Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice.

Exposure of mice to ultraviolet radiation results in the development of suppressor T lymphocytes in lymphoid organs, followed by the appearance of primary skin cancers. The presence or absence of these suppressor lymphocytes determines whether or not primary cancers will develop in the ultraviolet-irradiated skin. This demonstrates the importance of immunological regulatory pathways in carcinogenesis and provides an example of immunological surveillance.

Antigenic similarity between cells transformed by ultraviolet radiation in vitro and in vivo.

Cells of the 10T 1/2 mouse fibroblast line transformed in vitro by ultraviolet radiation are antigenically similar to those from skin cancers produced in mice by repeated exposure to ultraviolet radiation. Both types of tumor cells grew preferentially in ultraviolet-irradiated syngeneic mice relative to untreated animals, and both were recognized by ultraviolet radiation-induced tumor-specific suppressor lymphocytes. These properties were not shared by 10T 1/2 cells transformed in vitro by x-rays or 3-methylcholanthrene.

Immunologic parameters of ultraviolet carcinogenesis.

Skin tumors induced in mice by UV light are usually immunologically rejected by normal syngeneic recipents. We evaluated the immune status of primary hosts against these highly antigenic tumors immediately after surgical removal of the primary tumor. All primary hosts were susceptible to challenge with their autochthonous tumors, though most of these were rejected by untreated control mice. Primary hosts were also susceptible to challenge with isografts of antigenically dissimilar UV-induced neoplasms. The susceptibility of the primary hosts to tumor challenge was probably induced by chronic exposure to UV light, since UV-irradiated non-tumor-bearing mice were also susceptible to challenge with these tumors. Although UV-treated mice were unalbe to reject these syngeneic tumors, they could reject skin and tumor allografts. Further, UV irradiation did not interfere with the second-set rejection of syngeneic UV-induced tumors in mice that were specifically immunized before UV treatment.

In vivo immune responses of mice during carcinogenesis by ultraviolet irradiation.

In these experiments, we tested in various in vivo assays the immune responses of inbred C3H/HeN(MTV-) (C3H-) mice during carcinogenesis by chronic exposure to UV irradiation. Although the UV-treated mice were unable to reject syngeneic UV-induced tumor transplants, they rejected H-2-incompatible tumor allografts and H-2-compatible skin allografts. The primary hemagglutinin response to sheep red blood cells was normal in these mice, as were the induction of a local graft-versus-host reaction with lymphoid cells from UV-irradiated donors and the induction of an inflammatory response to dimethyl sulfoxide in the footpads of UV-treated mice. An early transient depression of two reactions in UV-irradiated mice occurred: delayed hypersensitivity to dinitrochlorobenzene measured by footpad swelling and the graft-versus-host reaction in UV-irradiated recipients measured by the use of the popliteal lymph node weight gain assay. Both of these reactions returned to a normal level before the development of primary tumors. We conclude that the inability of UV-irradiated mice to reject syngeneic and autochthonous UV-induced tumors was not due to a generalized immunosuppressive effect of chronic UV irradiation.

Photoreactivation of ultraviolet radiation-induced pyrimidine dimers in neonatal BALB/c mouse skin.

The numbers of ultraviolet light (UV)-induced pyrimidine dimers in the DNA of neonatal BALB/c mouse skin were measured by assessing the sensitivity of the DNA to Micrococcus luteus UV endonuclease. Irradiation of neonatal BALB/c mice with FS40 sunlamps caused a dose-dependent induction of endonuclease-sensitive sites (pyrimidine dimers) in DNA extracted from back skin. Exposure of these UV-irradiated neonatal mice to photoreactivating (PR) light ("cool white" fluorescent lamp and incandescent lamp) caused a reduction in the number of pyrimidine dimers in the DNA, as revealed by a shift in low-molecular-weight DNA to high-molecular-weight DNA. In contrast, DNA profiles of the skin of either UV-irradiated mice or UV-irradiated mice kept in the dark for the same duration as those exposed to PR light did not show a loss of UV-induced endonuclease-sensitive sites. Furthermore, reversing the order of treatment, i.e., administering PR light first and then UV, did not produce a reduction in pyrimidine dimers. These results demonstrate that PR or UV-induced pyrimidine dimers occurs in neonatal BALB/c mouse skin. The optimal wavelength range for in vivo PR appears to be in the visible region of the spectrum (greater than 400 nm). Although dimer formation could be detected in both dermis and epidermis, PR occurred only in the dermis. Furthermore, the PR phenomenon could not be detected in the skin of adult mice from the same inbred strain.

Enhanced metastatic potential of murine fibrosarcomas treated in vitro with ultraviolet radiation.

The purpose of this study was to determine whether repeated treatment of tumor cells in vitro with mutagenic doses of ultraviolet (UV) radiation could influence the metastatic behavior of these cells in vivo. Three cloned lines of UV-2237, a fibrosarcoma induced in a C3H- mouse by chronic irradiation with UV, and SF-19, a spontaneous C3H- fibrosarcoma, were grown in culture. These cell lines varied from low to high metastatic potential as determined by in vivo tests. The cultures were exposed to UV radiation from an FS40 sunlamp at a dose that killed 40% of the cells. These UV radiation exposures were repeated at 3- to 5-day intervals for a total of 5 treatments. The mutation frequency was analyzed by monitoring the appearance of ouabain-resistant colonies following UV irradiation. With all four tumor lines, the frequency of conversion to ouabain resistance was increased more than 10-fold. Tumor cells given 5 UV radiation treatments and control cultures carried in parallel without exposure to UV radiation were tested for metastatic potential in an in vivo lung colony assay. Cell lines treated in vitro with UV radiation produced more experimental metastases than the counterpart unirradiated cultures. We conclude that, in all four tumor lines, exposure of tumorigenic cells to mutagenic doses of UV radiation can alter their biological behavior and that this may contribute to the progression of tumors from low to high metastatic capability.

Ultraviolet radiation-induced suppression of contact hypersensitivity in relation to padimate O and oxybenzone.

Contact hypersensitivity (CHS) in mice can be induced by cutaneous sensitization followed by elicitation via ear-painting with trinitrochlorobenzene (TNCB). This CHS reaction is systemic and can be suppressed by exposure of mice to suberythemogenic doses of 280-315 nm radiation. In this study, we investigated whether a commercially available water-resistant sunscreen, either SPF-6 or SPF-15, containing Padimate O (UVB absorber) and oxybenzone (UVA absorber), was effective in preventing systemic suppression of CHS induced by either FS36 sunlamp exposure or solar simulating radiation. We observed that these two sunscreen preparations were totally incapable of preventing the immunologic suppression of contact hypersensitivity by UV radiation. These results indicate that application of sunscreen does not retard the development of suppression of CHS following repeated UV exposure under conditions where erythema is not clinically observed. Thus, erythema may not be a good end point for assessing systemic immune suppression and its consequences.

Further characterization of immunological unresponsiveness induced in mice by ultraviolet radiation. II. Studies on the origin and activity of ultraviolet-induced suppressor lymphocytes.

We are studying the development and mode of action of suppressor T cells induced by ultraviolet (UV) radiation, which prevent the rejection of syngeneic UV-induced tumors. Suppressor cells were induced in C3H mice by exposure to FS40 sunlamps for 1 hr, three times per week for 3 months. Neither thymectomy nor splenectomy prior to UV irradiation prevented the development of these suppressor T cells in other lymphoid tissues. The UV-induced suppressor cells functioned when injected s.c. with mixtures of normal lymphocytes and tumor cells in a Winn-type assay in immunodeficient recipients. When UV T cells were mixed with syngeneic UV-induced tumor cells they did not increase the incidence or growth rate of the tumors relative to tumor cells alone, suggesting that the suppressor cells function by interacting with normal lymphocytes and not by directly stimulating tumor growth. Although the suppressor cells were effective in vivo when injected i.v. or when injected locally with normal lymphocytes, they did not suppress cytotoxic effector lymphocytes in a short-term 51Cr release assay in vitro.

Further characterization of immunological unresponsiveness induced in mice by ultraviolet radiation. Growth and induction of nonultraviolet-induced tumors in ultraviolet-irradiated mice.

Ultraviolet (UV)-irradiated mice were compared with unirradiated mice for their susceptibility to primary and transplanted tumors etiologically unrelated to UV radiation. Although UV-irradiated mice are unable to reject transplants of highly antigenic syngeneic tumors induced by UV light, the growth of syngeneic, non-UV-induced tumors generally was not accelerated in these animals. Furthermore, UV-irradiated mice were no more susceptible to the induction of primary leukemias, mammary tumors, or sarcomas than were unirradiated animals. Tests of immune responses to weak transplantation antigens showed that UV-irradiated mice rejected H-Y-incompatible skin grafts as vigorously as did normal animals, and that the primary in vitro cytotoxic responses of spleen cells from UV-irradiated mice to trinitrophenyl (TNP)-modified syngeneic cells and to Hh antigens were unaffected. We conclude that the susceptibility of UV-irradiated mice to challenge with UV-induced tumors represents a selective unresponsiveness, and that it is not attributable to a generalized deficiency in the immune response to tumor-specific antigens or to weak transplantation antigens.

Pulmonary botryomycoma.

A patient with a mobile mass of anaerobic organisms in the pulmonary parenchyma is presented. Radiographically it resembled a fungous ball. This observed botryomycoma may be part of the spectrum of aspiration pneumonia.

Peripheral blood lymphocyte apoptosis: a clue to the diagnosis of acute infectious mononucleosis.

OBJECTIVE: To describe the morphology and significance of apoptotic lymphocytes in peripheral blood smears of patients with acute infectious mononucleosis. To our knowledge this has not been previously reported. DESIGN: Peripheral blood smears from 27 patients with a positive heterophile antibody test were collected and reviewed for the presence of apoptotic lymphocytes. Flow cytometry was performed on three cases to document the previously described low expression of bcl-2 in lymphocytes in infectious mononucleosis. Four control patient populations comprising 80 cases were similarly screened for the presence of apoptotic lymphocytes. SETTING: The specimens were collected over a 3-month period in two laboratories at our tertiary care hospital; all specimens were processed according to a standard protocol. PATIENTS: Young adult military recruits and their spouses, military dependent adolescents, and retired military personnel. RESULTS: Twenty-four (88.9%) of 27 peripheral blood smears of patients with acute infectious mononucleosis contained readily identifiable apoptotic lymphocytes. Three (3.75%) of 80 control peripheral blood smears were identified with rare apoptotic lymphocytes, all occurring in patients with viral upper respiratory infections. CONCLUSIONS: The finding of apoptotic lymphocytes in a peripheral blood smear is useful in the differential diagnosis of infectious mononucleosis and neoplastic hematolymphoid processes.

Diffuse panbronchiolitis: histologic diagnosis in unsuspected cases involving North American residents of Asian descent.

OBJECTIVE: To study and report two cases of diffuse panbronchiolitis in patients of Asian ancestry residing in the United States and to review the literature pertaining to this disease. DESIGN: Diffuse panbronchiolitis is a progressive interstitial pneumonitis occurring primarily in Japan. Rare cases are now being identified in Europe and North America. Patients often have a history of sinusitis, present with dyspnea on exertion, and show a restrictive pattern on pulmonary function tests. The clinical, radiologic, and pathologic features of two cases of the disease received for consultation at the Armed Forces Institute of Pathology, Washington, DC, are reported with a review of the literature. RESULTS: Chest radiographs revealed bilateral small nodular opacities with ill-defined borders. High-resolution computed tomography demonstrated the abnormalities to have a centrilobular distribution. Histologically, there was transmural chronic inflammation centered on the terminal bronchioles and an interstitial infiltrate of foamy macrophages. CONCLUSION: Diffuse panbronchiolitis may be mistaken for other more common small airway diseases and may be underrecognized in Western nations. The immigration of Asians and sporadic case reports involving non-Asians make recognition of this disease entity important, as the implications for therapy are different than that of other small airway diseases.

Two group therapy models for clients with a dual diagnosis of substance abuse and personality disorder.

OBJECTIVE: The relative effectiveness of two types of group therapy-the disease-and-recovery model and the cognitive-behavioral model-was examined in a public inpatient and outpatient setting with consumers who had a dual diagnosis of a personality disorder and a substance use disorder. Outcomes in four areas of problem severity were measured: alcohol use, drug use, social and family relations, and psychological functioning. METHODS: Using a quasiexperimental group design, 19 subjects in an inpatient mental health facility and 19 in a public outpatient facility were randomly assigned to the two experimental groups. The groups met three times a week for 12 weeks, and specific group leadership protocols were used. A third group at each setting received usual group treatment. Diagnoses of all subjects were verified using the Structured Clinical Interview for DSM-III-R. The Addiction Severity Index measured changes in problem severity. RESULTS: In the inpatient setting, subjects in both experimental groups had significantly improved social and family relations compared with the usual-treatment group; no posttest changes in the other three areas were noted. In the outpatient setting, cognitive-behavioral group therapy was significantly more effective than the other two group approaches in reducing alcohol use, improving social and family relations, and enhancing psychological functioning. CONCLUSIONS: Results suggest that the severity of mental health consumers' substance abuse problems can be substantially decreased in several areas in an outpatient public setting. In an inpatient setting, the use of either group therapy model was more effective in reducing problem severity than using no specific model.

Sparing of some accessory lobes in diffuse pulmonary edema.

In patients with diffuse pulmonary edema we have noted a number who had sparing of accessory lobes. We postulate that this is due to a combination of two factors: diminished perfusion of the peripheral lung parenchyma and accessory fissures preventing interalveolar drift.

Posterior inferior junction line and left pleuroesophageal stripe: their association with emphysema.

In an effort to define the posterior inferior junction line (PIJL) and its clinical associations more precisely, 64 posteroanterior radiographs demonstrating the PIJL or left pleuroesophageal stripe (LPES) were analyzed for the presence of emphysema, kyphosis, air-filled esophagus, and/or tortuous aorta. Pursuant to the possible association of a PIJL or LPES with an air-filled esophagus, posteroanterior radiographs of 66 patients with achalasia were evaluated for the presence of a PIJL or LPES. To determine the components of the PIJL or LPES, 50 randomly selected computed tomographs (CT) of the chest were reviewed. Finally, 118 posteroanterior radiographs of patients with emphysema were analyzed for the presence of a PIJL and/or LPES to determine the sensitivity of the line/stripe for emphysema. The finding of a PIJL and/or LPES had a combined sensitivity of 23% for emphysema. Although certain other anatomic constructs lead to the presence of a line or stripe, emphysema is the most commonly associated clinical entity with a positive predictive value of 65.8%. The line and/or stripe is formed by interfaces between lung/lung, lung/esophagus, or both at different levels.

Sternal dehiscence in patients with and without mediastinitis.

The authors compared patients with sternal dehiscence (SD) with and without mediastinitis with respect to: 1) time interval from surgery to diagnosis; and 2) frequency of sternal wire abnormalities on chest radiographs (CXR). Using a hospital information system to identify all patients with a diagnosis of SD from January 1993 through April 1999, the authors obtained clinical data by performing a retrospective chart review. For each patient, a CXR from the date of diagnosis of SD was retrospectively compared with the first postoperative CXR to assess for sternal wire displacement, rotation, and disruption. The timing of sternal wire alterations was correlated with clinical findings of SD or mediastinitis. The authors found that sternal wire abnormalities are evident radiographically in the majority of SD patients with and without mediastinitis; there is no significant difference in the frequency of sternal wire abnormalities between these two subgroups. Patients with SD and mediastinitis generally present later in the postoperative period than patients with isolated dehiscence.