Regulation of the immune response against UV-induced skin cancers: specificity of helper cells and their susceptibility to UV-induced suppressor cells

The purpose of this study was to determine the role of T helper (Th) cells in the immune response to UV-induced tumors. Repeated exposure of mice to UV radiation results in the production of suppressor T lymphocytes that facilitate tumor growth by inhibiting host immunity. To investigate whether the suppressor T cells inhibit the response to UV tumors by blocking the generation of Th, we employed an indirect method for measuring helper cell activity. We found that Th were produced in normal mice after immunization with UV-induced tumors. These Th appeared to be specific for the immunizing tumors, in contrast to the UV-induced suppressor cells, which recognize UV-induced tumors as a group. The suppressor T cells responsible for inhibiting tumor rejection have no effect on tumor-specific helper cell activity in vitro. However, UV-induced suppressor T cells transferred into unirradiated mice seem to block the generation of helper cell activity after immunization with UV-produced tumors. These results suggest the UV-induced suppressor cells may prevent tumor rejection by blocking the generation of Th.     

Theophylline delays human sleep phase

Twelve healthy male volunteers were given theophylline 250 mg in order to test effects on 24-hr rhythms. Rhythms of sleep/wake and subjective sleepiness were delayed. Ingestion of xanthines such as theophylline in coffee, tea, colas and chocolate may contribute to some sleep disorders. Theophylline might likewise be useful in treating disorders of circadian oscillators.     

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.     

Regulation of the immune response to tumor antigen. VIII. The effects of host specific anti-I-J antibodies on the immune response to tumors of different origin

The efficiency of in vivo therapy using alloantisera produced to interact specifically with I-J subregion encoded determinants has been investigated in two etiologically distinct syngeneic tumor systems, both of which have been shown to evoke suppressor T-cell host responses. Administration of 2 μl/day of anti-I-J^k alloantisera caused a significant reduction in the growth of the P815 methylcholanthrene (MCA)-induced mastocytoma or the 1316 ultraviolet (uv) radiation-induced fibrosarcoma in the syngeneic host. Inhibition of tumor growth with anti-I-J antibody treatment occurred in normal as well as in subcarcinogenically uv-treated hosts given the uv-induced 1316 fibrosarcoma, even though the normal host is capable of spontaneously rejecting the tumor graft in the absence of external manipulation. Evidence is also provided that the effects of anti-I-J antibody treatment are not due to direct interactions with the tumor cells, or to contaminating antiviral antibody activity within the antiserum. We have previously demonstrated the reduction of tumor growth in two antigenically distinct MCA-induced tumor systems (S1509a, SAI) using similar treatments. The data presented herein thus reinforce the possibility that such means of therapy may be beneficial to the treatment of a wide variety to tumor types where suppression represents a detrimental component of the host response, and may also provide some insight into the mechanisms underlying the effects of uv radiation on the immune response to tumor antigen.     

Immunologic significance of nonspecific suppressor cells in spleens of tumor-bearing mice.

Spleen cells from mice bearing a progressively growing syngeneic tumor failed to respond to stimulation with mitogens in vitro. This lack of reactivity was due to the presence of nylon wool-adherent cells in the population that could inhibit the mitogen response of normal lymphocytes. Paradoxically, at times when strong suppressor cell activity could be detected in tumor-bearing mice, the animals responded normally to in vivo immunization with sheep erythrocytes and allogeneic tumors, and to in vitro sensitization with allogeneic tumor cells. Regression of a highly antigenic syngeneic tumor also was unaffected by the presence of these suppressor cells. Thus, the occurrence of nonspecific suppressor cells in the spleens of tumor-bearing mice did not influence the overall immunologic competence of these animals.     

Circadian Phase in Adults of Contrasting Ages

There is evidence that aging may impair phase‐shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1‐wk wrist actigraphy at home and then by 72 h in‐laboratory study using an ultra‐short sleep‐wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights‐out and wake‐up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis‐derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase‐advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p<0.025), though the estimated half‐life of blood melatonin was shorter among elders (p<0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase‐angles among the studied circadian rhythms.     

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.     

Numerous transposed sequences of mitochondrial cytochrome oxidase I-II in aphids of the genus Sitobion (Hemiptera: Aphididae)

Polymerase chain reaction (PCR) products corresponding to 803 bp of the cytochrome oxidase subunits I and II region of mitochondrial DNA (mtDNA COI-II) were deduced to consist of multiple haplotypes in three Sitobion species. We investigated the molecular basis of these observations. PCR products were cloned, and six clones from one individual per species were sequenced. In each individual, one sequence was found commonly, but also two or three divergent sequences were seen. The divergent sequences were shown to be nonmitochondrial by sequencing from purified mtDNA and Southern blotting experiments. All seven nonmitochondrial clones sequenced to completion were unique. Nonmitochondrial sequences have a high proportion of unique sites, and very few characters are shared between nonmitochondrial clones to the exclusion of mtDNA. From these data, we infer that fragments of mtDNA have been transposed separately (probably into aphid chromosomes), at a frequency only known to be equalled in humans. The transposition phenomenon appears to occur infrequently or not at all in closely related genera and other aphids investigated. Patterns of nucleotide substitution in mtDNA inferred over a parsimony tree are very different from those in transposed sequences. Compared with mtDNA, nonmitochondrial sequences have less codon position bias, more even exchanges between A, G, C and T, and a higher proportion of nonsynonymous replacements. Although these data are consistent with the transposed sequences being under less constraint than mtDNA, changes in the nonmitochondrial sequences are not random: there remains significant position bias, and probable excesses of synonymous replacements and of conservative inferred amino acid replacements. We conclude that a proportion of the inferred change in the nonmitochondrial sequences occurred before transposition. We believe that Sitobion aphids (and other species exhibiting mtDNA transposition) may be important for studying the molecular evolution of mtDNA and pseudogenes. However, our data highlight the need to establish the true evolutionary relationships between sequences in comparative investigations.      

Studies on the role of antigen-presenting cells in the systemic suppression of contact hypersensitivity by UVB radiation

Exposure of mice to UVB radiation produces a highly selective, systemic immunosuppression associated with the appearance of suppressor T lymphocytes. Suppression of delayed hypersensitivity to hapten-coupled syngeneic cells has been shown to result from an altered distribution of antigen-presenting cells. The purpose of this study was to determine whether an alteration in the activity of antigen-presenting cells could account for the systemic suppression of contact hypersensitivity (CHS) by UVB radiation. Fluorescein isothiocyanate (FITC) was used for contact sensitization because it uses different antigen-presenting cells than does oxazolone to induce CHS. Our previous studies demonstrated that CHS to oxazolone was suppressed by UVB irradiation. In these studies, we show that exposure of mice to UVB radiation before epicutaneous application of FITC onto unirradiated skin markedly decreased the CHS response to FITC painted on unexposed ears. Cyclophosphamide-sensitive suppressor T cells were detectable in the spleens of mice exhibiting decreased CHS. The antigen-presenting activity of cells in lymph nodes draining the site of epicutaneous sensitization (DLN cells) was assessed by injecting them into the hind footpads of syngeneic recipients and measuring the CHS response to FITC 6 days later. Viable DLN cells from UVB-irradiated, FITC-sensitized mice were equal to those from unirradiated, FITC-sensitized mice in their ability to induce CHS in normal recipients. No sensitization resulted when killed DLN cells were used for immunization, indicating that sensitization was not caused by reprocessing of antigen by host cells. We conclude that impairment of the CHS reaction in UVB-irradiated mice does not appear to be blocked at an initial step of antigen uptake, processing, or presentation, but must be impaired at some other step in the immunologic pathway.     

Prevalent sleep problems in the aged.

Quality of sleep influences the level of daytime functioning, including stress levels, psychosomatic complaints, general health, and overall well-being. As people age, they complain more about disturbed sleep, insomnia, increased time in bed, and sleep fragmentation. These complaints can be related to circadian rhythm desynchronization, hypnotic or other medication use, chronic bedrest, napping, dementia, or to sleep apnea, a disorder of respiratory cessation which is quite prevalent in the elderly. We review here the results of 12 years of research on sleep in the elderly. In studies of three populations of elderly, it was found that between 24% and 42% had five or more apneas per hour of sleep and 4%-14% had 20 or more apneas per hour of sleep. Since apnea is related to dementia and even to mortality, this high prevalence of apnea is of extreme importance.