Skip to main content
SpringerLink
Log in

Age-Related Changes in Type 1 and Type 2 Cytokine Production in Humans

  • Living reference work entry
  • First Online:
Book cover Handbook of Immunosenescence

Abstract

Although aging is accompanied by several changes in immune function, altered T cell function represents the most consistent and dramatic change. Since cytokines modulate the immune response, it has been postulated that these age-associated changes in T cell function may be due to alterations in cytokine production. Data from murine studies generally support an age-related shift from a Th1-like (IL-2, IFN-γ) to a Th2-like (IL-4, IL-6, IL-10) cytokine response; however, whether or not such an age-related shift to a Type 2 cytokine response occurs in humans is still controversial. This chapter review of over 60 studies in humans, in which Type 1 and Type 2 cytokines were evaluated either alone or together, suggests that age-associated changes in cytokine production are inconsistent. Further, these age-associated changes in cytokine production do not always induce a shift to a Type 2 cytokine response. Importantly, these studies highlight that the stimulus used to induce cytokines influences both the level and pattern of immune response. Additional comprehensive evaluations in human studies are both critical and necessary to clearly identify the impact of altered cytokine production on age-related changes in immune function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Adibzadeh M, Pohla H, Rehbein A, Pawelec G (1995) Long- term culture of monoclonal human T lymphocytes: models for immunosenescence? Mech Ageing Dev 83:171–183

    Article  CAS  PubMed  Google Scholar 

  • Akbaraly TN, Hamer M, Ferrie JE, Lowe G, Batty GD, Hagger-Johnson G, Singh-Manoux A, Shipley MJ, Kivimäki M (2013) Chronic inflammation as a determinant of future aging phenotypes. CMAJ 185:E763–E770

    Article  PubMed  PubMed Central  Google Scholar 

  • Alberti S, Cevenini E, Ostan R, Capri M, Salvioli S, Bucci, L, Ginaldi, L, De Martinis M, Franceschi, C, Monti D (2006) Age-dependent modifications of Type 1 and Type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev 127:560–566

    Google Scholar 

  • Albright JW, Zuiga-Pflcker JC, Albright JF (1995) Transcriptional control of IL-2 and IL-4 in T cells of young and old mice. Cell Immunol 164:170–175

    Article  CAS  PubMed  Google Scholar 

  • Al-Rayes H, Pachas W, Mirza N, Ahern DJ, Geha RS, Vercelli D (1992) IgE regulation and lymphokine patterns in aging humans. J Allergy Clin Immunol 90:630–636

    Article  CAS  PubMed  Google Scholar 

  • Alvarez-Rodríguez L, López-Hoyos M, Muñoz-Cacho P, Martínez-Taboada VM (2012) Aging is associated with circulating cytokine dysregulation. Cell Immunol 273:124–132

    Article  PubMed  Google Scholar 

  • Barcellini W, Borghi MO, Sguotti C, Palmieri R, Frasca D, Meroni PL, Doria G, Zanussi C (1988) Heterogeneity of immune responsiveness in healthy elderly subjects. Clin Immunol Immunopathol 47:142–151

    Article  CAS  PubMed  Google Scholar 

  • Beharka AA, Meydani M, Wu D, Leka LS, Meydani A, Meydani SN (2001) Interleukin-6 production does not increase with age. J Gerontol Biol Sci 56A:B81–B88

    Article  CAS  Google Scholar 

  • Behzad H, Huckriede AL, Haynes L, Gentleman B, Coyle K, Wilschut JC, Kollmann TR, Reed SG, McElhaney JE (2012) GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J Infect Dis 205:466–473

    Article  CAS  PubMed  Google Scholar 

  • Bernstein ED, Murasko DM (1998) Effect of age on cytokine production in humans. Age 21:137–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernstein ED, Gardner EM, Abrutyn E, Gross P, Murasko DM (1998) Cytokine production after influenza vaccination in a healthy elderly population. Vaccine 16:1722–1731

    Article  CAS  PubMed  Google Scholar 

  • Bodnar Z, Steger MM, Saurwein-Teissl M, Maczek C, Grubeck-Loebenstein B (1997) Cytokine production in response to stimulation with tetanus toxoid, Mycobacterium tuberculosis and influenza antigens in peripheral blood mononuclear cells and T cell lines from healthy elderlies. Int Arch Allergy Immunol 112:323–330

    Article  CAS  PubMed  Google Scholar 

  • Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T, Fehm HL (1995) Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev 84:113–126

    Article  CAS  PubMed  Google Scholar 

  • Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (2000) Proliferative responses of blood mononuclear cells (BMNC) in a cohort of elderly humans: role of lymphocyte phenotype and cytokine production. Clin Exp Immunol 119:433–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cakman I, Rohwer J, Schutz RM, Kirchner H, Rink L (1996) Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mech Ageing Dev 87:197–209

    Article  CAS  PubMed  Google Scholar 

  • Candore G, DiLorenzo G, Melluso M, Cigna D, Colucci AT, Modica MA, Caruso C (1993) γ -interferon, interleukin-4 and interleukin-6 in vitro production in old subjects. Autoimmunity 16:275–280

    Article  CAS  PubMed  Google Scholar 

  • Castle S, Uyemura K, Wong W, Modlin R, Effros R (1997) Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents. Mech Ageing Dev 94:7–16

    Article  CAS  PubMed  Google Scholar 

  • Castle SC, Uyemura K, Crawford W, Wong W, Klaustermeyer WB, Makinodan T (1999) Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 34:243–252

    Article  CAS  PubMed  Google Scholar 

  • Cohen HJ (1999) Oncology and aging: general principles of cancer in the elderly. In: Hazard WR et al (eds) Principles of geriatric medicine and gerontology. McGraw-Hill, New York, pp 117–130

    Google Scholar 

  • Ershler WB (1993) Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 41:176–181

    Article  CAS  PubMed  Google Scholar 

  • Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker EB, Daynes RA, Weindruch R (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12:225–230

    CAS  PubMed  Google Scholar 

  • Fabbri E, An Y, Zoli M, Simonsick EM, Guralnik JM, Bandinelli S, Boyd CM, Ferrucci L (2015) Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J Gerontol A Biol Sci Med Sci 70:63–70

    Article  CAS  PubMed  Google Scholar 

  • Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375–2378

    Article  CAS  PubMed  Google Scholar 

  • Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124:487–493

    Article  CAS  PubMed  Google Scholar 

  • Gardner EM, Gonzalez EW, Nogusa S, Murasko DM (2006) Age-related changes in the immune response to influenza vaccination in a racially diverse, healthy elderly population. Vaccine 24:1609–1614

    Article  CAS  PubMed  Google Scholar 

  • Gillis S, Kozak R, Durante M, Weksler ME (1981) Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest 67:937–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goetzl EJ, Huang MC, Kon J, Patel K, Schwartz JB, Fast K, Ferrucci L, Madara K, Taub DD, Longo DL (2010) Gender specificity of altered human immune cytokine profiles in aging. FASEB J 24:3580–3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hessen MT, Kaye D, Murasko DM (1991) Heterogeneous effects of exogenous lymphokines on lymphoproliferation of elderly subjects. Mech Ageing Dev 58:61–73

    Article  CAS  PubMed  Google Scholar 

  • Hobbs MV, Weigle WO, Noonan DJ, Torbett BE, McEvilly RJ, Koch RJ, Cardenas GJ, Ernst DN (1993) Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J Immunol 150:3602–3614

    CAS  PubMed  Google Scholar 

  • Hobbs MV, Weigle WO, Ernst D (1994) Interleukin-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol 154:264–272

    Article  CAS  PubMed  Google Scholar 

  • Holbrook NJ, Chopra RK, McCoy MT, Nagel JE, Powers DC, Adler WH, Schneider EL (1989) Expression of interleukin-2 and the interleukin-2 receptor in aging rats. Cell Immunol 120:1–9

    Article  CAS  PubMed  Google Scholar 

  • James K, Premchand N, Skibinska A, Skibinski G, Nicol M, Mason JI (1997) IL-6, DHEA and the ageing process. Mech Ageing Dev 93:15–24

    Article  CAS  PubMed  Google Scholar 

  • Kania DM, Binkley N, Checovich M, Havighurst T, Schilling M, Ershler WB (1995) Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J Am Geriatr Soc 43:236–239

    Article  CAS  PubMed  Google Scholar 

  • Karanfilov CI, Liu B, Fox CC, Lakshmanan RR, Whisler RL (1999) Age-related defects in Th1 and Th2 cytokine production by human T cells can be dissociated from altered frequencies of CD45RA+ and CD45RO+ T cell subsets. Mech Ageing Dev 109:97–112

    Article  CAS  PubMed  Google Scholar 

  • Kuby J (2013) Immunology. WH Freeman, New York

    Google Scholar 

  • Le Garff-Tavernier M, Béziat V, Decocq J, Siguret V, Gandjbakhch F, Pautas E, Debré P, Merle-Beral H, Vieillard V (2010) Human NK cells display major phenotypic and functional changes over the life span. Aging Cell 9:527–535

    Article  PubMed  Google Scholar 

  • Li G, Ju J, Weyand CM, Goronzy JJ (2015) Age-associated failure to adjust type I IFN receptor signaling thresholds after T cell activation. J Immunol 195:865–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ligthart GJ, Coberand JX, Geertzen HGM, Meinders AE, Knook DL, Hijmins W (1990) Necessity of the assessment of health status in human immunogerontological studies: evaluation of the SENIEUR protocol. Mech Ageing Dev 55:89–105

    Article  CAS  PubMed  Google Scholar 

  • Lio D, D’Anna C, Gervasi F, Scola L, Potestio M, DiLorenzo G, Listi F, Colombo A, Candore G, Caruso C (1998) Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly. Mech Ageing Dev 102:211–219

    Article  CAS  PubMed  Google Scholar 

  • Lio D, Balistreri CR, Candore G, D’Anna C, DiLorenzo G, Gervasi F, Listi F, Scola L, Caruso C (2000) In vitro treatment with interleukin-2 normalizes type-1 cytokine production by lymphocytes from elderly. Immunopharmacol Immunotoxicol 22:195–203

    Article  CAS  PubMed  Google Scholar 

  • Llorente L, Richaud-Patin Y, Alvarado C, Vidaller A, Jakez-Ocampo J (1997) Autoantibody production in healthy elderly people is not promoted by interleukin-10 although this cytokine is expressed in them by a peculiar CD8+CD3+ large granular cell subpopulation. Scand J Immunol 45:401–407

    Article  CAS  PubMed  Google Scholar 

  • Lombard PR, Steiner G (1992) Preliminary report on cytokine determination in human synovial fluids: a consensus study of the European Workshop for Rheumatology Research. Clin Exp Rheumatol 10:515–520

    Google Scholar 

  • Lung TL, Saurwein-Teissi M, Parson W, Schonitzer D, Grubeck-Loebenstein B (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18:1606–1612

    Article  CAS  PubMed  Google Scholar 

  • McElhaney JE, Beattie BL, Devine R, Grynoch R, Toth EL, Bleackley RC (1990) Age-related decline in interleukin 2 production in response to influenza vaccine. J Am Geriatr Soc 38:652–658

    Article  CAS  PubMed  Google Scholar 

  • McElhaney JE, Meneilly GS, Beattie BL, Helgason CD, Lee SF, Devine RD, Bleackley RC (1992) The effect of influenza vaccination on IL2 production in healthy elderly: implications for current vaccination practices. J Gerontol 47:M3–M8

    Article  CAS  PubMed  Google Scholar 

  • McElhaney JE, Meneilly GS, Pinkoski MJ, Lechelt KE, Bleackley RC (1995) Vaccine-related determinants of the interleukin-2 response to influenza vaccination in healthy young and elderly adults. Vaccine 13:6–10

    Article  CAS  PubMed  Google Scholar 

  • Miller RA (1996) The aging immune system: primer and prospectus. Science 273:70–74

    Article  CAS  PubMed  Google Scholar 

  • Mohanty S, Joshi SR, Ueda I, Wilson J, Blevins TP, Siconolfi B, Meng H, Devine L, Raddassi K, Tsang S, Belshe RB, Hafler DA, Kaech SM, Kleinstein SH, Trentalange M, Allore HG, Shaw AC (2015) Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults. J Infect Dis 211:1174–1184

    Article  CAS  PubMed  Google Scholar 

  • Molteni M, Della Bella S, Mascagni B, Coppola C, De Micheli V, Zulian C, Birindelli S, Vanoli M, Scorza R (1994) Secretion of cytokines upon allogeneic stimulation: effect of aging. J Biol Regul Homeost Agents 8:41–47

    CAS  PubMed  Google Scholar 

  • Murasko DM, Goonewardene IM (1990) T-cell function in aging: mechanisms of decline. Annu Rev Gerontol Geriatr 10:71–96

    CAS  PubMed  Google Scholar 

  • Murasko DM, Weiner P, Kaye D (1987) Decline in mitogen induced proliferation in the increasing age. Clin Exp Immunol 70:440–448

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murasko DM, Nelson BJ, Matour D, Goonewardene IM, Kaye D (1991) Heterogeneity of changes in lymphoproliferative ability with increasing age. Exp Gerontol 26:269–279

    Article  CAS  PubMed  Google Scholar 

  • Murasko DM, Bernstein ED, Gardner EM, Gross P, Munk G, Dran S, Abrutyn E (2001) Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp Gerontol 37:427–439

    Article  Google Scholar 

  • Mysliwska J, Bryl E, Foerster J, Mysliwski A (1998) Increase of interleukin 6 and decrease of interleukin 2 production during the ageing process are influenced by the health status. Mech Ageing Dev 100:313–328

    Article  CAS  PubMed  Google Scholar 

  • Nagel JE, Chopra RK, Chrest FJ, McCoy MT, Schneider EL, Holbrook NJ, Adler WH (1988) Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest 81:1096–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nijhuis EW, Remarque EJ, Hinloopen B, Van Der Pouw-Kraan T, Van Lier RA, Ligthart GJ, Nagelkerken L (1994) Age-related increase in the fraction of CD27-CD4+ T cells and IL-4 production as a feature of CD4+ T cell differentiation in vivo. Clin Exp Immunol 96:528–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orson FM, Saadeh CK, Lewis DE, Nelson DL (1989) Interleukin 2 receptor expression by T cells in human aging. Cell Immunol 124:278–291

    Article  CAS  PubMed  Google Scholar 

  • Peterson PK, Chao CC, Carson P, Hu S, Nichol K, Janoff EN (1994) Levels of tumor necrosis factor, interleukin 6, interleukin 10, and transforming growth factor are normal in the serum of the healthy elderly. Clin Infect Dis 19:1158–1159

    Article  CAS  PubMed  Google Scholar 

  • Quyang Q, Cicek G, Westendorp RGJ, Cools HJM, Van der Klis RJ, Remarque EJ (2000) Reduced IFN-γ production in elderly people following in vitro stimulation with influenza vaccine and endotoxin. Mech Ageing Dev 121:131–137

    Google Scholar 

  • Rabinowich H, Goses Y, Reshef T, Klajman A (1985) Interleukin-2 production and activity in aged humans. Mech Ageing Dev 32:213–226

    Article  CAS  PubMed  Google Scholar 

  • Reiner SL, Locksley RM (1995) The regulation of immunity to Leishmania major. Annu Rev Immunol 13:151–179

    Article  CAS  PubMed  Google Scholar 

  • Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T (2000) Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol 120:267–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salkind AR (1994) Influence of age on the production of Fos and Jun by influenza virus-exposed T cells. J Leukoc Biol 56:817–820

    CAS  PubMed  Google Scholar 

  • Scheffer C, Zawotzky R, Rink L (2000) Interferon-γ levels finally become stable with increasing age as revealed by using an ELISA corresponding to the bioactivity. Mech Ageing Dev 121:47–58

    Article  CAS  PubMed  Google Scholar 

  • Schmitt V, Rink L, Uciechowski P (2013) The Th17/Treg balance is disturbed during aging. Exp Gerontol 48:1379–1386

    Article  CAS  PubMed  Google Scholar 

  • Schwab R, Pfeffer LM, Szabo P, Gamble D, Schnurr CM, Weksler ME (1990) Defective expression of high affinity IL-2 receptors on activated T cells from aged humans. Int Immunol 2:239–246

    Article  CAS  PubMed  Google Scholar 

  • Shearer GM (1997) Th1/Th2 changes in aging. Mech Ageing Dev 94:1–5

    Article  CAS  PubMed  Google Scholar 

  • Sindermann J, Kruse A, Frercks HJ, Schultz RM, Kirchner H (1993) Investigations of the lymphokine system in elderly individuals. Mech Ageing Dev 70:149–159

    Article  CAS  PubMed  Google Scholar 

  • Song LJ, Nagel JE, Chrest FJ, Collins GD, Adler WH (1992) Comparison of CD3 and CD2 activation pathways in T cells from young and elderly adults. Aging 4:307–315

    CAS  PubMed  Google Scholar 

  • Song L, Kim YH, Chopra RK, Proust JJ, Nagel JE, Nordin AA, Adler WH (1993) Age-related effects in T cell activation and proliferation. Exp Gerontol 28:313–321

    Article  CAS  PubMed  Google Scholar 

  • Stowe RP, Peek MK, Cutchin MP, Goodwin JS (2010) Plasma cytokine levels in a population-based study: relation to age and ethnicity. J Gerontol A Biol Sci Med Sci 65:429–433

    Article  PubMed  Google Scholar 

  • Vallejo AN, Brandes JC, Weyand CM, Goronzy JJ (1999) Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol 162:6572–6579

    CAS  PubMed  Google Scholar 

  • van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA, Kroesen BJ, Brouwer E, Boots AM (2014) Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol 60:190–196

    Article  PubMed  Google Scholar 

  • Weifeng C, Schulin L, Xinomei G, Xuewen F (1986) The capacity of lymphocyte production by peripheral blood lymphocytes from aged humans. Immunol Invest 15:575–583

    Article  Google Scholar 

  • Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ (1998) Functional properties of CD4+ CD28- T cells in the aging immune system. Mech Ageing Dev 102:131–147

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Meydani SN, Sastre J, Hayek M, Meydani M (1994) In vitro glutathione supplementation enhances interleukin-2 production and mitogenic response of peripheral blood mononuclear cells from young and old subjects. J Nutr 124:655–663

    CAS  PubMed  Google Scholar 

  • Xu X, Beckman I, Bradley J (1993) Age-related changes in the expression of IL-2 and high- affinity IL-2-binding sites. Int Arch Allergy Immunol 102:224–231

    Article  CAS  PubMed  Google Scholar 

  • Yen CJ, Lin SL, Huang KT, Lin RH (2000) Age-associated changes in interferon-γ and interleukin-4 secretion by purified human CD4+ and CD8+ T cells. J Biomed Sci 7:317–321

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Allison P. Boss for technical support on this chapter. This work was supported in part by NIH AG034949 (EMG).

Author information

Authors and Affiliations

  1. Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, 48824, USA

    Elizabeth M. Gardner

  2. Department of Biology, Drexel University, Philadelphia, PA, 19104, USA

    Donna M. Murasko

Authors
  1. Elizabeth M. Gardner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donna M. Murasko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth M. Gardner .

Editor information

Editors and Affiliations

  1. Division of Geriatrics Research Center on Aging, University of Sherbrooke Dept. of Medicine, Sherbrooke, Québec, Canada

    Tamas Fulop

  2. Dept of Experimental Pathology, University of Bologna, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, Tokyo, Japan

    Katsuiku Hirokawa

  4. Center for Medical Research, University of Tübingen, Tübingen, Germany

    Graham Pawelec

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, 1036 Rue Belvedere, J1H 4C4, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Cite this entry

Gardner, E.M., Murasko, D.M. (2018). Age-Related Changes in Type 1 and Type 2 Cytokine Production in Humans. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_39-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64597-1_39-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64597-1

  • Online ISBN: 978-3-319-64597-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation