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Karren Plain

Following a Bachelor of Science majoring in cell pathology at the University of Sydney, Plain undertook a PhD in transplantation immunology at the University of New South Wales. This thematic interest in immunological control mechanisms has flowed more recently into infectious diseases, where Plain’s experience and insight is revealing new pathways in the pathogenesis of mycobacterial diseases.

Research

Without control mechanisms (immune regulation), an immune response that is meant to protect you can severely damage the normal tissues in your body; this is a theme in both transplantation medicine and infectious diseases, but the two disciplines are rarely linked. Plain’s early work, which has continued quietly in the background, examined immune profiles associated with tolerance to transplanted tissues (ref 1,2,3, 4). This involved the use of new biological therapeutic agents to induce tolerance, such as antibodies against the T cell markers, CD3 and CD4 (refs 2,3). Her work on the use of non-activating anti-CD3 monoclonal antibodies to induce tolerance in the transplantation setting has contributed to the development of these biological therapeutic agents in the field of diabetes and islet cell transplantation (ref 3). In her PhD studies, Plain examined the molecular and cellular mechanism of graft survival, specifically cytokine and regulatory T pathways. This led to the identification by the research team of two novel ‘subtypes’ of regulatory T cells (Ts1 and Ts2) that are activated in parallel by differing arms of the immune response (Th1 and Th2 responses) (ref 4) and insights into the paradoxical role of Interleukin-4 in graft survival (ref 5).

Plain’s recent work examines molecular and immune signatures of disease, drawing on her early ideas. The desired outcome is the diagnosis of infection, but in an informed way through gaining a greater understanding the host response to an infection and the relationship between the host and the pathogen. Plain led the development of a nationally adopted PCR-based diagnostic test for Johne’s disease (JD) in sheep and cattle: the HT-J (High-throughput Johne’s) test (ref 6) and enhancements to an alternative type of test for cellmediated immunity, the interferon gamma response assay (IGRA) (ref 7).

Plain applied the principles from her work in immune tolerance to the study of paratuberculosis (Johne’s disease), which is a chronic mycobacterial disease similar to tuberculosis, where the infectious organism (Mycobacterium avium subspecies paratuberculosis) successfully evades immune attack. One form of evasion was hypothesised to be through the organism harnessing immune regulatory mechanisms that had evolved to protect the host. She discovered that a key regulatory molecule in pregnancy and cancer immune evasion, Indoleamine-2,3-dioxygenase (IDO), appeared to be playing a role in a very different setting (Ref 8). This potent regulatory pathway appeared to be ‘switched on’ in animals that progress from subclinical to clinical Johne’s disease. This natural animal disease may be providing clues for application in human tuberculosis, which affects 30% of the world’s population. Karren Plain, a scientist with great dedication, insight and patience is focusing different research themes on major issues in host-pathogen biology, to tackle some of the most difficult questions in microbiology and immunology.

Publications

1. Plain, K.M., Boyd, R., Verma, N.D., Robinson, C.M., Tran, G.T., Hodgkinson, S.J., Hall, B.M., 2007. Transplant tolerance associated with a Th1 response and not broken by IL-4, IL-5, and TGF-beta blockade or Th1 cytokine administration. Transplantation 83, 764-773.

2. Plain, K.M., Fava, L., Spinelli, A., He, X.Y., Chen, J., Boyd, R., Davidson, C.L., Hall, B.M., 1997. Induction of tolerance with nondepleting anti-CD4 monoclonal antibodies is associated with down-regulation of TH2 cytokines. Transplantation 64, 1559-1567.

3. Plain, K.M., Chen, J., Merten, S., He, X.Y., Hall, B.M., 1999. Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non-depleting anti-CD3 monoclonal antibody: association with TH2 cytokines not anergy. Transplantation 67, 605-613.

4. Verma, N.D.*, Plain, K.M.*, Nomura, M., Tran, G.T., Robinson, C., Boyd, R., Hodgkinson, S.J., Hall, B.M., 2009. CD4+CD25+ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses. Blood 113, 479-487. (*equal first authors).

5. Plain, K.M., Verma, N.D., Tran, G.T., Nomura, M., Boyd, R., Robinson, C.M., Hodgkinson, S.J., Hall, B.M., 2013. Cytokines affecting CD4(+) T regulatory cells in transplant tolerance. Interleukin-4 does not maintain alloantigen specific CD4(+)CD25(+) Treg. Transpl Immunol 29, 51-59.

6. Plain, K.M., Marsh, I.B., Waldron, A.M., Galea, F., Whittington, A.M., Saunders, V.F., Begg, D.J., de Silva, K., Purdie, A.C., Whittington, R.J., 2014. High-throughput direct fecal PCR assay for detection of Mycobacterium avium subsp. paratuberculosis in sheep and cattle. Journal of Clinical Microbiology 52, 745-757

7. Plain, K.M., Begg, D.J., de Silva, K., Purdie, A.C., Whittington, R.J., 2012. Enhancement of the interferon gamma assay to detect paratuberculosis using interleukin-7 and interleukin-12 potentiation. Veterinary Immunology and Immunopathology 149, 28-37.

8. Plain, K.M., de Silva, K., Earl, J., Begg, D.J., Purdie, A.C., Whittington, R.J., 2011. Indoleamine 2,3-dioxygenase (IDO), tryptophan catabolism and Mycobacterium avium subspecies paratuberculosis: a model for chronic mycobacterial infections. Infect. Immun. 79, 3821-3832.