Cancer Immunol Immunother. 2002 Dec;51(11-12):603-13. Epub 2002 Oct 18
Atanackovic D, Nierhaus A, Neumeier M,
Hossfeld DK, Hegewisch-Becker S.
Department of Oncology and Hematology, University Clinic Eppendorf,
Hamburg, Germany. atanackd@mskcc.org
Whole body hyperthermia (WBH) has been used as an adjunct to
radio-/chemotherapy in patients with various malignant diseases.
Although clear evidence is still missing, it has been hypothesized that
an activation of the immune system might contribute to the therapeutic
effect of WBH. To examine whether a treatment with 60-minute 41.8
degrees C WBH as an adjunct to chemotherapy (WBH-CT) induces an
activation of T cells, blood samples were collected at numerous time
points before and up to 48 h post-treatment. The aim of this study was
to examine the effect of WBH-CT on the expression of a broad range of
activation markers on peripheral blood lymphocytes (PBL), on serum
cytokines and intracellular cytokine levels in T cells, and the capacity
of these cells to proliferate. Immediately after 41.8 degrees C WBH-CT
treatment, a drastic increase in peripheral natural killer (NK) cells (
P<0.05) and CD56+ cytotoxic T lymphocytes (CTL; P<0.01) in the
patients' peripheral blood was observed. At 5 h post-treatment, the
percentages of both effector cell types had returned to baseline levels.
This transient phenomenon was accompanied by a short period of reduced T
cell activity, indicated by diminished serum levels of soluble
interleukin-2 receptors (sIL-2R) at 3 h post-WBH-CT ( P<0.05) and
decreased lymphocytic proliferation at the same point in time. This
first phase was followed by a marked but short-lived increase in the
patients' serum levels of interleukin-6 (IL-6; P<0.01) during the
first 5 h following treatment, with a subsequent decrease to baseline
levels at 24 h and significantly increased serum levels of tumor
necrosis factor-alpha (TNF-alpha) at 0 h ( P<0.01), 3 h ( P<0.05),
5 h ( P<0.05) and 24 h ( P<0.01) post-WBH-CT. The third phase of
the immunological consequences of WBH-CT consisted of an increase in the
percentage of peripheral cytotoxic T lymphocytes (CTL) expressing CD56,
reaching a maximum at 48 h post-WBH ( P<0.01). Furthermore, the
percentage of CD4+ T cells expressing the T cell activation marker CD69
increased nearly two-fold over time, reaching its maximum at 48 h (
P<0.05). As an additional marker for T cell activation, serum levels
of sIL-2R increased markedly ( P<0.01), reaching maximum levels at
the same point in time. Elevated intracellular concentrations of
interferon-gamma (IFN-gamma) and/or TNF-alpha in CD8+ T cells were found
in 4 out of 5 patients at 24 h post-WBH-CT. Since similar changes were
not observed in patients receiving chemotherapy alone, this is the first
study to provide evidence for prolonged WBH-CT-induced activation of
human T cells.
Downing JF, Martinez-Valdez H, Elizondo RS, Walker EB, Taylor MW.
Department of Biology, Indiana University, Bloomington 47405.
Induction of hyperthermia (39 degrees C) in human volunteers by
immersion in warm water (41-45 degrees C) rapidly alters the cell
populations in the peripheral blood. In addition to granulocytosis,
there is an alteration of the normal ratios among T-lymphocyte subsets.
Following in vitro mitogen stimulation, lymphocytes from hyperthermic
individuals produce as much as 10-fold more interferon-gamma (IFN-gamma)
than cells withdrawn at basal core temperatures from the same
individuals. A temperature threshold of 39 degrees C for this response
suggests potential relevance to fever. No change was noted in the
activity of the macrophage population. The possible involvement of
interleukin-2 (IL-2) in this enhanced production is discussed. No
changes were noted in the circulating levels of IFN-gamma
Hegewisch-Becker S, Braun K, Otte M,
Corovic A, Atanackovic D, Nierhaus A, Hossfeld DK, Pantel K.
Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf,
Hamburg D-20246, Germany. hegewisc@uke.uni-hamburg.de
PURPOSE: Combining heat with antineoplastic drugs has produced evidence
of antitumor synergism. An increasing number of trials are investigating
whole body hyperthermia (WBH) in combination with chemotherapy in
patients with advanced malignancies. Here we investigated whether the
hyperdynamic state of the circulation as a consequence of WBH may
stimulate dissemination of malignant cells. EXPERIMENTAL DESIGN: WBH in
combination with chemotherapy was administered by a radiant heat device
to 20 consecutive patients with advanced epithelial malignancies. One
WBH session lasted for approximately 4 h (90 min heating time, 60 min
plateau at 41.8 degrees C, and 60-80 min cooling). Peripheral blood was
drawn before WBH treatment (baseline), at the end of the plateau (1 h),
and 24 h and 48 h thereafter. After removal of leukocytes using
anti-CD45 magnetic beads, circulating tumor cells were detected
immunocytochemically using the monoclonal antibody A45-B/B3, which binds
to a common epitope present on various cytokeratins. RESULTS: The method
used to detect tumor cells in the peripheral blood proved to be specific
and very sensitive (detection limit 1 tumor cell per 1.7 x 10(5)
peripheral blood mononuclear cell). Before WBH, 6 of 20 patients had
cyto-keratin-positive cells in their blood. A treatment-induced increase
in the number of circulating tumor cells became statistically
significant at 24 h after WBH (P = 0.043) and was detected in a total of
9 patients, 5 of whom had no detectable malignant cells at baseline.
There was no evidence of a correlation between an increase in the number
of circulating tumor cells and increased metastasis frequency.
CONCLUSIONS: Our findings suggest that WBH might induce a temporary
release of tumor cells into the circulation, but this spread appears to
be clinically not significant in patients with advanced malignancies.
Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):821-6.
Shen RN, Lu L, Young P, Shidnia H,
Hornback NB, Broxmeyer HE.
Department of Medicine (Hematology-Oncology), Indiana University School
of Medicine, Walther Oncology Center, Indianapolis 46202-5121.
PURPOSE: To determine whether hyperthermia is to the benefit or
detriment of host immune function, the effect of hyperthermia was
evaluated on various functions of T-lymphocytes from human umbilical
cord blood and compared to that of adult blood. METHODS AND MATERIALS:
Nonadherent mononuclear cells from cord blood or adult blood were used
as the effector cells. To generate lymphokine activated killer (LAK)
cells, effector cells were kept in culture for 5 days in complete medium
containing recombinant human interleukin-2. To activate effector cells
to become cytotoxic, cells were kept in culture in complete medium
containing Con A. Cytotoxicity was determined in a standard 4-h chromium
release assay using K-562 human erythroleukemic cells (in the natural
killer cell activity assay) or Daudi cells (in the LAK cell activity or
Lectin dependent cytotoxicity assay) as targets. For heat effects, cells
in complete medium were heated at the desired temperature in a water
bath for 1 h. RESULTS: Lymphokine-activated killer cell activity, lectin-dependent
cytotoxicity and T-cell proliferative capacity were not deficient in
human cord blood. Cytotoxic activities of T-cells from adult blood as
well as from cord blood can be enhanced at febrile range (< or = 40
degrees C), and were significantly decreased by exposure to 1 h at 42
degrees C. CONCLUSION: The febrile responses (< or = 40 degrees C) to
infection, in the course of malignant disease and with biological
response modifiers treatment, may all be related to host defense
mechanisms. Based on these observations, whole body hyperthermia (<
or = 40 degrees C), in combination with the appropriate cytokines, may
have therapeutic potential in the treatment of neonatal infections and
malignancies under certain circumstances. Hyperthermia in febrile range
may, therefore, confer an important immunoregulatory advantage to the
host. In contrast, tumor killing therapeutic temperature (> 42
degrees C) which inhibits host immunocompetence should probably be used
only for local hyperthermia.
| Indian Pediatr. 1990 Sep;27(9):945-51. |
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2286438&dopt=Citation
Singh M, Singhi S, Walia BN.
Department of Pediatrics, Postgraduate Institute of Medical Education
and Research, Chandigarh.
In a prospective controlled evaluation of steam therapy, in severe acute
lower respiratory tract infection (ALRI) requiring hospitalization, 16
cases of bronchiolitis and 20 cases of pneumonia were assigned
alternately to receive steam therapy in a cloth tent (Study Group);
others served as controls. Respiratory status was assessed at the time
of admission and subsequently at 6 hourly interval for 48 hours. No
advantage of steam therapy could be identified in children with
pneumonia. Bronchiolitis patients on steam therapy, as compared to the
controls, showed a significant decrease in respiratory distress within
first 24 hours after hospitalization and took significantly shorter time
for recovery from the distress. The study patients also showed a
tendency for rapid improvement in hypoxemia. Further critically
controlled studies with a larger sample size are warranted.
Effects of artificially induced fever on serum proteins, vitamin levels and hematological values in human subjects
http://jap.physiology.org/cgi/content/abstract/14/5/768J Appl Physiol
14: 768-770, 1959;
8750-7587/59 $5.00
José Méndez 1, Nevin S. Scrimshaw 1, Carlos Salvadó 1, and Manuel López Selva 1
1
Institute of Nutrition of Central America and Panama (INCAP), and the Neuropsychiatric Hospital, Guatemala City, GuatemalaTen male subjects in apparently good health were submitted to artificial hyperpyrexia of 2°–3°C above their initial orally determined body temperature for 2-hour periods. The pulse rate was markedly increased and the diastolic blood pressure was markedly decreased. Other major changes observed were a highly significant decrease of serum vitamin A levels and a highly significant increase of the white cell count, due primarily to an increase of the neutrophils. An eosinopenic effect observed was believed to be related to the stress of fever treatment. Minor changes were observed in the red cell count and in the serum gamma globulin fraction, which showed a delayed decrease. No changes were observed in carotene, vitamin E, alkaline phosphatase, riboflavin, or ascorbic acid.
Lymphokine Res. 1987 Spring;6(2):103-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3495705&query_hl=5Downing JF, Taylor MW.
We have previously demonstrated that artificially induced hyperthermia
in man enhances the subsequent production of interferon gamma (IFN-gamma)
in isolated leukocyte cultures. The mechanism(s) responsible for this
response may involve changes in the circulating lymphocyte populations
and may also reflect activation processes occurring in vivo due to
hormonal influences. In order to determine whether hyperthermia was
associated with other immunostimulatory effects, we measured lymphocyte
activation, natural killer cell activity, interleukin-2 (IL-2)
production and endotoxin-induced tumor necrosis factor (TNF) activity in
blood samples obtained from normothermic (37 degrees C) and hyperthermic
(39 degrees C) individuals. Lymphocyte transformation was significantly
depressed in post-hyperthermic cultures compared to pre-hyperthermic
control cultures. Pre-hyperthermic autologous human plasma was less
effective than fetal calf serum in promoting DNA synthesis, while post-hyperthermic
plasma suppressed mitogen-induced activation. Natural killer (NK) cell
activity was increased by the elevation of core body temperature.
Interleukin-2 (IL-2) production in phytohemagglutinin-stimulated
mononuclear cell cultures was also elevated when cells were isolated
from hyperthermic individuals relative to a paired normothermic control
sample. Lipopolysaccharide-induced tumor necrosis factor (TNF) synthesis
in monocyte cultures was unchanged by elevation of the core body
temperature. This study indicates that in vivo hyperthermia can produce
an immunostimulatory effect, an immunosuppressive effect, or no effect
on different parameters of the immune system.
Acta Physiol Scand. 1994 Mar;150(3):293-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8010136&query_hl=2
Jezova D, Kvetnansky R, Vigas M.
Institute of Experimental Endocrinology, Slovak Academy of Sciences,
Bratislava.
Neuroendocrine response was investigated during and after a single 20
min bath in sauna (80 degrees C) in a group of 8 healthy men and 8
healthy women. In an additional group of 8 young men, the dynamics of
plasma ACTH and cortisol levels were studied during a 30 min sauna
exposure (90 degrees C). This dynamic study showed a biphasic response
of plasma cortisol which decreased during the initial phase of sauna
bath (15 min) and increased thereafter, reaching its maximum 15 min
after the end of bathing. Maximal increase in plasma ACTH levels
occurred 15 min earlier. In the first sauna exposed group the increase
in body temperature was the same (about 2 degrees C) in both sexes.
Nevertheless, the elevation in plasma ACTH concentration was
significantly more pronounced in women than in men. In the plasma
collected at the end of sauna bath inside the sauna room, a significant
rise in both adrenaline and noradrenaline levels was found. Though the
catecholamine responses were similar in both groups, the increase in
heart rate during sauna bath was significantly higher in women.
Sauna-induced prolactin release was also more pronounced in women
compared with men. Thus hyperthermia induced by sauna exposure resulted
in a more pronounced neuroendocrine activation in women compared with
men. Moreover, it is evident that repeated blood sampling is necessary
to reveal the sauna-induced activation of some hormonal systems
Heat Halts Pain Inside The Body
Main Category: Pain
/ Anesthetics News
Article Date: 06 Jul 2006 - 0:00am (PDT)
The old wives' tale that heat relieves
abdominal pain, such as colic or menstrual pain, has been scientifically
proven by a UCL (University College London) scientist, who will
presented the findings at the Physiological Society's annual conference
hosted by UCL.
Dr Brian King, of the UCL Department of Physiology, led the research
that found the molecular basis for the long-standing theory that heat,
such as that from a hot-water bottle applied to the skin, provides
relief from internal pains, such as stomach aches, for up to an hour.
Dr King said: "The pain of colic, cystitis and period pain is
caused by a temporary reduction in blood flow to or over-distension of
hollow organs such as the bowel or uterus, causing local tissue damage
and activating pain receptors.
"The heat doesn't just provide comfort and have a placebo effect -
it actually deactivates the pain at a molecular level in much the same
way as pharmaceutical painkillers work. We have discovered how this
molecular process works."
If heat over 40 degrees Celsius is applied to the skin near to where
internal pain is felt, it switches on heat receptors located at the site
of injury. These heat receptors in turn block the effect of chemical
messengers that cause pain to be detected by the body.
The team found that the heat receptor, known as TRPV1, can block P2X3
pain receptors. These pain receptors are activated by ATP, the body's
source of energy, when it is released from damaged and dying cells. By
blocking the pain receptors, TRPV1 is able to stop the pain being sensed
by the body.
Dr King added: "The problem with heat is that it can only provide
temporary relief. The focus of future research will continue to be the
discovery and development of pain relief drugs that will block P2X3 pain
receptors. Our research adds to a body of work showing that P2X3
receptors are key to the development of drugs that will alleviate
debilitating internal pain."
Scientists made this discovery using recombinant DNA technology to make
both heat and pain receptor proteins in the same host cell and watching
the molecular interactions between the TRPV1 protein and the P2X3
protein, switched on by capsaicin, the active ingredient in chilli, and
ATP, respectively.
###
Contact: Alex Brew
University College London
Acta Diabetol. 2003 Oct;40 Suppl 1:S207-9.
Servidio MF, Mohamed EI, Maiolo C,
Hereba AT, Perrone F, Garofano P, Iacopino L.
Divisions of Human Nutrition and Clinical Pathology, Faculty of Medicine
and Surgery, University of Tor Vergata, Rome, Italy.
Studies have suggested that long-term sauna bathing may lower blood
pressure in persons with hypertension by causing a direct loss of
extracellular water and plasma minerals. The objective of the present
study was to evaluate the effect of short-term sauna bathing on body
water compartments as estimated by bioelectric impedance analysis (BIA).
We recruited 15 men [mean age (+/-SD) of 23.93+/-5.12 years and mean
body mass index (BMI) of 23.25+/-2.84 kg/m(2)] and 10 women matched for
age and BMI. Total body resistance, reactance, and impedance were
measured for all participants using BIA, at baseline, after a short
sauna bath, and after a rest period. Total, extracellular, and
intracellular water compartments were calculated using BIA formulae.
There were no significant differences for any of the body water
compartments when comparing the measurements taken before and after the
sauna bath and after the rest period. However, it remains to be
determined whether or not BIA is sensitive to rapid changes in water
volume
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8256470&query_hl=2
Z Gesamte Inn Med. 1993 Oct;48(10):502-5.
Winterfeld HJ, Siewert H, Engelmann U, Aurisch R, Frenzel R, Bohm J,
Strangfeld D, Warnke H.
Poliklinik fur Physiotherapie, Medizinischen Fakultat (Charite) der
Humboldt-Universitat zu Berlin.
The authors report on the influence of a single sauna-stay of patients
following heart transplantation (HTX) during the rehabilitation phase
III. Investigations of blood pressure, heart rate, changer in
hemodynamics in the small and large vessels in 8 male patients following
HTX (medium age: 42 years) showed that sauna-hyperthermia is well
tolerated. We watched significant decreases of blood pressure (systolic
and diastolic values), an improvement of the microcirculation in the
small vessels, an increase of the left ventricular ejection fraction
(LVEF) and a decrease of the total peripheric vascular resistance
(TPVR). Possibilities and limitations of sauna-therapy for the therapy
of risk factors following HTX especially under immunosuppression are
discussed. First results are demonstrated.