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An experiment to examine the possible interrelationship of various classes of immunoglobulins by utilizing the effect of weightlessness as a stress factor and subsequently measuring inhibitory, compensatory, or enhancing interrelationships. A second objective of the experiment is to investigate the state of immune competency under conditions of sustained weightlessness.
Production of interferon (I) in response to protozoan infection, and the interferon-mediated inhibition of parasite replication were studied in order to determine if these effects may be related to immunologic-mediated resistance of the hosts. Two extracellular parasites-Trypanosoma brucei rhodesiense and Naegleria fowlei were used. Upon infection with the trypanosome, only resistant strains of mice produced I. An early peak of alpha/beta I is followed by appearance of gamma I, which coincided with antibody production and a drop in parasitemia. In case of the amoeba, pretreatment of its suspension with alpha/beta I inhibits its replication in vitro, and appears to protect mice from the infection and the disease. It is proposed that production of interferon, with its regulatory effect on the immune responses, may play a major role in regulating the processes of protozoan-caused diseases.
Tests showed that bipolar chips in the attitude control computer of the Galileo spacecraft would likely cause catastrophic mission failure due to single particle upset. This paper describes the design and testing of CMOS replacements which are speed compatible with the bipolar parts and are immune to upset by 165-MeV krypton ions.
Serum was collected from rabbits at 2-day intervals following a single injection with tetanus toxoid or at weekly intervals following multiple injections with Micrococcus lysodeikticus cell walls. These sera were analyzed for the presence of individual clonotypes of specific antitetanus or antimicrococcal antibodies by isoelectric focusing in immobilized pH gradients with added carrier ampholytes followed by affinity immunoblotting. The affinity immunoblots obtained clearly defined both the rapid disappearance and late appearance of distinct subsets of antibody clonotypes during the response. These data demonstrate the application of affinity immunoblotting combined with immobilized pH gradients for detecting the subtle changes in specific antibody clonotype patterns which occur during an immune response.
Experiments were carried out on cells from rats that had been flown on Soviet Biosputnik Cosmos 1887 to explore the effects of speceflight on immune responses. Rat bone marrow cells were examined for their response to colony stimulating factor-M. Rat spleen and bone marrow cells were stained with antibodies directed against cell surface antigenic markers. The results of the studies indicate that bone marrow cells from flown rats showed a decreased response to colony stimulating factor. There was a higher percentage of spleen cells from flown rats staining positively for pan-T-cell, suppressor-T-cell, and interleukin-2 receptor cell surface antigens. A small increase in the percentage of cells staining positively for helper-T-cell antigens was also noted. In addition, a higher percentage of cells that appeared to be part of the myelogenous population of bone marrow cells from flown rats stained positively for surface immunoglobulin.
Results are presented on changes in cellular immunity and in the production of lymphokine in spacecrews during spaceflights. Measurements were carried out on blood samples collected from 50 cosmonauts before and after spaceflights of different duration, on board Salyut-6, Salyut-7, or Mir. Additional data were obtained from rats flown on board the Cosmos-1667 and Cosmos-1887 biosatellites. The parameters measured included the PHA responsiveness of T lymphocytes, the activity of T-helper cells and of nonspecific T suppressors, the activity of the so-called natural killer lymphocytes, the production of gamma-interferon, and the cell-surface markers. Results showed that the frequency and the extent of changes in the immunologic resistance of subjects depended on the duration of the flight. However, even after the most prolonged (365 days) spaceflight, the changes observed were mostly of a functional character with subsequent rapid return to normal.
The cell-mediated immune (CMI) mechanism was evaluated in 10 space shuttle astronauts by measuring their delayed-type hypersensitivity response to seven common recall antigens. The Multitest CMI test system was used to administer antigens of tetanus, diphtheria, Streptococcus, Proteus, old tuberculin, Candida, and Trichophyton to the forearm 46 h before nominal mission termination; readings were conducted 2 h after landing. The mean number of reactions was reduced from 4.5 preflight to 3.0 inflight, and the mean reaction score was reduced from 21.4 to 13.7 mm inflight. The data presented suggest that the CMI system is still being degraded by space flight conditions on day 4 and that between day 5 and day 10, the depression maximizes and the system begins to adjust to the new conditions. The relation of these in vivo findings to previously reported in vitro results is discussed.
A new logic family, which is immune to single event upsets, is described. Members of the logic family are capable of recovery, regardless of the shape of the upsetting event. Glitch propagation from an upset node is also blocked. Logic diagrams for an Inverter, Nor, Nand, and Complex Gates are provided. The logic family can be implemented in a standard, commercial CMOS process with no additional masks. DC, transient, static power, upset recovery and layout characteristics of the new family, based on a commercial 1 micron CMOS N-Well process, are described.
Test results for three SEU logic/circuit hardened CMOS memory circuits verify upset and latch-up immunity for two configurations to be in excess of 120 MeV cm(exp 2)/mg using a commercial, non-radiation hardened CMOS process. Test chips from three separate fabrication runs in two different process were evaluated.
Fault testing of resistive manufacturing defects is done on a recently developed single event upset immune logic family. Resistive ranges and delay times are compared with those of traditional CMOS logic. Reaction of the logic to these defects is observed for a NOR gate, and an evaluation of its ability to cope with them is determined.
This compendium includes abstracts and synopses of clinical observations and of more basic studies involving physiological mechanisms concerning interaction of physical exercise and the human immune system. If the author's abstract or summary was appropriate, it was included. In other cases, a more detailed synopsis of the paper was prepared under the subheadings 'Purpose,' 'Methods,' 'Results,' and 'Conclusions.' Author and subject indices are provided, plus a selected bibliography of related work or those papers received after the volume was being prepared for publication. This volume includes material published from 1902 through 1991.
The effects of restraint on immunological parameters was determined in an 18 day ARRT (adult rhesus restraint test). The monkeys were restrained for 18 days in the experimental station for the orbiting primate (ESOP), the chair of choice for Space Shuttle experiments. Several immunological parameters were determined using peripheral blood, bone marrow, and lymph node specimens from the monkeys. The parameters included: response of bone marrow cells to GM-CSF (granulocyte-macrophage colony stimulating factor), leukocyte subset distribution, and production of IFN-a (interferon-alpha) and IFN-gamma (interferon-gamma). The only parameter changed after 18 days of restraint was the percentage of CD8+ T cells. No other immunological parameters showed changes due to restraint. Handling and changes in housing prior to the restraint period did apparently result in some restraint-independent immunological changes. Handling must be kept to a minimum and the animals allowed time to recover prior to flight. All experiments must be carefully controlled. Restraint does not appear to be a major issue regarding the effects of space flight on immune responses.
Two different experiments were carried out in this segment of the immunology protocol for samples received from rats flown on Cosmos 2044. Control groups included vivarium, synchronous and antiorthostatically suspended rats. In the first experiment, rat bone marrow cells were examined in Moscow for their response to recombinant murine colony stimulating factor-granulocyte / monocyte (CSF-GM). In the second experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States for analysis on a flow cytometer. The results of the studies indicated that bone marrow cells from flown and suspended rats showed a decreased response to CSF-GM as compared to bone marrow cells from control rats. Spleen cells from flown rats showed increased percentages of suppressor-cytotoxic-T and helper-T cells amongst the entire cell population. Bone marrow cells showed an increase in the percentage of helper-T cells in the myelogenous population and increased percentages of anti-asialo GM-1 bearing, interleukin-2 receptor bearing, pan-T and helper-T cells in the lymphocytic population. Cell populations from rats suspended antiorthostatically did not follow the same pattern of distribution of leukocytes as cell populations for flown rats. These results are similar, but not identical to, earlier results from Cosmos 1887, and confirm that space flight can have profound effects on immune system components and activities.
The effects of restraint on immunological parameters was determined in an 18 day ARRT (adult rhesus restraint test). The monkeys were restrained for 18 days in the experimental station for the orbiting primate (ESOP), the chair of choice for Space Shuttle experiments. Several immunological parameters were determined using peripheral blood, bone marrow, and lymph node specimens from the monkeys. The parameters included: response of bone marrow cells to GM-CSF (granulocyte-macrophage colony stimulating factor), leukocyte subset distribution, and production of IFN-alpha (interferon-alpha) and IFN-gamma (interferon-gamma). The only parameter changed after 18 days of restraint was the percentage of CDB+ T cells. No other immunological parameters showed changes due to restraint. Handling and changes in housing prior to the restraint period did apparently result in some restraint-independent immunological changes. Handling must be kept to a minimum and the animals allowed time to recover prior to flight. All experiments must be carefully controlled. Restraint does not appear to be a major issue regarding the effects of space flight on immune responses.
In the grant period, we perfected techniques for determination of interleukin production and leukocyte subset analysis of rhesus monkeys. These results are outlined in detail in publication number 2, appended to this report. Additionally, we participated in the ARRT restraint test to determine if restraint conditions for flight in the Space Shuttle could contribute to any effects of space flight on immune responses. All immunological parameters listed in the methods section were tested. Evaluation of the data suggests that the restraint conditions had minimal effects on the results observed, but handling of the monkeys could have had some effect. These results are outlined in detail in manuscript number 3, appended to this report. Additionally, to help us develop our rhesus monkey immunology studies, we carried out preliminary studies in mice to determine the effects of stressors on immunological parameters. We were able to show that there were gender-based differences in the response of immunological parameters to a stressor. These results are outlined in detail in manuscript number 4, appended to this report.
Reactivation of Epstein-Barr virus (EBV) and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at two Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity skin testing was used as an indicator of the CMI response, which was evaluated two times before winter isolation and three times during isolation. At all five evaluation times, 8 or more of the 16 subjects had a diminished. CMI response. Diminished CMI was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal CMI responses for all five tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, after, and during the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least one occasion. The probability of EBV shedding increased (p=0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (p<0.0005) when CMI responsiveness was diminished than when CMI status was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter results in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.
Interactions between the immune system and skeletal muscle may play a significant role in modulating the course of muscle injury and repair after modified musculoskeletal loading. Current evidence indicates that activation of the complement system is an early event during modified loading, which then leads to inflammatory cell invasion. However, the functions of those inflammatory cells are complex and they seem to be capable of promoting additional injury and repair. Recent findings implicate an early invading neutrophil population in increasing muscle damage that is detected by the presence of muscle membrane lesions. Macrophages that invade subsequently serve to remove cellular debris, and seem to promote repair. However, macrophages also have the ability to increase damage in muscle in which there is an impaired capacity to generate nitric oxide. In vivo and in vitro evidence indicates that muscle-derived nitric oxide can serve an important role in protecting muscle from membrane damage by invading inflammatory cells. Collectively, these findings indicate that the dynamic balance between inflammatory cells, the complement system, and muscle-derived free radicals can play important roles in the secondary damage of muscle during modified musculoskeletal loading.
Hair cells in the vestibular organs of birds have a relatively short life span. Mature hair cells appear to die spontaneously and are then quickly replaced by new hair cells that arise from the division of epithelial supporting cells. A similar regenerative mechanism also results in hair cell replacement after ototoxic damage. The cellular basis of hair cell turnover in the avian ear is not understood. We are investigating the signaling pathways that lead to hair cell death and the relationship between ongoing cell death and cell production. In addition, work from our lab and others has demonstrated that the avian inner ear contains a resident population of macrophages and that enhanced numbers of macrophages are recruited to sites of hair cells lesions. Those observations suggest that macrophages and their secretory products (cytokines) may be involved in hair cell regeneration. Consistent with that suggestion, we have found that treatment with the anti-inflammatory drug dexamethasone reduces regenerative cell proliferation in the avian ear, and that certain macrophage-secreted cytokines can influence the proliferation of vestibular supporting cells and the survival of statoacoustic neurons. Those results suggest a role for the immune system in the process of sensory regeneration in the inner ear.