Modelling Gene-Environment Interactions in Th1- and Th2-Dominated Diseases of Laboratory Animals

  • G. A. W. Rook
  • R. Martinelli
  • L. Rosa Brunet
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 50)

3.6 Conclusions

In conclusion, the “old friends hypothesis” seeks to explain the increasing prevalence of many chronic inflammatory disorders as a failure of immunoregulation secondary to decreased exposure to certain microorganisms that have been present throughout our evolutionary history. It is argued that these organisms are effectively part of our physiology, and are recognised as harmless by the innate immune system, which then activates immunoregulatory circuits, including Treg and regulatory APCs. The “old friends” consequently act as adjuvants for other antigens such as self, allergens, and gut contents, and so limit chronic inflammatory immunoregulatory disorders. These mechanisms can be revealed by altering the microbial exposure, or by studying the presence of polymorphisms of the innate immune system, since these two factors provide a series of classical gene-environment interactions. An important consequence of this understanding is the fact that the enormous variability of animal models of inflammatory disorders in different laboratories can now be exploited to investigate these gene-environment interactions. Experiments based on these differences, perhaps involving collaborations between laboratories, or the use of gnotobiotic mice reconstituted with one or a few microbial species, can be applied to those animal models where variable microbial exposure is already known to exert a profound influence.


Innate Immune System Allergy Clin Immunol Hygiene Hypothesis Microbial Exposure Nate Immune System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alm JS, Sanjeevi CB, Miller EN et al (2002) Atopy in children in relation to BCG vaccination and genetic polymorphisms at SLC11A1 (formerly NRAMP1) and D2S1471. Genes Immun 3:71–77PubMedCrossRefGoogle Scholar
  2. Arkwright PD, David TJ (2001) Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 107:531–534PubMedCrossRefGoogle Scholar
  3. Asadullah K, Sterry W, Volk HD (2003) Interleukin-10 therapy; review of a new approach. Pharmacol Rev 55:241–269PubMedCrossRefGoogle Scholar
  4. Asea A, Rehli M, Kabingu E et al (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034PubMedCrossRefGoogle Scholar
  5. Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920PubMedCrossRefGoogle Scholar
  6. Baker BS, Ovigne JM, Powles AV et al (2003) Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 148:670–679PubMedCrossRefGoogle Scholar
  7. Baldini M, Lohman IC, Halonen M et al (1999) A Polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20:976–983PubMedGoogle Scholar
  8. Belkaid Y, Piccirillo CA, Mendez S et al (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502–507PubMedCrossRefGoogle Scholar
  9. Braun-Fahrlander C, Riedler J, Herz U et al (2002) Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347:869–877PubMedCrossRefGoogle Scholar
  10. Breban MA, Moreau MC, Fournier C et al (1993) Influence of the bacterial flora on collagen-induced arthritis in susceptible and resistant strains of rats. Clin Exp Rheumatol 11:61–64PubMedGoogle Scholar
  11. Brunkow ME, Jeffery EW, Hjerrild KA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73PubMedCrossRefGoogle Scholar
  12. Bulut Y, Faure E, Thomas L et al (2002) Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 168:1435–1440PubMedGoogle Scholar
  13. Camporota L, Corkhill A, Long H et al (2003) The effects of Mycobacterium vaccae on allergen-induced airway responses in atopic asthma. Eur Respir J 21:287–293PubMedCrossRefGoogle Scholar
  14. Caramalho I, Lopes-Carvalho T, Ostler D et al (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403–411PubMedCrossRefGoogle Scholar
  15. Contractor NV, Bassiri H, Reya T et al (1998) Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J Immunol 160: 385–394PubMedGoogle Scholar
  16. Curry JL, Qin JZ, Bonish B et al (2003) Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 127:178–186PubMedGoogle Scholar
  17. Douek IF, Leech NJ, Gillmor HA et al (1999) Children with type-1 diabetes and their unaffected siblings have fewer symptoms of asthma. Lancet 353:1850PubMedCrossRefGoogle Scholar
  18. Dutronc Y, Porcelli SA (2002) The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60:337–353PubMedCrossRefGoogle Scholar
  19. Edinger M, Hoffmann P, Ermann J et al (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumour activity while inhibiting graft-versus-host disease after bone-marrow transplantation. Nat Med 9:1144–1150PubMedCrossRefGoogle Scholar
  20. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 4:330–336PubMedCrossRefGoogle Scholar
  21. Ghoreschi K, Thomas P, Breit S et al (2003) Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med 9:40–46PubMedCrossRefGoogle Scholar
  22. Groux H, O’Garra A, Bigler M et al (1997) A CD4+ subset inhibits antigen-specific T cell responses and prevents colitis. Nature 389:737–742PubMedCrossRefGoogle Scholar
  23. Hanngren A, Odham G, Eklund A et al (1987) Tuberculostearic acid in lymph nodes from patients with sarcoidosis. Sarcoidosis 4:101–104PubMedGoogle Scholar
  24. Hansen G, Berry G, DeKruyff RH et al (1999) Allergen-specific Thl cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 103:175–183PubMedCrossRefGoogle Scholar
  25. Heldwein KA, Fenton MJ (2002) The role of Toll-like receptors in immunity against mycobacterial infection. Microbes Infect 4:937–944PubMedCrossRefGoogle Scholar
  26. Hensen P, Asadullah K, Windemuth C et al (2003) Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis. Br J Dermatol 149:381–385PubMedCrossRefGoogle Scholar
  27. Hernandez-Pando R, Aguilar D, Garcia Hernandez ML et al (2003) Pulmonary tuberculosis in Balb/c mice with non-functional IL-4 genes; changes in the inflammatory effects of TNF-α in the regulation of fibrosis. Eur J Immunol 34:174–183CrossRefGoogle Scholar
  28. Hikita I, Yoshioka T, Mizoguchi T et al (2002) Characterization of dermatitis arising spontaneously in DS-Nh mice maintained under conventional conditions: another possible model for atopic dermatitis. J Dermatol Sci 30:142–153PubMedCrossRefGoogle Scholar
  29. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061PubMedCrossRefGoogle Scholar
  30. Jahnsen FL, Moloney ED, Hogan T et al (2001) Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 56:823–826PubMedCrossRefGoogle Scholar
  31. Jones CA, Holloway JA, Popplewell EJ et al (2002) Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both. J Allergy Clin Immunol 109:858–866PubMedCrossRefGoogle Scholar
  32. Kabesch M, Peters W, Carr D et al (2003) Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 111:813–817PubMedCrossRefGoogle Scholar
  33. Kalliomaki M, Isolauri E (2003) Role of intestinal flora in the development of allergy. Curr Opin Allergy Clin Immunol 3:15–20PubMedCrossRefGoogle Scholar
  34. Kalliomaki M, Salminen S, Arvilommi H et al (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial Lancet 357:1076–1079PubMedCrossRefGoogle Scholar
  35. Karhukorpi J, Ikaheimo I, Karvonen J et al (2002) Promoter region polymorphism of the CD14 gene (C-159T) is not associated with psoriasis vulgaris. Eur J Immunogenet 29:57–60PubMedCrossRefGoogle Scholar
  36. Kingo K, Koks S, Silm H et al (2003) IL-10 promoter polymorphisms influence disease severity and course in psoriasis. Genes Immun 4:455–457PubMedCrossRefGoogle Scholar
  37. Kohashi O, Kohashi Y, Takahashi T et al (1985) Reverse effect of gram-positive bacteria vs. gram-negative bacteria on adjuvant-induced arthritis in germfree rats. Microbiol Immunol 29:487–497PubMedGoogle Scholar
  38. Kojima Y, Kinouchi Y, Takahashi S et al (2001) Inflammatory bowel disease is associated with a novel promoter polymorphism of natural resistance-associated macrophage protein 1 (NRAMP1) gene. Tissue Antigens 58: 379–384.PubMedCrossRefGoogle Scholar
  39. Kotze MJ, de Villiers JN, Rooney RN et al (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis 27:44–53PubMedCrossRefGoogle Scholar
  40. Krug N, Madden J, Redington AE et al (1996) T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol 14:319–326PubMedGoogle Scholar
  41. Kukreja A, Maclaren NK (2002) NKT cells and type-1 diabetes and the “hygiene hypothesis” to explain the rising incidence rates. Diabetes Technol Ther 4:323–333PubMedCrossRefGoogle Scholar
  42. Lammas DA, Casanova JL, Kumararatne DS (2000) Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin Exp Immunol 121:417–425PubMedCrossRefGoogle Scholar
  43. Lauener RP, Birchler T, Adamski J et al (2002) Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 360: 465–466PubMedCrossRefGoogle Scholar
  44. Lim S, Crawley E, Woo P et al (1998) Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352:113PubMedCrossRefGoogle Scholar
  45. Lindberg E, Lindquist B, Holmquist L et al (2000) Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. J Pediatr Gastroenterol Nutr 30:259–264PubMedCrossRefGoogle Scholar
  46. Matricardi PM, Rosmini F, Riondino S et al (2000) Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma; epidemiological study. Brit Med J 320:412–417PubMedCrossRefGoogle Scholar
  47. McIntire JJ, Umetsu SE, Akbari O et al (2001) Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109–1116PubMedCrossRefGoogle Scholar
  48. Moudgil KD, Kim E, Yun OJ et al (2001) Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 166:4237–4243PubMedGoogle Scholar
  49. Najarian DJ, Gottlieb AB (2003) Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol 48:805–821; quiz 822–824PubMedCrossRefGoogle Scholar
  50. Nickoloff BJ (1999) Skin innate immune system in psoriasis: friend or foe? J Clin Invest 104:1161–1164PubMedCrossRefGoogle Scholar
  51. O’Neill LA (2002) Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal? Trends Immunol 23:296–300PubMedCrossRefGoogle Scholar
  52. Ogura Y, Bonen DK, Inohara N et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606PubMedCrossRefGoogle Scholar
  53. Oppmann B, Lesley R, Blom B et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725PubMedCrossRefGoogle Scholar
  54. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036PubMedCrossRefGoogle Scholar
  55. Penhale WJ, Young PR (1988) The influence of the normal microbial flora on the susceptibility of rats to experimental autoimmune thyroiditis. Clin Exp Immunol 72:288–292PubMedGoogle Scholar
  56. Raby BA, Klimecki WT, Laprise C et al (2002) Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med 166:1449–1456PubMedCrossRefGoogle Scholar
  57. Rachmilewitz D, Karmeli F, Takabayashi K et al (2002) Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122:1428–1441PubMedCrossRefGoogle Scholar
  58. Rahman P, Bartlett S, Siannis F et al (2003) CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 73:677–681PubMedCrossRefGoogle Scholar
  59. Rath HC (2002) Role of commensal bacteria in chronic experimental colitis: lessons from the HLA-B27 transgenic rat. Pathobiology 70:131–138PubMedCrossRefGoogle Scholar
  60. Re F, Strominger JL (2001) Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 276:37692–37699PubMedCrossRefGoogle Scholar
  61. Rehakova Z, Capkova J, Stepankova R et al (2000) Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol 61:555–558PubMedCrossRefGoogle Scholar
  62. Riedler J, Braun-Fahrlander C, Eder W et al (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358:1129–1133PubMedCrossRefGoogle Scholar
  63. Rodriguez MR, Gonzalez-Escribano MF, Aguilar F et al (2002) Association of NRAMP1 promoter gene polymorphism with the susceptibility and radiological severity of rheumatoid arthritis. Tissue Antigens 59:311–315PubMedCrossRefGoogle Scholar
  64. Rook GA, Brunet LR (2002) Give us this day our daily germs. Biologist (London) 49:145–149PubMedGoogle Scholar
  65. Rook GA, Martinelli R, Brunet LR (2003) Innate immune responses to mycobacteria and the downregulation of atopic responses. Curr Opin Allergy Clin Immunol 3:337–342PubMedCrossRefGoogle Scholar
  66. Rook GAW (2000) Clean living increases more than atopic disease. Immunology Today 21:249PubMedCrossRefGoogle Scholar
  67. Rook GAW, Stanford JL (1998) Give us this day our daily germs. Immunol Today 19:113–116PubMedCrossRefGoogle Scholar
  68. Satoguina J, Mempel M, Larbi J et al (2002) Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect 4:1291–1300PubMedCrossRefGoogle Scholar
  69. Sawczenko A, Sandhu BK, Logan RF et al (2001) Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 357:1093–1094PubMedCrossRefGoogle Scholar
  70. Schultz M, Veltkamp C, Dieleman LA et al (2002) Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflammatory Bowel Diseases 8:71–80PubMedCrossRefGoogle Scholar
  71. Seddon B, Mason D (1999) Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC-cells and CD4(+)CD8(-) thymocytes. J Exp Med 189: 279–288PubMedCrossRefGoogle Scholar
  72. Sengler C, Haider A, Sommerfeld C et al (2003) Evaluation of the CD14 C-159 T polymorphism in the German Multicenter Allergy Study cohort. Clin Exp Allergy 33:166–169PubMedCrossRefGoogle Scholar
  73. Sepp E, Julge K, Vasar M et al (1997) Intestinal microflora of Estonian and Swedish infants. Acta Paediatr 86:956–961PubMedCrossRefGoogle Scholar
  74. Smit JJ, Van Loveren H, Hoekstra MO et al (2003) Influence of the macrophage bacterial resistance gene Nrampl (Slc11a1) on the induction of allergic asthma in the mouse. FASEB J 17:958–960PubMedGoogle Scholar
  75. Stanford JL, Nye PM, Rook GA et al (1981) A preliminary investigation of the responsiveness or otherwise of patients and staff of a leprosy hospital to groups of shared or species antigens of mycobacteria. Lepr Rev 52: 321–327PubMedGoogle Scholar
  76. Steel C, Nutman TB (2003) CTLA-4 in filarial infections: implications for a role in diminished T cell reactivity. J Immunol 170:1930–1938PubMedGoogle Scholar
  77. Stene LC, Nafstad P (2001) Relation between occurrence of type 1 diabetes and asthma. Lancet 357:607PubMedCrossRefGoogle Scholar
  78. Strachan DP, Taylor EM, Carpenter RG (1996) Family structure, neonatal infection, and hay fever in adolescence. Arch Dis Child 74:422–426PubMedCrossRefGoogle Scholar
  79. Sudo N, Sawamura S, Tanaka K et al (1997) The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159:1739–1754PubMedGoogle Scholar
  80. Sudo N, Yu XN, Aiba Y et al (2002) An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy 32:1112–1116PubMedCrossRefGoogle Scholar
  81. Taurog JD, Richardson JA, Croft JT et al (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359–2364PubMedCrossRefGoogle Scholar
  82. Thompson SJ, Elson CJ (1993) Susceptibility to pristane-induced arthritis is altered with changes in bowel flora. Immunol Lett 36:227–231PubMedCrossRefGoogle Scholar
  83. Tomita K, Lim S, Hanazawa T et al (2002) Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol 102:258–266PubMedCrossRefGoogle Scholar
  84. Tremlett HL, Evans J, Wiles CM et al (2002) Asthma and multiple sclerosis: an inverse association in a case-control general practice population. Qjm 95:753–756PubMedCrossRefGoogle Scholar
  85. Umetsu DT, McIntire JJ, Akbari O et al (2002) Asthma: an epidemic of dysregulated immunity. Nat Immunol 3:715–720PubMedCrossRefGoogle Scholar
  86. van de Langerijt AG, van Lent PL, Hermus AR et al (1994) Susceptibility to adjuvant arthritis: relative importance of adrenal activity and bacterial flora. Clin Exp Immunol 97:33–38PubMedGoogle Scholar
  87. van den Biggelaar AH, van Ree R, Rodrigues LC et al (2000) Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356:1723–1727PubMedCrossRefGoogle Scholar
  88. van den Broek MF, van Bruggen MC, Koopman JP et al (1992) Gut flora induces and maintains resistance against streptococcal cell wall-induced arthritis in F344 rats. Clin Exp Immunol 88:313–317PubMedGoogle Scholar
  89. Van der Kleij D, Latz E, Brouwers JF et al (2002) A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J Biol Chem 277:48122–48129PubMedCrossRefGoogle Scholar
  90. Van der Kleij D, Van Remoortere A, Schuitemaker JH et al (2002) Triggering of innate immune responses by schistosome egg glycolipids and their carbohydrate epitope GalNAc beta 1–4(Fuc alpha l–2Fuc alpha 1–3) GlcNAc. J Infect Dis 185:531–539PubMedCrossRefGoogle Scholar
  91. Van Eden W, Koets A, van Kooten P et al (2003) Immunopotentiating heat shock proteins: negotiators between innate danger and control of autoimmunity. Vaccine 21:897–901PubMedCrossRefGoogle Scholar
  92. Verdu EF, Bercik P, Cukrowska B et al (2000) Oral administration of antigens from intestinal flora anaerobic bacteria reduces the severity of experimental acute colitis in BALB/c mice. Clinical and Experimental Immunology 120:46–50PubMedCrossRefGoogle Scholar
  93. Vincent MS, Leslie DS, Gumperz JE et al (2002) CDl-dependent dendritic cell instruction. Nat Immunol 3:1163–1168PubMedCrossRefGoogle Scholar
  94. Watanabe A, Takeuchi M, Nagata M et al (2003) Spontaneous development of dermatitis in DS-Nh mice under specific pathogen-free conditions. Exp Anim 52:77–80PubMedCrossRefGoogle Scholar
  95. Wildin RS, Ramsdell F, Peake J et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20PubMedCrossRefGoogle Scholar
  96. Yazdanbakhsh M, Kremsner PG, van Ree R (2002) Allergy, Parasites, and the Hygiene Hypothesis. Science 296:490–494PubMedCrossRefGoogle Scholar
  97. Zuany-Amorim C, Manlius C, Trifilieff A et al (2002) Long-term protective and antigen-specific effect of heat-killed Mycobacterium vaccae in a murine model of allergic pulmonary inflammation. J Immunol 169:1492–1499PubMedGoogle Scholar
  98. Zuany-Amorim C, Sawicka E, Manlius C et al (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8:625–629PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • G. A. W. Rook
    • 1
  • R. Martinelli
    • 2
  • L. Rosa Brunet
    • 2
  1. 1.Centre for Infectious Diseases and International Health, Windeyer Institute of Medical SciencesRoyal Free and University College Medical SchoolLondonUK
  2. 2.SR Pharma, Windeyer Institute of Medical SciencesRoyal Free and University College Medical SchoolLondonUK

Personalised recommendations