.

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Allergy and Immunology↗
PubMed1990

Immunogenicity and cross-reactivity of syngeneic murine melanomas.

Non-melanoma skin cancers induced in mice by chemical carcinogens or ultraviolet radiation are often antigenic but rarely induce cross-protective immunity when tested by in vivo transplantation methods. We wished to determine whether melanocytic skin tumors behave similarly or whether they exhibit cross-reactive antigens in vivo. Three melanomas induced in C3H/HeNCr(MTV-) mice by initiation with ultraviolet radiation and promotion with croton oil or initiation with 7,12-dimethyl-benz[a]anthracene and promotion with 12-O-tetradecanoyl-phorbol-13-acetate or croton oil plus ultraviolet radiation were tested for immunogenicity and cross-reactivity in vivo. The three melanomas were highly immunogenic, and all induced some degree of protection against the other melanomas. Non-melanoma skin cancers induced by the same carcinogens were less immunogenic and did not immunize against the melanomas. We conclude that unlike other skin cancers, melanocytic tumors induced by chemical carcinogens and ultraviolet radiation are highly cross-reactive in vivo and thus represent a unique subset of murine skin cancers.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Effects of a new bifunctional psoralen, 4,4',5'-trimethylazapsoralen and ultraviolet-A radiation on murine dendritic epidermal cells.

Although some psoralens are therapeutically active in the treatment of cutaneous hyperproliferative diseases when combined with UVA (320-400 nm) radiation, the toxic effects of these compounds have led physicians to seek new photochemotherapeutic agents. One such agent is 4,4',5'-trimethylazapsoralen (TMAP), a new bifunctional psoralen compound. We investigated the effects of repetitive treatments with TMAP plus UVA radiation on the number of dendritic immune cells in murine epidermis and on the induction of phototoxicity. Mice treated 3 times per week for 4 weeks with 129 microgram TMAP plus 10 kJ/m2 UVA radiation exhibited no gross or microscopic evidence of phototoxicity. During this treatment, the numbers of ATPase+, Ia+, and Thy-l+ dendritic epidermal cells were greatly reduced, and by the end of the treatment period, few dendritic immune cells could be detected. We conclude that morphological alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that TMAP plus low-dose UVA radiation decreases the numbers of detectable Langerhans cells and Thy-1+ cells in murine skin.

Animals↗
PubMed1990

Photocarcinogenesis in mice by 4,4',6 trimethylangelicin plus UVA radiation.

The carcinogenic effect of a new monofunctional psoralen 4,4',6-trimethylangelicin (TMA) plus UVA radiation was examined in C3H/HeN mice and compared with that of the parent compound angelicin. TMA carcinogenic effects were also compared with the previously reported effects of 8-methoxypsoralen. Using 2 different doses of TMA (25 micrograms and 250 micrograms) combined with 1 J/cm2 of UVA radiation, we found that 42% and 52% of the mice (respectively) developed tumors on the treated site. A dose of angelicin (215 micrograms) equimolar to the highest dose of TMA combined with 1 J/cm2 of UVA radiation produced tumors in 28% of the mice (P greater than 0.05). All tumors were squamous cell carcinomas. No metastases were found in any of the mice. We conclude that, although TMA + UVA radiation is carcinogenic in mice, it seems to be an equally active, but less phototoxic and less carcinogenic psoralen than 8-methoxypsoralen. The parent compound angelicin is not significantly less carcinogenic, and its clinical efficacy is poor.

Animals↗