The role of cytotoxic lymphocytes (CTL and NK cells) in human disease

X-linked lymphoproliferative disease
We have cloned and sequenced a novel mutation in the gene responsible for the fatal childhood disease, X-linked lymphoproliferative disease (XLP), thus resolving a longstanding mystery of unexplained male deaths in a large aboriginal family from northern Canada. The presence of the mutation in this extended family allows us to study the specific role of the lymphocyte cell protein, SLAM-associated protein (SAP) in human immunity to viruses and tumours. In particular, we are investigating the role of SAP in the cellular and molecular dysfunction of cytotoxic T lymphocytes and natural killer cells and the relationship between these abnormalities and the clinical phenotype of disease.

Autoimmunity in type 1 diabetes
Type 1 (juvenile-onset) diabetes mellitus arises from a T-cell-mediated autoimmune process directed against pancreatic beta cells in both humans and non-obese diabetic (NOD) mice. The destruction of beta cells is mediated by CD8+ cytotoxic T lymphocytes (CTL). Using MHC Class 1 tetrameric complexes to detect and determine the frequency of autoreactive CTL in NOD mice we have developed a predictive algorithm for disease. In collaboration with Drs. Bruce Verchere and Dina Panagiotopoulos we are hoping to extend these findings to humans through the identification of human MHC class I restricted epitopes. The laboratory is also studying several different areas of the pathogenesis of type 1 diabetes including the role of autoreactive CTL and the role of natural killer cells.

Medical microbiology, virology and infection control (clinical)
The medical microbiology laboratory in the Department of Pathology & Laboratory Medicine at BC Children's Hospital (BCCH) is a leader in the development of molecular diagnostic assays for pediatric infectious diseases. For example, molecular assays have been developed for human herpesvirus 6 (HHV-6), enteroviruses and Epstein-Barr virus, for the diagnosis and typing of Neisseria meningitidis (meningococcus) and for novel agents such as human metapneumovirus. The laboratory is continually adapting and developing new real-time (Taqman) and rapid Smart Cycler PCR diagnostics for a variety of bacterial and viral pathogens.  In addition the laboratory
is engaged in changing the primary care management of common respiratory illnesses by providing a VIral RAPid testing program (VIRAP) that allows for the rapid (<4 hour) diagnosis of common respiratory pathogens.

A. Aoukaty and R. Tan. Role for glycogen synthase kinase-3 in natural killer cell cytotoxicity and X-linked lymphoproliferative disease. J Immunol. In Press. 2005.

B. Chung, A. Aoukaty, J. Dutz , C. Terhorst and R. Tan. Cutting Edge: SLAM-associated protein controls natural killer T cell functions. J Immunol. 2005;174:3153

L. Hoang, E. Thomas S. Tyler, A.J. Pollard, G. Stephens, L. Gustafson, A. McNabb, I. Pocock, R. Tsang, R. Tan. Rapid and Fatal Meningococcal Disease Due to a cnl Strain of N. meningitidis in an immunocompetent patient. Clinical Infectious Diseases. 2005; 40:e38­42.

H. Qin, J. Trudeau, G. Reid, I.F. Lee, J. Dutz , P. Santamaria, B. Verchere and R. Tan. Progression of spontaneous autoimmune diabetes is associated with a switch in the killing mechanism used by autoreactive CTL. Int Immunol. 2004;16:1657.

I.F. Lee, H. Qin, J. Trudeau, J. Dutz and R. Tan. Regulation of autoimmune diabetes by complete Freund's adjuvant is mediated by NK cells. J Immunol. 2004;172:937.

C. Panagiotopoulos C, H. Qin, R. Tan and B. Verchere. Identification of a beta-cell-specific HLA class I restricted epitope in type 1 diabetes. Diabetes. 2003;52:2647.

J. Trudeau, C. Kelly-Smith, C.B. Verchere, J. Dutz , J. Elliott, D. Finegood, P. Santamaria and R. Tan. Prediction of spontaneous autoimmune diabetes by quantification of autoreactive T cells in peripheral blood. Journal of Clinical Investigation. 2003; 111(2): 217-223.

A. Aoukaty and R. Tan. Association of the XLP gene product SAP/SH2D1A with 2B4, a natural killer cell activating molecule, is dependent on phosphoinositide 3-kinase. Journal of Biological Chemistry. 2002;277:13331-7.

J. Dutz , X. Wang, L. Benoit, A. Junker, D. De Sa and R. Tan. Lymphocytic vasculitis in X-linked lymphoproliferative disease. Blood 2001; 97:95-100.

L. Benoit, X. Wang, J. Dutz and R. Tan. Cutting Edge: Defective natural killer cell activation in X-linked lymphoproliferative disease. Journal of Immunology. Cutting Edge. 2000; 165-3549.

Peter Wall Institute of Advanced Studies Early Career Scholar, University of British Columbia – 2003-2004

Research & Discovery Award, Department of Pathology & Laboratory Medicine, University of British Columbia - 2002
Lotte Strauss Prize, Society for Pediatric Pathology - 2001
Samuel F. McLaughlin Fellowship in Medicine - 1995-1997

Xiaoxia Wang - Research assistant/Lab manager
Ala Aoukaty - Research associate (MSFHR recipient)
Huilian Qin - Research assistant
Qin Ouyang - Postdoctoral fellow (JDRF Fellow)
Erica Lee - Graduate student (CIHR Transplantation Award recipient)
Brian Chung - Graduate student (David Hardwick Studentship recipient)