Colin Anderson, PhD
Office: 5-002B Li Ka Shing Centre for Health Research Innovation
Mailing: University of Alberta, Edmonton Alberta Canada T6G 2E1
Associate Professor, Department of Surgery; Cross-appointment in the Department of Medical Microbiology & Immunology; AHFMR Senior Scholar; Director, Immunology Core, Alberta Diabetes Institute
Immunology, transplantation, diabetes
Our research is focused on three main goals,
1. Generating a basic understanding of the mechanisms by which the immune system can become tolerant of some antigens while at the same time responding to others (commonly known as ‘self/non-self discrimination’).
2. Determining the mechanistic basis for failures in self-tolerance leading to autoimmune disease.
3. Devising ways to induce tolerance to donor islet transplants in order to generate a clinical islet transplant protocol for the treatment of diabetes that does not require continuous immunosuppressive therapy of the patient.
Current Research Activities
In order to study the mechanisms of tolerance vs. immunity we employ T cell antigen receptor transgenic mice that have a monoclonal population of T cells specific to donor graft antigens. This allows us to track the fate of the graft reactive T cells, both under conditions of immunity or tolerance. We are using these models to study natural peripheral tolerance and to dissect out the factors that control indirect recognition of transplants and killing of ‘bystander’ cells in proximity to donor tissue. Using gene knockout animals we are studying the function of co-inhibitory receptors in: natural self-tolerance, the control of homeostatic T cell activation, the control of innate immunity, and in transplant tolerance and immunity. In order to generate tolerance protocols for islet cell transplantation we are developing new methods of establishing chimerism with donor bone marrow cells.
Our studies are carried out in collaboration with many other researchers at the University of Alberta, and members of other Faculties/Departments/Institutions in the USA, Europe, and Japan. Our basic research has been supported by the Canadian Institutes of Health Research, the AIHS/Alberta Heritage Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the Canadian Diabetes Association, the National Institutes of Health, the Alberta Diabetes Institute, and the Edmonton Civic Employees Charitable Assistance Fund.
My laboratory has championed the power of transplantation models to reveal an understanding of the default rules of immunity. We have used transplantation experiments to answer such fundamental questions as: Which cells induce tolerance in the thymus? Is there really a period early in life critical for self tolerance induction? How many antigens can peripheral tolerance handle? How specific is the delivery of the effector output of the immune response and what limits collateral damage? In addition, our studies have identified conditions determining whether passenger lymphocytes and the resulting chimerism generate transplant tolerance or immunity and have provided a new understanding of the role of specific ‘co-inhibitory’ receptors in immune control.
Our work demonstrated that microchimerism can lead to tolerance (centrally induced) or immunity depending on the maturity of the recipients’ T cell population and on the degree of antigenic mismatch between donor and recipient. We showed that NK cells can prevent the establishment of microchimerism, and that tolerance induced by microchimerism was tissue specific. We also demonstrated that passenger lymphocytes in transplants, and not just the previously identified passenger dendritic cells, provide a significant source of immunogenic donor antigen. In 2007 we published the first studies to clearly resolve the paradox of immunity to tissue that is transplanted before the recipient’s immune system generates (pre-immunocompetence transplants). We showed that the expected result of a pre-immunocompetence transplant, that is tolerance of the transplant, generally only occurs when the donor antigens are present systemically. In contrast, when donor antigens are only present in a localized fashion they trigger immunity. These studies have important implications not only for our general understanding of how the immune system is regulated (the rules of ‘self-nonself discrimination’), but also the strategies that are used to induce transplantation tolerance. This work resolved a critical paradox in transplantation, providing an explanation for the various outcomes when cells/tissues are transplanted prior to development of immunocompetence of the recipient (e.g. during the fetal/neonatal period). In studies aimed at developing chimerism through hematopoietic stem cell transplantation as a means to induce donor specific tolerance, our studies have established new, milder conditioning protocols that successfully generate mixed chimerism in a challenging pre-clinical model of type-1 diabetes.
In examing the mechanisms of peripheral tolerance, we recently identified the most critical function of an important co-inhibitory receptor, PD-1, is to control newly generated T cells in the context of lymphopenia. These studies have important implications for situations where the immune system is restarted (e.g. bone marrow transplantation).
University of Western Ontario, 1990-1994
Institut Curie. Paris France, 1994-1996
National Institutes of Health. Bethesda Maryland, 1996-2001
Al-Adra, D.P., Pawlick, R., Shapiro, A.M.J., and Anderson, C.C. (2012). Targeting cells causing split tolerance allows fully allogeneic islet survival with minimal conditioning in NOD mixed chimeras. Am. J. Transplant., In Press.
*Al-Adra, D.P., *Chan, W.F.N., and Anderson, C.C. (2011). Nonobese diabetic natural killer cells: a barrier to allogeneic chimerism that can be reduced by rapamycin. Transplantation, 92, 977-984. *co-first authors
Thangavelu, G., Parkman, J.C., Ewen, C.L., Uwiera, R.R.E., Baldwin, T.A. and Anderson, C.C. (2011). Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis. J. Autoimmunity, 36, 301-312.
Thangavelu, G., Murphy, K.M., Yagita, H., Boon, L., and Anderson, C.C. (2011). The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants. Immunobiology, 216, 918-924.
Al-Adra, D.P. and Anderson, C.C. (2011). Mixed Chimerism and Split Tolerance: Mechanisms and Clinical Correlations. Chimerism, 2, 89-101.
Truong, W., Hancock, W.W., Plester, J.C., Merani, S., Rayner, D.C., Thangavelu, G., Murphy, K.M., *Anderson, C.C., and *Shapiro A.M.J. (2009). BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in non-obese diabetic mice. J. Leukoc. Biol., 86, 41-51. *co-senior author; See also- Editorial, pp. 5-8.
Anderson, C.C. (2009). Placing regulatory T cells into global theories of immunity: An analysis of Cohn’s challenge to integrity (Dembic). Scand. J. Immunol., 69, 306-309.
Chan, W.F.N., Razavy, H., Luo, B., Shapiro A.M.J., and Anderson, C.C. Development of either split tolerance or robust tolerance, together with humoral tolerance to donor and third party alloantigens in nonmyeloablative mixed chimeras. J. Immunol., 180, 5177-5186, 2008.
Chan, W.F.N., Razavy, H., and Anderson, C.C. (2008). Differential susceptibility of allogeneic targets to indirect CD4 immunity generates split tolerance. J. Immunol., 181, 4603-4612.
WFN Chan, A Perez-Diez, H Razavy, CC Anderson. The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits. Biol. Direct, 2, 10, 2007.
B Luo, WFN Chan, AMJ Shapiro, CC Anderson. Non-myeloablative mixed chimerism approaches and tolerance, a split decision. Eur. J. Immunol., 37, 1233-1242, 2007.
A Perez-Diez, N Joncker, K Choi, WFN Chan, CC Anderson, O Lantz, P Matzinger. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood, 109, 5346-5354, See also- Editorial, pp. 5070-5071, 2007.
Goldman, K.P., Park, C.-S., Kim, M., Matzinger, P., and Anderson, C.C. (2005). Thymic cortical epithelium induces self tolerance. Eur. J. Immunol., 35, 709-717.
Anderson, C.C., Carroll, J.M., Gallucci, S., Ridge, J.P., Cheever, A., and Matzinger, P. (2001). Testing Time-, Ignorance-, and Danger-based Models of Tolerance. J. Immunol. 166, 3663-3671.
Anderson, C.C., and Matzinger, P. (2001). Tolerance or Immunity: Opposite outcomes of microchimerism from skin-grafts. Nature Med., 7, 80-87. See also- Editorial, pp. 24-25.
Trainees (year completed)
Kristofor Ellestad, PhD
Selena Wang, PhD
David Al-Adra, MD, PhD (2012)
Christa Smolarchuk, MSc (2011)
Govindarajan Thangavelu, PhD (2011)
William Chan, PhD (2008)
Shaheed Merani, PhD (2008)
Wayne Truong, MD, PhD (2007)
Sulaiman Nanji, MD, PhD (2004)