7
Immunology and Microbiology

INTRODUCTION

The immune system plays a fundamental role in protecting the host against the development and persistence of infections and tumors. There have been a wide range of alterations in measures of cell-mediated immune function after long-term and short-term spaceflight (alterations in cytokine production, inhibited leukocyte proliferation, inhibited skin test reactions that measure immune memory, alterations in distribution of leukocytes, inhibited natural killer cell activity, and decreased responses of bone marrow cells to colony-stimulating factors) (Sonnenfeld, 1998). These are standard measures of immune function. Although there can be little doubt after 20 years of work that immune responses are altered after exposure to spaceflight conditions, the physiological and medical significance of these spaceflight-induced changes for crew health remains unknown. There have been only limited reports of difficulty with infections during or after spaceflight, and infectious diseases have not been a major issue. Nevertheless, with the advent of longer-term spaceflights, including a permanent presence on the International Space Station (ISS) and other longer flights, the potential for development of infectious diseases in crews may increase as a result of prolonged alterations in immune parameters. Changes in the composition of indigenous microbial flora during long-term spaceflight and, perhaps, in the properties of microorganisms and the effectiveness of antimicrobial drugs also could potentially pose problems.

Immunology and microbiology are linked together because of the fundamental role of the immune system in resistance to infection. However, alterations in immune responses could also lead to changes in tumor immunity and to the development of allergic and autoimmune diseases, either in flight or postflight.

Changes in the immune system and in the properties of microorganisms induced by spaceflight conditions have been recognized by NASA and others as an area for further study (NASA, 1998; NRC, 1998). In the 1998 Strategy report (NRC, 1998), major priorities included (1) determining whether alterations in immune responses induced by spaceflight conditions actually resulted in compromised resistance to infection and (2) defining the interactions of the immune systems with other systems, in



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Review of NASA’s Biomedical Research Program 7 Immunology and Microbiology INTRODUCTION The immune system plays a fundamental role in protecting the host against the development and persistence of infections and tumors. There have been a wide range of alterations in measures of cell-mediated immune function after long-term and short-term spaceflight (alterations in cytokine production, inhibited leukocyte proliferation, inhibited skin test reactions that measure immune memory, alterations in distribution of leukocytes, inhibited natural killer cell activity, and decreased responses of bone marrow cells to colony-stimulating factors) (Sonnenfeld, 1998). These are standard measures of immune function. Although there can be little doubt after 20 years of work that immune responses are altered after exposure to spaceflight conditions, the physiological and medical significance of these spaceflight-induced changes for crew health remains unknown. There have been only limited reports of difficulty with infections during or after spaceflight, and infectious diseases have not been a major issue. Nevertheless, with the advent of longer-term spaceflights, including a permanent presence on the International Space Station (ISS) and other longer flights, the potential for development of infectious diseases in crews may increase as a result of prolonged alterations in immune parameters. Changes in the composition of indigenous microbial flora during long-term spaceflight and, perhaps, in the properties of microorganisms and the effectiveness of antimicrobial drugs also could potentially pose problems. Immunology and microbiology are linked together because of the fundamental role of the immune system in resistance to infection. However, alterations in immune responses could also lead to changes in tumor immunity and to the development of allergic and autoimmune diseases, either in flight or postflight. Changes in the immune system and in the properties of microorganisms induced by spaceflight conditions have been recognized by NASA and others as an area for further study (NASA, 1998; NRC, 1998). In the 1998 Strategy report (NRC, 1998), major priorities included (1) determining whether alterations in immune responses induced by spaceflight conditions actually resulted in compromised resistance to infection and (2) defining the interactions of the immune systems with other systems, in

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Review of NASA’s Biomedical Research Program particular the neuroendocrine system, that could contribute to compromised resistance to infections and tumors in spaceflight. These recommendations are discussed in greater detail in Appendix A. NASA’S CURRENT RESEARCH PROGRAM IN IMMUNOLOGY AND MICROBIOLOGY In FY 1999, nine grants for immunology and microbiology (including funding for the National Space Biomedical Research Institute (NSBRI)) were funded, at a level of approximately $1.160 million (see Table 7.1). These include investigations at Johnson Space Center (JSC), the NSBRI program, and other extramural NASA Research Announcement (NRA)-supported laboratories. Ames Research Center (ARC) is not currently involved in studies in immunology and microbiology. Late in 1999, four new immunology-related projects were approved through the Gravitational Biology and Ecology (GB&E) program of the NRA process for a total funding of about $265,000. Studies are well coordinated between JSC and NSBRI laboratories and between JSC and independent university laboratories for the immunology and microbiology disciplines. For FY1999, one additional grant was funded by the Biomedical Research and Countermeasures (BR&C) program, and five basic research grants were funded by the GB&E program. There is no specific request for proposals in immunology or microbiology in the FY 2000 NASA Research Announcements for Biomedical Research and Countermeasures, but the call for physiology experiments could encompass immunology and microbiology (NASA, 1999b). Immunology and microbiology remain areas of relatively low priority for NASA-funded research. There is considerable overlap and integration between the fields of immunology and microbiology. Experiments focus on the effects of spaceflight on immunological parameters. In-flight and ground-based studies in analogue settings, such as Antarctic overwintering, on human immune responses and resistance to infections are ongoing and planned. Additionally, an animal model (rodent hindlimb unloading) is being used to test the effects of spaceflight on immune responses and resistance to viral and bacterial infection. There are also studies using animal models to determine possible effects of spaceflight on the development of immune responses. In addition, there are very active ongoing research programs on the rapid identification of microorganisms and the effects of the spaceflight environment and ground-based models on microbial growth that are supported by NSBRI and NASA. The priorities outlined in the Strategy report are beginning to be considered. Studies to determine whether changes in immune parameters induced by spaceflight conditions affect resistance to infection were a priority of the Strategy report. JSC, NSBRI, and NRA-funded university investigators have undertaken both ground-based and spaceflight studies to address the question of reactivation of latent TABLE 7.1 Summary of FY 1999 Funding for Immunology and Microbiology   NRA   NSBRI   Subdiscipline Total ($ thousands) No. of Projects Total ($ thousands) No. of Projects Immunology 135 2 365 1 Microbiology 330 4 330 2 Total 465 6 695 3 NOTE: The bulk of NRA funding for immunology and microbiology comes from the GB&E program (now the FBRP) and not from the Biomedical Research and Countermeasures program.

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Review of NASA’s Biomedical Research Program viral infections. These should begin to provide answers as to whether spaceflight-induced changes in immune parameters can affect resistance to infection. This approach is in very preliminary stages and should be expanded. The FY 1999 NRA awards include a flight study to explore this issue. Interdisciplinary investigation of the interaction of the neuroendocrine system hypothalamus-pituitary-adrenal (HPA) axis with the immune system under spaceflight conditions was a second priority of the Strategy report. Although some studies have been carried out in this area, there is no directed program to address this issue. The Strategy report did not specifically address priorities for microbiology research. However, the approach to develop new techniques for detection of microbes and new approaches for disinfection is appropriate to empower future space exploration. In summary, the current activities in immunology and microbiology are congruent with the recommendations of the Strategy report, except that minimal effort is directed at the interaction of the immune system with the HPA axis. Immunology and microbiology remain areas of relatively low priority for NASA-funded research. PROGRAMMATIC BALANCE Balance of Subdiscipline Areas The Proceedings of the First Biennial Space Biomedical Investigators’ Workshop (NASA and USRA, 1999), the NASA Life Sciences Program Tasks (NASA, 1999a), and NRA awards for FY 1999 (NASA, 1999b) indicate an appropriate balance between immunology and microbiology. For FY 1999, there were three funded immunology grants (total funding approximately $500,000) and six microbiology tasks (total funding $660,000). There is overlap between the subdisciplines, and several microbiology projects contain immunological components. The major focus of the immunology and microbiology program is investigation of whether changes in immune responses in spaceflight result in alterations in resistance to infection. An additional focus of the program is rapid detection of microorganisms. Balance of Ground and Flight Studies The majority of investigations are ground based (NASA and USRA, 1999), due in part to reduced opportunities for spaceflight as a result of ISS construction. There are currently two experiments scheduled for spaceflight, one involving cell culture experiments on the effects of spaceflight on macrophage maturation (NASA, 1999a), the other aimed at determining the effects of spaceflight on virus reactivation (NASA headquarters, personal communication, 1999). The date for flight of these experiments is not yet available. NSBRI-funded research in immunology and microbiology is currently limited to ground-based studies, in accord with the institute’s charter (NSBRI, 1998). Emphasis Given to Fundamental Mechanisms The NSBRI group and NASA-funded investigators have begun studies on fundamental mechanisms involved in spaceflight-induced alterations in immune responses, using cell culture, human, and rodent models. These include studies on the mechanisms of immune cell function and the mechanisms of the effects of rodent hindlimb unloading on delayed hypersensitivity. Additional studies to determine new methods for the detection of bacteria in extreme environments are also of a fundamental nature. The study of these fundamental mechanisms is in accord with the recommendations of the Strategy report.

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Review of NASA’s Biomedical Research Program There appears to be little attention currently given to the role of the HPA axis in spaceflight-induced changes in resistance to infection. Studies analyzing interactions between the HPA axis and the immune system in modulating resistance to infection are not currently being carried out, although such studies were accorded high priority in the Strategy report. Utilization and Validation of Animal Models There has been some validation of animal models. Spaceflight-induced changes in immunological parameters are similar in humans and rodents (Sonnenfeld, 1998). Ground-based experiments with the rat hindlimb-unloading model and simultaneous spaceflight experiments showed generally similar immunological changes, except for leukocyte subset distribution (Sonnenfeld et al., 1992). Rodent hindlimb unloading is currently being used by NSBRI investigators to examine resistance to viral infections. There appear to be no plans as yet for flight experiments using rodent or other animal model systems (NASA, 1998, 1999b). In summary, there is appropriate balance between the immunology and microbiology subdisciplines, and appropriate emphasis on the study of fundamental mechanisms. Use and validation of animal models are being carried out as outlined in the Strategy report. The balance between ground-based and flight studies is congruent with the recommendations of the Strategy report to carry out precursor ground-based studies. Determination of the physiological and biomedical significance of spaceflight-induced changes in immune responses should include future flight experiments. DEVELOPMENT AND VALIDATION OF COUNTERMEASURES There is an effective countermeasure available for potential problems with respiratory tract infections. The Health Stabilization Program developed as part of the Apollo Program has diminished the frequency of respiratory tract infections in crews (Hawkins and Ziegschmid, 1975), probably due to limitations in preflight social contacts. As the duration of spaceflight increases, the risk of infection may also increase if immune function is compromised. The goal of the NSBRI is to develop additional countermeasures to deal with potential problems of infection that may be encountered during and after long-term spaceflight (NSBRI, 1998). The existing countermeasure for respiratory tract infections has proven effective. Development of further countermeasures should await confirmation of the physiological and biomedical significance of spaceflight-induced changes in immune responses, as recommended in the Strategy report. EPIDEMIOLOGY AND MONITORING Monitoring of respiratory tract infections during the Apollo Program led to the Health Stabilization Program for Astronauts, which has decreased the incidence of infections (Hawkins and Ziegschmid, 1975). The only ongoing monitoring and epidemiology studies are those involving the crew health program (NASA, 1998), for which data have not been generally available. The proposed Integrated Testing Regimen (ITR) for spaceflight crews provides for microbiological (parameters established) and immunological (parameters to be determined) monitoring. If information from the Integrated Testing Regimen is made available to the research community and the parameters chosen for immunological monitoring are appropriate, then there may be congruence with the Strategy report recommendation for development of a monitoring program. There does not appear to be a program for epidemiological studies available for research purposes.

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Review of NASA’s Biomedical Research Program SUPPORT OF ADVANCED TECHNOLOGIES Rapid detection of microorganisms is of prime importance in ensuring astronaut health for the entire space program. To meet this need, NASA, in collaboration with industry, is supporting the development of several new technologies for the detection of microorganisms during spaceflight (NASA,1999a; NASA and USRA, 1999; NSBRI, 1998). The support for advanced technology development for microbiology is congruent with the general recommendation of the Strategy report. There is no current technology development specific to immunology. SUMMARY The immunology and microbiology program has begun to develop priorities in accordance with those suggested in the Strategy report for ground-based experiments using animal models prior to the development of spaceflight studies. The extensive use of models by the programs, including animal models such as hindlimb unloading of rodents, tissue culture in the rotating cell vessel apparatus, and analogue environments such as isolation and polar overwintering, should permit critical testing of mechanistic hypotheses in space. Additional efforts should be directed toward such mechanistic studies and toward studies involving interactions with the HPA axis. The number of investigators and funded projects for the entire immunology and microbiology programs is small, and the need for additional studies will become more pressing as prolonged exposure of crews to spaceflight conditions becomes the norm. REFERENCES Hawkins, W.R., and J.F. Ziegschmid. 1975. Aspects of crew health. P. 43 in Biomedical Results of Apollo. R.F. Johnston, L.F. Dietlen, and C.A. Berr, eds. SP-368. Houston, Tex.: NASA. National Aeronautics and Space Administration (NASA), Space and Life Sciences Directorate. 1998. Astronaut Medical Evaluation Requirements Document–Appendix B, Selection, Annual, Pre- and Postflight Medical Evaluation Requirements. Houston, Tex.: NASA. NASA, Office of Life and Microgravity Sciences and Applications. 1999a. Life Sciences Program Tasks and Bibliography for FY 1998. Washington, D.C.: NASA. NASA. 1999b. Research Announcement—Research Opportunities in Space Life Sciences. Biomedical Research and Countermeasures. Washington, D.C.: NASA. NASA and Universities Space Research Association (USRA). 1999. Proceedings of the First Biennial Space Biomedical Investigators’ Workshop, January 11-13, 1999, League City, Texas. Houston, Tex.: NASA and USRA. National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press. National Space Biomedical Research Institute (NSBRI). 1998. Annual Report, October 1, 1997-September 30, 1998. Houston, Tex.: NSBRI. Sonnenfeld, G. 1998. Immune responses in space flight. Int. J. Sports Med. 19:S195-S2. Sonnenfeld, G., A.D. Mandel, I.V. Konstantinova, W.D. Berry, G.R. Taylor, A.T. Lesnyak, B.B. Fuchs, and A.L. Rakhmilevich. 1992. Spaceflight alters immune cell function and distribution. J. Appl. Physiol. 73:191S-195S.