Bovine Immune Mechanisms

The bovine immune mechanisms research group is funded by both BBSRC and DEFRA. The overarching aim of the work of the group is to further understand immune responses in cattle. This knowledge can be applied to understanding infection and immunity processes; this is central to the development of improved vaccination or control strategies for economically important diseases of cattle, including bovine tuberculosis (bTB).

The development of reagents allowing detailed immunological analysis in cattle has been a long term goal of the IAH, and is vital to facilitate detailed studies of immune function in healthy and diseased animals. The bovine immune mechanisms group is part of the multi-site, multi-species BBSRC funded Immunological Toolbox consortium which aims to generate, characterise and provide reagents, knowledge and tools for the veterinary research community (see www.immunologicaltoolbox.co.uk).

A major area of research, being carried out in collaboration with the Veterinary Laboratories Agency, is to assess the protective efficacy of bTB vaccines and to define correlates of protective immunity in cattle that might be targeted by effective vaccination strategies. The incidence of TB in cattle is increasing rapidly causing major economic losses and increasing human health risks from this zoonotic disease. It is recognized that elimination of the disease in both cattle and humans will depend on effective vaccines and sensitive, specific diagnostic tests. The development of new vaccines for TB has been the subject of intense research since the development of the attenuated Bacille Calmette Guerin (BCG) vaccine strain of Mycobacterium bovis almost 100 years ago. Despite the development and testing of subunit vaccines, DNA vaccines, attenuated and modified mycobacteria strains and more, BCG remains the gold standard and is still most effective vaccine particularly against TB in children.

Vaccination of neonatal humans with BCG induces significantly better immune responses than vaccination of adults. We showed that BCG vaccination of neonatal calves aged less then one month old induced a significant level of protection against experimental M. bovis infection. The duration of immunity induced by BCG vaccination of neonatal calves is currently being assessed and has been shown to be at least 12 months. Our current studies will enable the efficacy of BCG at two and three years post-vaccination to be assessed. One prerequisite for the use of a bTB vaccine is a test that can distinguish vaccinated cattle from those which are infected with bTB. We have developed a rapid, sensitive test that can distinguish BCG vaccinates from infected cattle. Translation of this test to human TB diagnosis is being studied with partners at Trinity College Dublin with promising early results. Commercialisation of this test is currently being explored.

Why neonatal calves are protected so effectively from bovine TB following BCG vaccination is a major area of research by the Bovine Immune Mechanisms group. It is known that neonatal calves have significantly higher levels of circulating innate immune cells, natural killer (NK) cells and gd T cells, than adult cattle. Each of these cell populations can interact with M. bovis-infected antigen presenting cells and secretes high levels of interferon gamma (IFNg), a key cytokine in protective immune responses. Whether NK cells or gd T cell responses can be boosted by vaccination and the role these cells play in protection is currently being assessed. How mycobacteria interact with dendritic cells (DC) and the interaction of DC with NK cells and gd T cells is also under investigation. Early interactions with DC are likely to be key in determining the outcome of infection.

The capacity to analyze ex vivo DC in cattle following cannulation of afferent lymphatic vessels has enabled detailed characterization of the properties of DC subsets. Only a small proportion of afferent lymph DC draining the skin can interact with mycobacteria. Mechanisms to target expression of mycobacterial antigens by a greater proportion of DC, and the effects of such targeting on the induction of antigen-specific immune responses, are being investigated. Targeted vaccination strategies to induce appropriately biased immune responses are likely to be central to the successful control of diseases of major economic and social impact in the UK, and worldwide.

Publications:

  • Price SJ, Hope JC (2009). Enhanced secretion of IFNg by bovine γδ T cells induced by co-culture with Mycobacterium bovis infected dendritic cells: evidence for reciprocal activating signals. Immunology, 126, 201 [Abstract]. 
  • Sopp P, Coad M, Whelan A, Vordermeier HM, Hewinson G, Howard CJ, Harris J, Ni Cheallaigh C, J Keane, Hope JC (2008). Development of a Simple, Sensitive, Rapid Test which Accurately Discriminates BCG Vaccinated from Mycobacterium bovis Infected Cattle. Vaccine, 26, 5470 [Abstract]. 
  • Thom ML, Howard CJ, Villarreal-Ramos B, Mead EB, Vordermeier HM, Hope JC (2008). Consequence of prior exposure to environmental mycobacteria on BCG vaccination and diagnosis of tuberculosis infection. Tuberculosis, 88, 324 [Abstract]. 
  • Hope JC, Villarreal-Ramos B (2008). Bovine TB and the development of new vaccines. Comparative Immunology Microbiology and Infectious Diseases, 31, 77 [Abstract]. 
  • Price SJ, Sopp P, Howard CJ, Hope JC (2007). Workshop cluster 1 gamma delta T-cell receptor T cells from calves express high levels of interferon-gamma in response to stimulation with interleukin-12 and -18. Immunology, 120, 57 [Abstract]. 
  • Hope JC, Howard CJ, Prentice H, Charleston B (2006). Isolation and purification of afferent lymph dendritic cells that drain the skin of cattle. Nature Protocols, 1, 982 [Abstract]. 
  • Sopp P, Howard CJ, Hope JC (2006). Flow cytometric detection of gamma interferon can effectively discriminate Mycobacterium bovis BCG-vaccinated cattle from M. bovis-infected cattle. Clinical and Vaccine Immunology, 13, 1343 [Abstract]. 
  • Hope JC, Vordermeier HM (2005). Vaccines for bovine tuberculosis: current views and future prospects. Expert Review of Vaccines, 4, 891 [Abstract]. 
  • Hope JC, Thom ML, Villarreal-Ramos B, Vordermeier HM, Hewinson RG, Howard CJ (2005). Exposure to Mycobacterium avium induces low-level protection from M. bovis infection but compromises diagnosis of disease in cattle. Clincial and Experimental Immunology, 141, 432 [Abstract]. 
  • Hope JC, Thom ML, Villarreal-Ramos B, Vordermeier HM, Howard CJ (2005). Vaccination of neonatal calves with Mycobacterium bovis BCG induces protection against challenge with virulent Mycobacterium bovis. Clinical and Experimental Immunology, 139, 48 [Abstract].