Effects of Brain Irradiation in Immune-Competent and Immune-Compromised Mouse Models.

Patient-derived orthotopic xenografts (PDOXs) closely recapitulate primary human glioblastoma (GBM) tumors in terms of histology and genotype. Compared to other mouse strains, NOD-scid IL2Rgammanull (NSG) mice show excellent tumor take rates, which makes them an ideal host for PDOXs. However, NSG mice harbor a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), which renders them relatively radiosensitive. This has been a frequently voiced concern in studies involving ionizing radiation. In this study, we assessed brain toxicity in NSG mice compared to three other different mouse strains frequently used in radiation studies at radiation doses commonly used in experimental combination therapy studies. C3H/Sed/Kam, C57Bl/6, nude and NOD-scid IL2Rgammanull mice received a single dose of 4 Gy to the right brain hemispheres using an image-guided small animal irradiator. Brains were stained using H&E, luxol fast blue, and antibodies against IBA1 and GFAP one, two, four or six months postirradiation. Additional animals of all four strains were exposed to five daily fractions of 2 Gy (5 × 2 Gy), and tissue sections were stained 72 h later against gH2AX, NeuN, GFAP and IBA1. None of the mouse strains displayed radiation-induced toxicity at any of the time points tested. Radiation doses relevant for testing combination therapies can be safely applied to the brains of NSG mice without the occurrence of radiation-induced normal tissue toxicity.

Neuritis óptica postencefalitis por virus de Epstein-Barr en niños inmunocompetentes. Caso clínico / Optic neuritis following Epstein-Barr virus encephalitis in immunocompetent children: a case report

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Immune responses of a wall lizard to whole-body exposure to radiofrequency electromagnetic radiation.

PURPOSE: During the last three decades, the number of devices that emit non-ionizing electromagnetic radiation (EMR) at the wireless communication spectrum has rapidly increased and possible effects on living organisms have become a major concern. The purpose of this study was to investigate the effects of radiofrequency EMR emitted by a widely used wireless communication device, namely the Digital Enhanced Communication Telephony (DECT) base, on the immune responses of the Aegean wall lizard (Podarcis erhardii). MATERIALS AND METHODS: Adult male lizards were exposed 24 h/day for 8 weeks to 1880-1900 MHz DECT base radiation at average electric field intensity of 3.2 V/m. Immune reactivity was assessed using the phytohemagglutinin (PHA) skin swelling and mixed lymphocyte reaction (MLR) tests. RESULTS: Our results revealed a noticeable suppression (approximately 45%) of inflammatory responses in EMR-exposed lizards compared to sham-exposed animals. T cell-mediated responses were marginally affected. CONCLUSION: Daily radiofrequency EMR exposure seems to affect, at least partially, the immunocompetence of the Aegean wall lizard.

Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells.

Immunodeficiency is a severe side effect of radiation therapy, notably at high radiation doses. It may also impact healthy individuals exposed to environmental ionizing radiation. Although it is believed to result from cytotoxicity of bone marrow cells and of immunocompetent cells in the peripheral blood, the response of distinct bone marrow and blood cell subpopulations following exposure to ionizing radiation is not yet fully explored. In this review, we aim to compile the knowledge on radiation sensitivity of immunocompetent cells and to summarize data from bone marrow and peripheral blood cells derived from mouse and human origin. In addition, we address the radiation response of blood stem and progenitor cells. The data indicate that stem cells, T helper cells, cytotoxic T cells, monocytes, neutrophils and, at a high degree, B cells display a radiation sensitive phenotype while regulatory T cells, macrophages, dendritic cells and natural killer cells appear to be more radioresistant. No conclusive data are available for basophil and eosinophil granulocytes. Erythrocytes and thrombocytes, but not their precursors, seem to be highly radioresistant. Overall, the data indicate considerable differences in radiosensitivity of bone marrow and blood normal and malignant cell populations, which are discussed in the light of differential radiation responses resulting in hematotoxicity and related clinical implications.

Linfoma primario del sistema nervioso central con linfomatosis cerebri en un niño inmunocompetente: hallazgos de la MRI y 18F-FDG PET-TC / Primary central nervous system lymphoma with lymphomatosis cerebri in an immunocompetent child: MRI and 18F-FDG PET-CT findings

El linfoma primario del sistema nervioso central (LPSNC) es extremadamente raro en niños inmunocompetentes. Presentamos los hallazgos de la imagen de resonancia magnética (MRI) y de tomografía por emisión de positrones-tomografía computarizada (PET-TC) con 18F-FDG en un niño inmunocompetente de 14 años de edad. En este paciente el LPSNC se asoció con linfomatosis cerebri. Estar familiarizado con los hallazgos de esta rara afectación mejorará la confianza diagnóstica del médico nuclear y evitará un diagnóstico erróneo (AU)

Primary central nervous system lymphoma (PCNSL) is extremely rare in immunocompetent children. We present the magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) findings of such a case in a 14-year old immunocompetent boy. In this patient, PCNSL was associated with lymphomatosis cerebri. Familiarity with the findings of this rare condition will improve the diagnostic confidence of the nuclear radiologist and avoid misdiagnosis (AU)

UVB-irradiated apoptotic cells induce accelerated growth of co-implanted viable tumor cells in immune competent mice.

The presence of a solid tumor is the result of a complex balance between rejection, tolerance and regeneration in which the interactions of tumor cells with cells of the host immune system contribute strongly to the final outcome. Here we report on a model where lethally UVB-irradiated cells cause accelerated growth of viable tumor cells in vitro and in allogeneic immune competent mice. UVB-irradiated tumor cells alone did not form tumors and failed to induce tolerance for a second challenge with the same allogeneic tumor. Our data show an important role for dying cells in promoting accelerated tumor cell growth of a small number of viable tumor cells in a large inoculum of UVB-irradiated tumor cells. This occurs when viable and dying/dead tumor cells are in close proximity, suggesting that mobile factors contribute to growth promotion. The anti-inflammatory and growth promoting properties of apoptotic cells are based on several independent effects. UVB-irradiated apoptotic cells directly release a growth promoting activity and clearance by macrophages of apoptotic cells is accompanied by the secretion of IL10, TGFß, and PGE2. Growth promotion is even observed with dying heterologous cells implying a conserved mechanism. Future experiments should focus on the effects of dying tumor cells generated in vivo on the outgrowth of surviving tumor cells which is prone to have implications for cancer therapy.

[The investigation of prevalence of genital inflammation in women of second generation of descendants whose ancestors were in the area of radiation exposure].

There are the results of a comprehensive clinical examination of 112 women of childbearing age who are second generation descendants of those who were in the area of radiation exposure over 25 ED cSv. Incidence and factors leading to chronic inflammation of pelvic organs were studied. Immune status was evaluated by studying of subpopulation of immune cells in peripheral blood and levels of basic inflammatory cytokines. High incidence of the pelvic organs inflammatory diseases in women second-generation offspring due to disturbances in the complex chain of immunocompetent system was defined.

Photoprotection in immunocompetent and immunocompromised people.

Ultraviolet radiation (UVR) exposure from the sun and artificial UV sources has been widely acknowledged as the major culprit for skin cancer and premature skin ageing. Skin cancers are among the most dangerous (cutaneous malignant melanoma) and the most numerous (basal cell carcinoma, actinic keratosis and invasive squamous cell carcinoma) of all neoplasms in the caucasian population worldwide. Skin cancers therefore have a significant impact on public health and healthcare costs, and will continue to do so. It is obvious that adequate photoprotection - seeking shade, wearing protective clothing and using sunscreens - is the key to reducing the harmful effects of UVR in both immunocompetent and immunocompromised people. This article provides background information on UVR, photoprotection (including the concept of topical sunscreen formulations), associated concerns regarding efficacy and safety, and behavioural and educational aspects of photoprotection and skin cancer prevention in immunocompetent and immunocompromised people. Certain persistent misconceptions and mistakes regarding photoprotection are also addressed.

[Immunity and health: the accelerated aging of immune system in veterans of extra risk divisions].

This article presents the data about state of health and immunity in veterans of extra risk divisions. The increased morbidity and immunity infringement in the remote terms after nuclear tests, and also while liquidation of consequences of radiating failures on nuclear submarines are shown. Changes of humoral factors of nonspecific protection, concentration of immunoglobulinums, in blood whey, a sensitization of lymphocytes to respiratory viruses, humoral and cellular autoimmune shifts are registered. Some of the revealed changes (complement, lysozyme, concentration of immunoglobulinums) are a consequence of advanced age and accompanying diseases in the people surveyed, and others (autoimmune shifts, a sensitization to respiratory viruses) can be connected with carrying out of tests of the nuclear weapon. Some of immunological changes are apparently a consequence of joined actions of radiating and not radiating factors. Among the last ones stress plays the essential role. For the characteristic of a state of health in 20-40 years after carrying out nuclear tests and possible radiating influence the estimation of autoimmune changes has a great value. The important role of such changes in morbidity of veterans of extra risk divisions is shown.

Evidence for beneficial low level radiation effects and radiation hormesis.

Low doses in the mGy range cause a dual effect on cellular DNA. One is a relatively low probability of DNA damage per energy deposition event and increases in proportion to the dose. At background exposures this damage to DNA is orders of magnitude lower than that from endogenous sources, such as reactive oxygen species. The other effect at comparable doses is adaptive protection against DNA damage from many, mainly endogenous, sources, depending on cell type, species and metabolism. Adaptive protection causes DNA damage prevention and repair and immune stimulation. It develops with a delay of hours, may last for days to months, decreases steadily at doses above about 100 mGy to 200 mGy and is not observed any more after acute exposures of more than about 500 mGy. Radiation-induced apoptosis and terminal cell differentiation also occur at higher doses and add to protection by reducing genomic instability and the number of mutated cells in tissues. At low doses reduction of damage from endogenous sources by adaptive protection maybe equal to or outweigh radiogenic damage induction. Thus, the linear-no-threshold (LNT) hypothesis for cancer risk is scientifically unfounded and appears to be invalid in favour of a threshold or hormesis. This is consistent with data both from animal studies and human epidemiological observations on low-dose induced cancer. The LNT hypothesis should be abandoned and be replaced by a hypothesis that is scientifically justified and causes less unreasonable fear and unnecessary expenditure.

Prevention of immunosuppression by sunscreens in humans is unrelated to protection from erythema and dependent on protection from ultraviolet a in the face of constant ultraviolet B protection.

Sunscreens have been advocated as an important means of preventing skin cancer. Ultraviolet radiation induced immunosuppression is recognized as an important event in skin cancer development, yet the effectiveness of sunscreens in protecting the human immune system from ultraviolet radiation (i.e. ultraviolet radiation) is still unclear. The only currently accepted method of sunscreen rating is the sun protection factor system based on the prevention of erythema. We determined immune protection factors for six commercially available sunscreens using a nickel contact hypersensitivity model in humans. Both sun protection factor and immune protection factor testing was performed using the same solar simulated ultraviolet radiation source and dose-responses were used to determine endpoints both with and without sunscreens. We found that the immune protection factor did not correlate with the sun protection factor; however, immune protection factor was significantly correlated to the ultraviolet A protective capability of the sunscreens, indicating that sunscreen protection from ultraviolet A is important for the prevention of ultraviolet immunosuppression, when there is constant ultraviolet B protection. We recommend that sunscreens should be rated against their immune protective capability to provide a better indication of their ability to protect against skin cancer.

Effects of glycyrrhizae and glycyrrhizic acid on cellular immunocompetence in low-dose gamma-ray irradiated mice.

BACKGROUND: For both animals and human beings, it is important to prevent damage from ionizing radiation and to restore immunocompetence following irradiation. The present study was conducted to investigate the effects of glycyrrhizae (GL) and glycyrrhetinic acid (GA) on cellular immunocompetence in low dose gamma-ray-irradiated mice. METHODS: Six- to 8-week-old ICR strain' Crl:CD-1-ICR (BR) strain male mice, bred in the Institute of Cancer Research, U.S.A., were chosen and divided into four groups. Group A was the normal control. Group B, the experimental control, received 1 Gy of whole body gamma-ray irradiation. Groups C and D, the experimental groups, were treated with 500 mg/kg of GL (orally) and 5 mg/kg body weight of GA (i.p.), respectively, once a day, 5 days a week for 2 weeks after gamma-irradiation. The tested mice were killed, at 6 different intervals to measure their leukocyte and differential counts. Cellular immunocompetence was measured by the 3H-thymidine uptake in each group. RESULTS: One gray of gamma-ray irradiation had evident inhibition on the leukocyte and differential counts and the cellular immunity of mice. GL and GA could help to restore the decreased leukocyte counts and the cellular immunocompetence in low dose gamma-irradiated mice. CONCLUSION: GL and GA could help to restore decreased leukocyte counts and the cellular immunocompetence in low-dose gamma-ray-irradiated mice.

Modulation of acute coronavirus-induced encephalomyelitis in gamma-irradiated rats by transfer of naive lymphocyte subsets before infection.

Clinical course, recovery of infectious virus from brain tissue and histopathology of the central nervous system were examined in gamma-irradiated Lewis rats reconstituted by naive lymphocytes before infection with coronavirus MHV-4 (strain JHM). Up to 9 days past infection, no differences were seen between immunologically competent and immuno-deficient animals in terms of onset and progression of neurological disease. However, in the latter animals neurological symptoms were dominated by signs of encephalitis instead of paralytic disease as usually seen in immunocompetent animals. Nevertheless, despite high titers of infectious virus in the CNS of immunodeficient animals only mild histopathological changes were noticeable. In contrast, infectious virus in the CNS of immunologically competent animals was below the detection limit of the assay. Paralytic disease and tissue destruction were T lymphocyte mediated because gamma-irradiated rats that were reconstituted by CD4+ or CD8+ T lymphocyte enriched cells in the absence of B lymphocytes revealed an earlier onset of clinical symptoms and a more rapid deterioration of their clinical state compared to fully competent animals. Whereas in CD4+ T cell reconstituted animals infectious virus was moderately reduced and tissue destruction as well as inflammatory changes in the CNS were focal, in CD8+ T cell reconstituted animals vacuolizing white matter inflammation was diffuse without reduction of infectious virus in brain tissue. From the presented data we conclude that in the acute stage of JHMV-induced encephalomyelitis of Lewis rats: (i) tissue destruction and paralytic clinical symptomatology are mainly T cell-mediated; (ii) CD4+ T lymphocytes can directly contribute to reduction of viral load in the brain and (iii) only coordinated action of both, the T and the B cell compartment enables animals to survive the infection and recover from disease.

[Ex vivo study of ultraviolet-B inactivating immunocompetence and hematopoietic potential of cord blood].

OBJECTIVE: To determine the differences of the effect of ultraviolet-B(UVB) on lymphocyte and hematopoietic progenitor cell in cord blood. METHODS: The viability, proliferative response and stimulatory activity in mixed lymphocyte culture (MLC), colony forming unit-granulo-monocyte (CFU-GM) colony growth and percentage of CD34+ cell of cord blood in Hanks medium after 0, 5, 10, 20, 50 mJ/cm2 UVB-irradiation were compared. RESULTS: Like the proliferative response and stimulatory activity, CFU-GM colony also showed UVB-irradiation dose dependent decrease. However, much less colonies were destroyed by UVB irradition less than 10 mJ/cm2. More obvious differences were found when 20%(vol/vol) bovine serum was added to the MNC medium. The percentage of CD34+ cell remained unchanged after UVB exposure. CONCLUSION: A lower dose of UVB exposure can slectively inactivate cord blood lymphocyte and antigen presenting cell while sparing hematopoietic progenitor cells. The data indicates the possibility of utility of UVB irradiation for graft-versus-host disease prophylaxis in cord blood transplantation.

In vivo analysis of the 'bystander effect': a cytokine cascade.

The "bystander effect" refers to the death of unmodified tumor cells when in contact with ganciclovir (GCV)-exposed, herpes simplex virus-thymidine kinase (HSV-TK)-modified tumor cells. Although the exact mechanism or mechanisms involved in mediating the bystander effect in vivo are unknown, our findings suggest that an intact host immune system is required for the phenomenon to occur. The present study was designed to establish the effect of HSV-TK-modified tumor cells and GCV on the tumor and its microenvironment in vivo. In sublethally irradiated and immunodeficient Balb/c mice, the bystander effect was observed to be diminished or abrogated. Histopathologic examination of the tumor mass from immunocompetent mice demonstrated centralized hemorrhagic tumor necrosis (38%) after inoculation of the HSV-TK-modified tumor cells and GCV in tumor-bearing mice compared with the control mice (5%), indicating that cytokines such as tumor necrosis factor-alpha (TNF-alpha) were being released locally. This hypothesis was underscored using reverse transcriptase polymerase chain reaction (RT-PCR), by the demonstration of cytokine mRNA expression in mice treated with HSV-TK-expressing tumors and GCV. Semiquantitative PCR analysis for TNF-alpha using PCR-MIMIC on tumor samples from mice treated on days 1 and 4 showed a two-fold increase in the level on mRNA expression. Also, immunohistochemical staining for TNF-alpha showed that mononuclear inflammatory cells infiltrating the tumor were its source. Finally, characterization of tumor-infiltrating lymphocytes (TIL) in experimental animals demonstrated a two- to three-fold increase in the number of macrophages and T cells compared with control animals. These results demonstrate that, in vivo, the bystander effect is mediated in part by an antitumor response through the release of cytokines. Further, the cytokine milieu and tumor microenvironment can be modulated following injection of HSV-TK cells and GCV to enhance the host immune response, which is of potential use in clinical trials.

Sunlight induced progression of AIDS.

Ultraviolet B (UVB) radiation in sunlight damages the cutaneous immune system of individuals primarily by converting trans-urocanic acid (UCA) to its cis isoform which in turn instigates excessive local, and eventually systemic, levels of tumor necrosis factor-alpha (TNF alpha). UVB radiation and TNF alpha have been found to activate HIV from the latent state, and TNF alpha has been implicated in the pathogenesis of several manifestations of the acquired immune deficiency syndrome (AIDS). We hypothesize that the immunosuppressant properties of TNF alpha and cis-UCA, released by intense sun exposure, can accelerate the onset and progression of AIDS in HIV-infected individuals.