Biomedical subjects

G M Halliday

Publications and source records attributed to G M Halliday.

At least 73 records · Page 4Linked to original sources

PubMed2000

Cytokine profiles in spontaneously regressing basal cell carcinomas.

BACKGROUND: Basal cell carcinomas (BCCs) can cause considerable morbidity due to their ability to enlarge progressively and to destroy underlying tissues. However, some BCCs may undergo spontaneous regression in the absence of therapy capable of inducing antineoplastic effects. Histological criteria for this process have been described, and previous studies have suggested that it may be mediated by infiltrating activated CD4-positive T cells. OBJECTIVES: The purpose of this study was to compare the expression of cytokines in actively regressing and non-regressing BCCs, to ascertain if active regression is associated with a particular cytokine profile. METHODS: Reverse transcriptase-polymerase chain reaction, a sensitive, quantitative technique allowing analysis of multiple cytokines from small tumour samples, was used. RESULTS: Interferon (IFN)-gamma was significantly elevated in actively regressing BCCs compared with non-regressing BCCs. Furthermore, interleukin (IL)-2, tumour necrosis factor (TNF)-beta and CD3 delta tended to be elevated in actively regressing tumours, although not to statistically significant levels. IFN-gamma, IL-2, IL-10, TNF-beta, granulocyte-macrophage colony-stimulating factor and Fas ligand showed strong positive correlations with CD3 delta, indicating an association between infiltrating T cells and these cytokines. CONCLUSIONS: These findings support a role for T-helper 1 type cytokines in mediating spontaneous regression of BCCs.

CD3 Complex↗

PubMed2000

Topical retinoic acid enhances, and a dark tan protects, from subedemal solar-simulated photocarcinogenesis.

Studies into the effects of topical retinoic acid on photocarcinogenesis have yielded ambiguous findings. This may be due to different Experimental protocols and ultraviolet spectra. Retinoic acid is commonly used for a range of dermatologic conditions, and therefore it is important to resolve whether it affects skin tumor formation. To address this issue we used a protocol to mimic as closely as possible human use of retinoic acid. Two mouse strains were used: Skh:HR-1 (albino) and Skh:HR-2 (lightly pigmented). The pigmented mice more closely resemble Caucasian skin as they develop a light tan in response to ultraviolet radiation. This tan is greatly augmented by retinoic acid. As these are congenic mice, any differences can be attributed to the development of a tan. Mice were exposed to solar-simulated ultraviolet radiation, followed by treatment with 0.05% retinoic acid. This modeled exposure to sunlight during the day followed by retinoic acid treatment and a night-time period in the absence of sunlight. As it is recommended that ultraviolet exposure is minimized when using topical retinoic acid, the mice were only exposed to one-third of minimal edemal dose of ultraviolet radiation per day. This retinoic acid protocol augmented photocarcinogenesis. Retinoic acid decreased the latency period, reduced the probability that a mouse would survive without a tumor, and increased the number of tumors per mouse. All tumors induced were squamous cell carcinomas, and the skin between the tumors on mice treated with retinoic acid was found to contain carcinoma in situ upon histologic diagnosis. The light tan of the solvent-treated pigmented mice did not provide any protection, whereas the dark tan, which developed in Skh:HR-2 mice in response to retinoic acid, reduced photocarcinogenesis but did not overcome the augmenting effect of retinoic acid. Thus, using this experimental design, topical retinoic acid augmented photocarcinogenesis, and the ability to develop a dark but not light tan provided some, but limited, protection.

Administration, Topical↗

PubMed2000

Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus.

Whereas there has been recent interest in interactions between dendritic cells and pathogenic viruses, the role of dendritic cells in the initiation of protective immunity to such organisms has not been elucidated. The aim of this study was to examine whether a resident dendritic cell population in the skin, Langerhans cells, respond to cutaneous viral infections which are effectively cleared by the immune system. We therefore characterized the ability of Langerhans cells to migrate to local draining lymph nodes following infection with the arthropod-borne viruses, West Nile virus or Semliki Forest virus. The data show that major histocompatibility complex class II+/NLDC145+/E-cadherin+ Langerhans cell numbers are increased in the draining lymph nodes of infected mice and this increase is accompanied by a concomitant decrease in the Langerhans cell density in the epidermis. Langerhans cell migration is associated with an accumulation of leukocytes in the lymph node, which is one of the earliest events in the initiation of an immune response. Both the migratory response and the draining lymph node leukocyte accumulation were abrogated if ultraviolet-inactivated instead of live viruses were used, suggesting the activation and subsequent migration of Langerhans cells requires a live, replicating antigen. Our findings are likely to have wider implications for the development of epidermally delivered vaccines and suggest that mobilization of dendritic cells may be involved in the development of immune responses to arthropod-borne viruses.

Alphavirus Infections↗

PubMed2000

Ultraviolet B-induced suppression of immune responses in interleukin-4-/- mice: relationship to dermal mast cells.

Ultraviolet B radiation is immunosuppressive by multiple mechanisms. In interleukin-4-/- mice, ultraviolet B radiation was not able to suppress delayed-type hypersensitivity or contact hypersensitivity responses when the sensitizing antigen was applied to nonirradiated sites. In contrast, ultraviolet B significantly suppressed contact hypersensitivity responses to haptens applied to irradiated sites in interleukin-4-/- mice. In mast cell depleted Wf/Wf mice, ultraviolet B radiation also significantly suppressed contact hypersensitivity responses to sensitizing antigens applied to irradiated but not to unirradiated sites. In both interleukin-4-/- mice and Wf/Wf mice, the mast cell product, histamine, was immunosuppressive implicating mast cells as the dysfunctional cell in interleukin-4-/- mice. The prevalence of dermal mast cells was similar in wild-type and interleukin-4-/- mice. Dermal mast cells of interleukin-4-/- mice, however, express very low levels of c-kit and did not significantly degranulate in response to ultraviolet B. Ultraviolet radiation induced significant and similar levels of serum interleukin-10 in wild-type and interleukin-4-/- mice. We conclude that interleukin-4 indirectly affects ultraviolet B suppression of contact hypersensitivity and delayed-type hypersensitivity responses to sensitizing antigens applied at sites other than those irradiated by providing a critical differentiative signal for dermal mast cells. This study further emphasizes the central role of mast cells in the initial processes by which ultraviolet B radiation is immunomodulatory for immune responses to sensitizing antigens applied to nonirradiated sites.

Animals↗

PubMed2000

A role for the substantia nigra pars reticulata in the gaze palsy of progressive supranuclear palsy.

We examined the topography and degree of cell loss within basal ganglia structures commonly involved in progressive supranuclear palsy in order to identify any relationship between degeneration in these nuclei and gaze palsy. Serial section analyses and unbiased quantitative techniques were applied to brain tissue from six cases with progressive supranuclear palsy (four with gaze palsy and two without) and six controls with no neurological or neuropathological abnormalities. The total number of nucleolated neurons within the substantia nigra pars compacta (SNc) and reticulata (SNr), the subthalamic nucleus, and the internal and external segments of the globus pallidus was determined for all subjects and the data expressed as percentages of control values to compare degeneration across these basal ganglia structures. The density of neurofibrillary tangles was also evaluated within these structures. Despite significant subcortical neurofibrillary tangle formation in all cases, there was considerable variability in the degree of neuronal cell loss in all basal ganglia regions, except the SNc which was consistently affected. There was no correlation between the ranked density of neurofibrillary tangles and the degree of neuronal cell loss in any basal ganglia region. Comparisons between cases with and without gaze palsy revealed a 40% greater decrease in the number of SNr neurons in cases with gaze palsy (75 +/- 8% loss) compared with those without (35 +/- 14% loss). This was the largest difference between these cases. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in progressive supranuclear palsy.

Aged↗

PubMed2000

Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations.

Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices. Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia. Two affected family members presented with symptoms of dementia and later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls. The mutation is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.

Aged↗

PubMed2000

Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications.

Whilst many reports mention neurofibrillary tangle pathology in the thalamus in progressive supranuclear palsy, there has been little detailed regional analysis of the distribution and density of thalamic pathology in this disease or in other parkinsonian syndromes. The caudal intralaminar thalamic nuclei are the major thalamic regulators of the caudate nucleus and putamen, areas known to be dysfunctional in progressive supranuclear palsy and Parkinson's disease. We investigated whether these thalamic nuclei degenerate in patients with these disorders compared with age-matched, neurologically normal controls. Neurofibrillary tangle and Lewy body pathology was assessed and unbiased optical disector methods were used to quantify total neuronal number. Despite different thalamic pathology, there was a dramatic reduction in the total neuronal number in the caudal intralaminar nuclei in both progressive supranuclear palsy and Parkinson's disease (40-55% loss). In contrast, there was no loss of volume or total neuronal number in the limbic thalamic nuclei in either disease group, indicating selective degeneration of the caudal intralaminar nuclei. In Parkinson's disease, Lewy bodies were found in these regions, while in progressive supranuclear palsy abundant intracellular neurofibrillary tangles and glial tangles concentrated in the caudal intralaminar nuclei. However, tangle formation accounted for only a small proportion of cell loss (</=10%) in the thalamus in progressive supranuclear palsy. These findings have several implications. The caudal intralaminar thalamus appears to be one of three basal ganglia sites commonly affected in both progressive supranuclear palsy and Parkinson's disease. These sites are the dopaminergic substantia nigra, the cholinergic pedunculopontine tegmental nucleus and, from our results, the glutamatergic caudal intralaminar thalamus. In both diseases these sites contain characteristic but different pathologies, indicating disease-specific mechanisms of neurodegeneration. Interestingly, the proportion of remaining neurons affected by these pathologies is low. This may indicate additional (possibly common) cellular mechanisms responsible for the degeneration in these regions. Both the dopaminergic nigra and the glutamatergic caudal intralaminar thalamus are the major regulators of basal ganglia function via the caudate nucleus and putamen. The pedunculopontine tegmental nucleus has major projections to both of these regulators. These findings indicate that dysregulation of two neurotransmitter systems within the basal ganglia may underlie common parkinsonian symptoms in these disorders. For patients with Parkinson's disease, this loss of glutamate regulation may help explain some problems with dopamine replacement therapies, particularly over time. For patients with progressive supranuclear palsy, more widespread degeneration of basal ganglia structures would contribute to poor treatment outcomes.

Aged↗

PubMed2000

Enhanced tumor growth in UV-irradiated skin is associated with an influx of inflammatory cells into the epidermis.

UV radiation causes a number of cellular changes within the skin which play a role in tumor outgrowth, including immunosuppression and production of growth-enhancing cytokines. Both of these enable tumors to grow but their relative importance in carcinogenesis is poorly defined. In this study, C3H/HeN mice were exposed to a single inflammatory dose of 410 mJ/cm(2) UVB radiation (plus 100 mJ/cm(2) UVA radiation) followed by the inoculation of a regressor squamous cell carcinoma into or the painting of oxazolone onto the treated skin. Tumors transplanted 2 or 3 but not 4 days after irradiation had a significantly higher growth rate than tumors inoculated into unirradiated control mice. In contrast, mice failed to respond to hapten when it was applied 2, 3 or 4 days after irradiation. Cytofluorimetric analysis demonstrated that the number of F4/80(+) Langerhans cells was not significantly reduced until 4 days after irradiation, while the number of dendritic epidermal T cells was significantly lower at all time points observed after UV-irradiation. Furthermore, a large cellular infiltration of CD11b(+), Gr-1(+), CD45(+) MHC class II(+) and CD45(+) MHC class II(-) cells into the epidermis was observed 2 and 3 days after irradiation, which corresponded with the enhanced tumor growth. To a lesser extent tumor growth was also associated with CD45(+) MHC class II(hi) cells, possibly the previously described UV-induced macrophage. In contrast, suppression of contact hypersensitivity corresponded with the reduction in dendritic epidermal T cells but not with other cell changes. The results suggest that, in this model, where immunosuppression did not appear to be responsible for enhanced tumor growth, inflammatory infiltrates may contribute to the promotion of skin tumor growth within UV-irradiated skin.

Adjuvants, Immunologic↗

PubMed2000

Degeneration of the centré median-parafascicular complex in Parkinson's disease.

Two major noncortical inputs to the striatum originate from the substantia nigra and the thalamic centré median-parafascicular complex. Although it is established that in Parkinson's disease there is degeneration of the nigral dopaminergic neurons, there has been little analysis of the glutamatergic centré median-parafascicular complex. We therefore evaluated these and neighboring thalamic nuclei (for specificity of any changes) in 9 Parkinson's disease patients and 8 age-matched controls. Degeneration in the substantia nigra and centré median-parafascicular complex was estimated by using quantitative neuronal counts. On average, 70% of the pigmented nigral neurons degenerated and there was 30% to 40% neuronal loss in the centré median-parafascicular complex in Parkinson's disease. Thalamic degeneration was marked in neuronal subpopulations (50% loss of parvalbumin-positive neurons in the parafascicular, and 70% loss of non-parvalbumin-positive neurons in the centré median nuclei). In contrast, adjacent thalamic nuclei did not degenerate, which supports a selective neurodegeneration of the centré median-parafascicular complex. Our results show that the thalamic centré median-parafascicular complex is an additional nondopaminergic site of neurodegeneration in Parkinson's disease. Because this thalamic region provides important sensorimotor feedback to the striatum, degeneration of this region is likely to exacerbate the clinical signs and symptoms of Parkinson's disease.

Aged↗

PubMed2000

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease.

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.

Aged↗

PubMed1999

The external globus pallidus in patients with Parkinson's disease and progressive supranuclear palsy.

Underactivity of the external segment of the globus pallidus is thought to contribute to the generation of parkinsonian hypokinetic symptoms in association with striatal dopaminergic dysfunction and overactivity of the subthalamus. These symptoms can be corrected by neurosurgical techniques aimed at normalizing subthalamic overactivity. The aim of the present study was to compare the amount of neurodegeneration and changes in the calcium-binding protein parvalbumin in the external segment of the globus pallidus in parkinsonian disorders. Cases with progressive supranuclear palsy were compared with cases with Parkinson's disease and control subjects. The number of neurones and neurofibrillary tangles was estimated using unbiased stereologic techniques. The external segment of the globus pallidus in Parkinson's disease was not significantly different from that in control subjects. In contrast, most patients with progressive supranuclear palsy had significant neurodegeneration of the external pallidum, particularly patients with significant degeneration of both the subthalamus and substantia nigra. These results suggest that the parkinsonian symptoms in progressive supranuclear palsy are caused by the degeneration of the external segment of the globus pallidus because such degeneration would increase thalamic inhibition through the basal ganglia output nuclei, particularly in patients with a loss of excitatory drive from the subthalamus.

Age Factors↗

PubMed1999

The internal globus pallidus is affected in progressive supranuclear palsy and Parkinson's disease.

Our structural studies of the substantia nigra in parkinsonian patients identified previously unsuspected changes in the pars reticulata, suggesting significant dysfunction in this basal ganglia output. There have been few similar structural studies of the other major basal ganglia output, the internal segment of the globus pallidus. This is despite significant evidence that this basal ganglia region is crucially important for generating parkinsonian symptoms. In fact current surgical interventions target this region in Parkinson's disease. The cellular anatomy of the internal globus pallidus was compared among five controls, six patients with Parkinson's disease, and five patients with progressive supranuclear palsy. Neurons and pathological structures were quantified using the unbiased fractionator method. Only cases with progressive supranuclear palsy had detectable pathology within the internal globus pallidus in the form of tau-positive neuronal and glial tangles and substantial neurodegeneration. Cases with Parkinson's disease had a significant reduction in the proportion of neurons containing parvalbumin but were without significant neurodegeneration, consistent with dysfunction of both basal ganglia output nuclei in advanced parkinsonism. Surgical ablation of the internal globus pallidus for Parkinson's disease appears at odds with the significant neurodegeneration in the similarly akinetic and rigid patients with progressive supranuclear palsy. The results are discussed in association with current hypotheses of basal ganglia function and recent experimentation in patients undergoing pallidotomy for hyperkinetic disorders.

Aged↗

PubMed1999

Clinical and neuropathological abnormalities in baboons treated with HPTP, the tetrahydropyridine analog of haloperidol.

Tardive dyskinesia (TD) is relatively common among psychiatric patients on maintenance therapy with typical neuroleptics and persists in more than 20% even after withdrawal of the medication. Such persistence suggests an underlying pathology due to neurotoxicity. We present evidence for such a neurotoxic mechanism in a baboon model of TD. Four baboons were treated chronically with the dehydration product of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP), which is metabolized, similarly to haloperidol, to two neurotoxic pyridinium species. The animals developed orofacial dyskinesia which persisted after HPTP was ceased. Serial sections of the entire brain from the four treated animals and four vehicle-treated controls revealed volume loss in the basal forebrain and hypothalamus. Histological evaluation demonstrated a reduction in the density of magnocellular neurons in the anterior region of the nucleus basalis of Meynert (NbM). We speculate that the loss of these NbM neurons may be associated with the persistent orofacial dyskinesia observed in the HPTP-treated animals. These findings may contribute to a better understanding of neuroleptic-induced TD.

Animals↗

PubMed1999

Brain shrinkage in alcoholics: a decade on and what have we learned?

Brain atrophy in alcoholics has been identified using both radiological and pathological techniques. However the magnitude and topography of the atrophy, and the factors which contribute to it, are unclear. This review compares the results of imaging and pathological studies in alcoholics examining variables which may contribute to any discrepancies. We conclude that significant brain damage does occur as a result of alcohol abuse per se, that the damage is regionally specific with the frontal lobes being particularly affected, and that both grey matter and white matter components are damaged.

Alcoholism↗

PubMed1999

Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy.

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

Adult↗

PubMed1999

Keratoacanthomas have an immunosuppressive cytokine environment of increased IL-10 and decreased GM-CSF compared to squamous cell carcinomas.

To investigate the relationship between keratoacanthoma (KA) and squamous cell carcinoma (SCC), cytokine mRNA in 12 KA and eight SCC were compared. Normal skin was also studied. Reverse transcription polymerase chain reaction (RT-PCR) was used to quantitate mRNA in each sample utilizing DNA standards. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control, and CD3delta as an indication of the T-cell infiltrate. KAs showed a significant increase in interleukin (IL)-10, and a decrease in granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA compared to SCCs. CD3delta mRNA was also increased in the KAs. There was no difference between KAs and SCCs in expression of lymphotoxin-alpha, IL-2, interferon-gamma (IFN-gamma), IL-13, transforming growth factor-beta (TGF-beta), or the pro-inflammatory cytokines IL-8 or tumour necrosis factor-alpha (TNF-alpha). These results indicate that KAs spontaneously resolve in an immunosuppressive environment. KAs grow rapidly over a period of weeks and then involute. It is possible that a suppressed immune response enables unimpeded growth and that the KA cells rapidly undergo the finite number of cell divisions of which they are capable, and then die without reaching immortality.

CD3 Complex↗

PubMed1999

Sun protection factor measurement of sunscreens is dependent on minimal erythema dose.

This study investigates the influence of skin colour and minimal erythema dose (MED) on the in vivo determination of sunscreen sun protection factors (SPFs). The MEDs of groups of 10-20 subjects were measured on the lower back with a 1000-W solar-simulated xenon arc lamp. Five sunscreens, with commercially measured SPFs ranging from 4 to 30 + were then tested on the different groups, and their SPFs were correlated with volunteers' MEDs. We found that the sunscreens had higher SPF values when tested on subjects with lower MEDs and paler skin. The SPF values obtained with our ultraviolet (UV) source were lower than the SPF values reported with commercially used solar simulators. We conclude that while SPF tests with artificial UV sources and pale-skinned volunteers can and should be used to rank the efficacy of various sunscreens in preventing sunburn, they should not be interpreted as measures of a sunscreen's absolute level of sun protection. Factors such as the differences in skin colour and MED between subjects used for SPF testing and the general population, the spectral differences between sunlight and artificial UV, as well as the tendency of the public to apply only small amounts of sunscreen and to re-apply it infrequently, mean that laboratory and sunlight SPFs may be markedly different.

Adult↗

PubMed1999

Progressor but not regressor skin tumours inhibit Langerhans' cell migration from epidermis to local lymph nodes.

Langerhans' cells (LC) are found in high numbers infiltrating skin tumours, the functional significance of which remains unknown. To study the mechanism by which tumours increase the number of LC we developed a procedure whereby supernatant from cultured T7 tumour cells applied topically increases the number of LC. Tumour factors increased the number of resident epidermal LC and did not attract LC precursors into parental murine skin grafted onto F1 hybrids. There was no evidence for increased LC division in response to the tumour-derived factors. LC migration from the epidermis to local lymph nodes, induced by topical fluorescein isothiocyanate (FITC), was inhibited by the tumour supernatant. To examine the functional significance of this, FITC-induced migration of LC from the epidermis overlying progressor tumours, which evade immunological destruction, and regressor tumours, which are immunologically destroyed, was examined. The progressor tumour T7 growing subcutaneously in syngeneic mice inhibited FITC-induced migration of LC from overlying epidermis. Furthermore, two progressor, but not two regressor murine skin tumour lines growing in BALB/c nu/nu mice inhibited LC migration from the epidermis. Our results demonstrate that progressor skin tumours produce factor(s) which inhibit LC migration from the epidermis to lymph nodes, leading to LC accumulation. Inhibition of LC migration by tumour-derived factors may enable tumours to evade the activation of protective immunity as regressor tumours do not interfere with the normal trafficking of LC.

Animals↗