Assistant Professor, Department of Medicine
Link: Laboratories of Andrew Macpherson and Kathy McCoy
Year of appointment: 2006
Mucosal immunology, development of the immune system, allergic disease.
am interested in how hygiene status, or exposure to microbial stimulus early
in life, can influence susceptibility to diseases
such as allergy and
autoimmunity. Using germ-free and gnotobiotic techniques my research
program aims to determine the impact of microbial exposure on the developing
immune system and focuses on elucidation of the mechanisms involved, with
particular emphasis on long-range effects on development of allergic
Axenic and gnotobiotic
techniques, in vivo animal models, flow cytometry, RT-PCR, ELISA,
immunohistochemistry, cell culture, laser capture microscopy, B and T cell
functional assays, bacteriology.
Title: Investigation of the impact of environmental microbes on B cell development and IgE production.
Background: Allergic disorders are prevalent in our Westernized society and this poses a serious biological and medical problem for Canada. The lower intestine of humans and other mammals contains an enormous load of bacteria, which are physically excluded from entering the body by only a single layer of epithelial cells and a mucous barrier. It is evident that the endogenous flora of the intestine provides a wealth of stimuli for the developing immune system. Although there is strong epidemiological evidence that hygiene status (the extent of microbial exposure) early in life has a clear impact on susceptibility to allergy, the mechanisms by which this occurs are not known.
Objectives: This is a three-year award to investigate the impact of environmental microbiota on B cell development and IgE production in health and disease.
Title: Infrastructure to assess the impact of environmental microbiota on development of the immune system in health and disease.
Background: Epidemiologists have found considerable evidence that our exposure to microbes early in life can reduce our susceptibility to allergies or autoimmune diseases as adults. Such findings have given rise to a field known as gnotobiotics, which examines how microbes interact with the immune system.
Objectives: This is an infrastructure grant to enable outfitting a laboratory to study the specific biochemical mechanisms that cause microbes to elicit an immune response.
Title: Mechanisms of normal intestinal lamina propria CD4 responses that
ensure mutualism with commensal intestinal bacteria
Co-applicant with Andrew Macpherson
Background: Mammals normally live peacefully with an enormous number of commensal bacteria in the lower intestine. These intestinal microbes do not cause disease in most people. Unfortunately, the protective mechanisms fail in Crohn’s disease or ulcerative colitis, causing damaging inflammation that characterises these nasty conditions.
Objectives: This is a three-year grant to investigate the way in which normal subsets of intestinal T cells are induced when germ-free mice are colonised with intestinal bacteria and how they protect the intestine from bacterial penetration.
Title: CIHR Team in Mucosal Immunity
Co-applicant with Jack Gauldie, Stephen Collins, Andrew MacPherson, Zhou Xing, Manel Jordana, Kenneth Rosenthal, Jonathan Bramson, Martin Stampfli, Karen Mossman, Charu Kaushic, Ali Ashkar
Background: The majority of human pathogens initiate infection through mucosal surfaces and the mucosal site of entry heavily influences the immune response generated. Very little is currently known about the communication or cross talk between different mucosal tissues. Objectives: This is a 5-year team grant to investigate innate immunity at mucosal sites with analysis of the cross talk between different sites and the functional outcomes.
Title: Type 1 diabetes protection through commensal intestinal bacterial exposure
Juvenile Diabetes Research Foundation International (JDRFI), 2008-2011
Co-applicant with Andrew Macpherson
Background: Insulin-dependent (type-1) diabetes (T1D) is an autoimmune disorder where there is T cell-mediated damage to the Islets of Langerhans in the pancreas. There is significant discordance in T1D in identical twins and the incidence of T1D is rising dramatically in Western populations, suggesting that this immunological process is shaped by environmental factors. The non-obese diabetic (NOD) mouse and the Biobreeding (BB) rat are two spontaneous rodent models of diabetes and the incidence of T1D in the NOD model depends on the hygiene status of the animal facility housing the colony.
Objectives: This is a 3-year operating grant to define the bacterial and host requirements for protection from diabetes by commensal intestinal bacteria and to determine how commensal bacterial priming shapes the pre-diabetic immune system. In addition, we will define the mechanisms underlying commensal bacterial protection from diabetes.
- Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MAE, Geuking MB, Beutler B,
Tedder TF, Hardt W-D, Bercik P, Verdu EF,McCoy KD, Macpherson AJ. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 2009; 325: 617-620. PDF
- Schildknecht A, Probst HC, McCoy KD, Miescher I, Brenner C, Leone DP, Suter U, Ohashi PS, van den Broek M. Antigens expressed by myelinating glia cells induce peripheral cross-tolerance of endogenous CD8+ T cells. Eur J Immunol 2009; 39(6): 1505-15. PDF
- Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol 2008; 1(1): 11-22. PDF
- McCoy KD, Stoel M, Stettler R, Merky P, Fink K, Senn BM, Schaer C, Massacand J, Odermatt B, Oettgen HC, Zinkernagel RM, Bos NA, Hengartner H, Macpherson AJ, Harris NL. Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection. Cell Host Microbe 2008; 4(4): 362-73. PDF
- Pochanke V, Koller S, Dayer R, Hatak S, Ludewig B, Zinkernagel RM, Hengartner H, McCoy KD. Identification and characterization of a novel antigen from the nematode Nippostrongylus brasiliensis recognized by specific IgE. Eur J Immunol 2007; 37(5): 1275-84. PDF
- Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 2007; 19(2): 59-69. PDF
- Pochanke V, Hatak S, Hengartner H, Zinkernagel RM, McCoy KD. Induction of IgE and allergic-type responses in fur mite-infested mice. Eur J Immunol 2006; 36(9): 2434-45. PDF
- Hangartner L, Zellweger RM, Giobbi M, Weber J, Eschli B, McCoy KD, Harris N, Recher M, Zinkernagel RM, Hengartner H. Nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread. J Exp Med 2006; 203(8): 2033-42. PDF
- McCoy KD, Harris NL, Diener P, Hatak S, Odermatt B, Hangartner L, Senn BM, Marsland BJ, Geuking MB, Hengartner H, Macpherson AJ, Zinkernagel RM. Natural IgE production in the absence of MHC Class II cognate help. Immunity 2006; 24(3): 329-39. PDF
- Macpherson AJ, Geuking MB, McCoy KD. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005; 115(2): 153-62. PDF
- Martinic MM, Rocha B, McCoy KD, Hengartner H, Zinkernagel RM. Role of TCR-restricting MHC density and thymic environment on selection and survival of cells expressing low-affinity T cell receptors. Eur J Immunol 2004; 34(4): 1041-9. PDF
- Senn KA, McCoy KD, Maloy KJ, Stark G, Fröhli E, Rülicke T, Klemenz R. T1-deficient and T1-Fc-transgenic mice develop a normal protective Th2-type immune response following infection with Nippostrongylus brasiliensis. Eur J Immunol 2000; 30(7): 1929-38. PDF
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