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Immune Regeneration Laboratory“Combining immunology and stem cells to rejuvenate and re-program the immune system for better health” Group leaderProfessor Richard Boyd
Postal address: Level 3, STRIP – Building 75 Laboratory Members
Research overviewThe Immune regeneration laboratory focuses on the:
An enigmatic feature of the immune system is that the thymus undergoes profound degeneration from puberty. A loss in the generation of new naive T cells means that the TCR repertoire becomes progressively restricted with age and this is associated with a skewing towards memory cells. This in turn translates to declining immune responsiveness to neoantigens in adults and the aged. Despite the broad acceptance of thymic atrophy and associated severe clinical conditions, there have been remarkably few attempts to reverse this process and none that have been applied clinically (with any success). Our approach to this problem over many years has been to understand how the thymus functions, through exhaustive research on the stromal cells that constitute the specific inductive microenvironment/niche of this organ. We have developed invaluable reagents and techniques to study these complex stromal cells and as a consequence have been able to map its development through ontogeny and its response to physiological signals throughout life. Using our unique technologies we also evaluated the aged thymus and established that although severely atrophic and infiltrated with adipose cells, all the thymocytes and stromal cell subsets are present but the architectural structure is severely disrupted. Our research programs investigate ways in which the immune system, particularly the thymus, but also more recently the bone marrow, can be functionally restored following their destruction by aging, chemotherapy, radiotherapy and corticosteroids. We have two main approaches to this: utilising the body’s own rules to reverse the aging process, and using stem cell research to build a new thymus. We have shown that inhibition of the sex steroids responsible for inducing thymic atrophy induces a dramatic reversal of its degenerative state, fully restoring it to its youthful maximum potential. This occurs equally in males and females. The reduction in sex steroids can be achieved surgically but more practically chemically (reversible) through the hormone Lutenising Hormone Releasing Hormone (LHRH, also known as GnRH). There are several models of immune function being evaluated in the laboratory: response to influenza and hepatitis immunisations, challenge with cancer and chemotherapy/BMT, and treatment of autoimmune disease. The data on sex steroid blockage through LHRH, have collectively resulted in Phase II clinical trials being performed to restore immune capacity in leukaemia patients receiving bone marrow or HSC transplantation. We were invited to extend this trial in the USA as part of the American Society of BMT Clinical Trials Network and with NIH funding through a PO1 grant for a consortium of clinicians headed by Dr. Lee Nadler (Dana Faber Cancer Centre, Boston) at three of the most prominent centres: Dana Faber, MD Anderson, and University of Minnesota Centre for Transplantation. The protocol has received FDA approval. We also have a preclinical large animal study on the induction of transplantation tolerance using thymic regrowth technology combined with donor HSC, with Dr. David Sachs at MGH, Boston. We are also using sophisticated molecular expression profiling to investigate the factors that cause thymic (and bone marrow) re-growth which may eventually lead to new therapies. Futhermore, we have identified a population of thymic progenitor epithelial cells with our mAb MTS 24, with the capacity to induce the formation of an entire functioning thymus. We have more recently found this antibody to identify a population of epidermal stem cells in the skin. Rebuilding the immune system should allow much better defence against infections and cancer, and better responses to vaccines. Importantly by manipulating the restoration of thymic function we can also “educate” the immune system to prevent rejection of foreign transplants – including new stem cell-derived cellular therapies. Re-educating the immune system using a combination of thymus rejuvenation and uptake of HSC together with inhibition of the aberrant immune system, also provides for the first time, a realistic means of overcoming the devastating effects of autoimmune disease. The research from the laboratory has resulted in a suite of Patents. These have been licensed to a Melbourne based biotech company Norwood Immunology, which was successfully listed on the UK Alternative Investment stock Market (AIM) in 2004. Monash University is an Equity holder in Norwood Immunology. Norwood Immunology provides a large part of the funding for the laboratory and facilitates the clinical translation of the resulting technology.The laboratory has also formed a strong alliance with the Australian Stem Cell Centre (Boyd directs the Immunology Platform) and receives substantial funding for its program on immune tolerance, which has an important application in enabling patients to accept foreign stem cell-based grafts. We, together with Professors Alan Trounson, Claude Bernard and Ban Hock, were awarded a ~$5million, 5 year NH&MRC program grant on "Innovative stem cell based strategies to establish immune tolerance and tissue repair", from 2007 – 2011. Dr Ann ChidgeyDeputy Group Leader
Postal address: Level 3, STRIP – Building 75 Thymic and bone marrow niche in aging and regeneration - a molecular analysisThymic stromal cells form the complex microenvironment with which bone marrow derived haematopoietic precursors interact as they differentiate and mature, migrating in a directed fashion between niches. Thymic epithelial cells (TECs) form an essential component of the thymic stroma. Once thought to be a static population, TECs have been found by our laboratory to be a dynamic population comprised of precursor cells, transit amplifying cells and terminally differentiated cells. These populations change with age - primarily due to influences from the neuroendocrine system, leading to massive thymic involution from puberty to only about 1-5% of its full capacity. The bone marrow niche also changes with age, likely influencing the numbers and lineage potential of haematopoietic stem cells. By removing the influence of the neuroendocrine axis, for example by sex steroid ablation (surgical or reversible chemical), we are able to regenerate the immune system, both at the level of the bone marrow and the thymus. The involuted thymus returns to its young potential, seeding the periphery with a new repertoire of mature, functional T cells. The main focus of our research in the Gene Discovery Program is to investigate the mechanisms of aging and regeneration in the thymus and bone marrow niche, including the factors influencing the migration of haematopoietic precursors into the thymus. We are also investigating the influence of sex steroid ablation in niche ‘protection’ and regeneration after chemotherapy. We predominantly use flow cytometry and immunohistology techniques to investigate cellular changes in sub-populations of stromal cells, such as epithelial cells (cortical, medullary), non-epithelial stromal cells (endothelium, fibroblasts) and extracellular matrix from the thymus, and endosteal and vascular niche stromal cells from bone marrow (osteoblasts, osteoclasts, fibroblasts, adipocytes, endothelial cells, etc). To analyse the molecular changes in purified populations of stromal cells, we use real-time PCR and microarrays and proteomics techniques to analyse serum proteins. Our laboratory has previously produced an antibody (MTS24) that identifies a thymic epithelial precursor. When isolated, reaggregated and grafted under the kidney capsule, as few as 2,500 cells from the E15 embryonic thymus, can form a fully functional thymic organ that attracts haematopoietic precursors from the bone marrow and supports full T cell development. These cells do not appear to have the same capacity in the adult. We are thus further defining the precursor ability of MTS24+ cells at different stages in the embryo and adult and investigating whether growth factors provided by embryonic neural crest derived mesenchyme or the use of 3D-biomatrices, can assist in the survival, differentiation and proliferation of the epithelial precursors in the adult. We are also investigating differentially expressed molecules in embryonic thymic precursor cells, compared to non-precursor cells, to identify molecules specific to epithelial progenitor capacity. Publications 2007 - 2008Barnard, A., D. Layton, M. Hince, S. Sakkal, C. Bernard, A. Chidgey, and R. Boyd, (2008), Impact of the neuroendocrine system on thymus and bone marrow function: Neuroimmunomodulation, v. 15, p. 7-18. Barnard, A.L., A.P. Chidgey, C.C. Bernard, and R.L. Boyd, Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis. Blood First Edition Paper, prepublished online September 29, 2008; DOI 10.1182/blood-2008-05-156042. Chidgey, A.P. and R.L. Boyd, PREVIEWS: Immune privilege for stem cells: not as simple as it looked. Cell Stem Cell, 2008. 3: 357-8. Chidgey, A.P., N. Seach, J. Dudakov, M.V. Hammett, and R.L. Boyd, Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches. Semin Immunopathol, 2008. E-Pub. Hince, M., S. Sakkal, K. Vlahos, J. Dudakov, R. Boyd, and A. Chidgey, REVIEW: The role of sex steroids and gonadectomy in the control of thymic involution. Cell Immunol, 2008. 252: 122-138. Giudice, A. and A. Trounson, REVIEW: Genetic modification of human embryonic stem cells for derivation of target cells. Cell Stem Cell, 2008. 2: 422-433. Millar, J., R. Boyd, and J. Sutherland, LETTER TO THE EDITOR: An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions: In Regard to Lawton et al. (Int J Radiat Oncol Biol Phys 2007;69:646-655.). Int J Radiat Oncol Biol Phys, 2008. 71: 316. Chidgey, A.P. (2008) Effects of growth hormone in enhancing thymic regrowth and immune reconstitution. Expert Rev Clinical Immunol 4(4): 433-439 Kelly, R.M., Highfill, S.L., Panoskaltsis-Mortari, A., Taylor, P.A., Boyd, R.L., Hollander, G.A., and Blazar, B.R. (2008) Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution following murine bone marrow transplantation. Blood First Edition, Prepublished online March 11, 2008; DOI 10.1182/blood-2008-01-136531 Giudice, A.*, and Trounson, A.O. (2008). Genetic Modification of Human Embryonic Stem Cells for Derivation of Target Cells. Cell Stem Cell 2: 422-433. Layton DS, Bean AG, Dodge N Strom ADG, Sandrin MS, Ierino FL (2008) Modified porcine dendritic cells: Distinct cytokine expression and differential regulation of human anti-pig xenogeneic responses. Xenotransplantation (accepted) Chidgey, A.P., Layton, D., Trounson, A., Boyd, R.L. (2008) Tolerance strategies for stem-cell-based therapies. Nature 453: 330 – 337 Seach, N., Ueno, T., Fletcher, A.L., Lowen, T., Mattesich, M., Engwerda, C.R., Scott, H.S., Ware, C.F., Chidgey, A.P., Gray, D.H., Boyd, R.L. (2008) The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cels. J.Immunol. 180: 384-92 Kenins, L., Gill, J.W., Boyd, R.L., Hollander, G.A., and Wodnar-Filipowicz, A., (2008) Intra-thymic expression of Flt3 ligand enhances thymic recovery following irradiation, J Exp Med, (in press) doi:10.1084/jem.20072065 Hince, M., Sakkal, S., Vlahos, K., Dudakov, J., Boyd, R.L., Chidgey, A.P. (2008)_The role of sex steroids and gonadectomy in the control of thymic involution. Cell Immunol. Sutherland, JS., Spyroglou, L., Muirhead, J.L., Heng, T.S., Prieto-Hinojosa, A., Prince, H.M., Chidgey, A.P., Schwarer, A.P, Boyd, R.L. (2008) Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin Cancer Res 15: 1138-49 Gray, D.H., Fletcher, A.L., Hammett, M., Seach, N., Ueno, T., Young, L.F., Barbuto, J., Boyd, R.L, Chidgey, A.P. (2008) Unbiased analysis, enrichment and purification of thymic stromal cells. J Immunol Methods 329: 56-66 Chidgey, A., Dudakov, J, Seach, N., Boyd, R. (2008) Impact of niche aging on thymic regeneration and immune reconstitution. Semin Immunol 19:331-40 Chidgey, A.P. (2008) Effects of growth hormone in enhancing thymic regrowth and immune reconstitution. Expert Rev Clinical Immunol 4(4) in press Soh, C-L., Lim, J.M.C., Boyd, R.L., Chidgey, A.P. (2008) Epithelial stem cells and the development of the thymus, parathyroid and skin.Regulatory Networks in Stem Cells. Humana/Springer Press (Book chapter) In Press. Fletcher, A.L., and Boyd, R.L., (2008) Immunology, In Scientifica, - The comprehensive guide to the world of science, Sydney: Millenium. In press. Dudakov, J.A., and Boyd, R.L., (2008) Stem Cells, In Scientifica, - The comprehensive guide to the world of science, Sydney: Millenium. In press. Fletcher, A.L., Reiseger, J.J., Vlahos, K., Seach, N.L., Dudakov, J.A., Chidgey, A.P., and Boyd, R.L. (2008) Thymic regeneration in mice and humans following sex steroid ablation. In Fulop, T., Hirokawa, K., Franceschi, C., and Pawelec, G. (Eds) Handbook on Immunosenescence, Springer. In press. Seach N, Layton D, Lim J, Chidgey A and R. Boyd (2007) Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies. Curr Opin Biotec 18:1-7. Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS, Boyd RL, Jenkinson EJ, Anderson G.(2007) Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol. 37(9): 2411-8. Goldberg GL, Alpdogan O, Muriglan SJ, Hammett MV, Milton MK, Eng JM, Hubbard VM, Kochman A, Willis LM, Greenberg AS, Tjoe KH, Sutherland JS, Chidgey A, van den Brink MR, Boyd RL.(2007) Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation (2007) J Immunol. 178(11):7473-84. Gray DH, Tull D, Ueno T, Seach N, Classon BJ, Chidgey A, McConville MJ, Boyd RL. (2007) A unique thymic fibroblast population revealed by the monoclonal antibody MTS-15. J Immunol. 178(8):4956-65. Gray, D.H., Tull, D., Ueno, T., Seach, N., Classon, B.J., Chidgey, A., McConville, M.J., Boyd, R.L. (2007) A unique thymic fibroblast population revealed by the monoclonal antibody MTS-15. J Immunol 178:4956-65 Chidgey, A., Boyd, R., Hugo, P. (2007) The thymic niche and thymopoiesis. Encylopedia of Life Sciences doi: 10.1002/9780470015902.a0000526.pub2 Layton DS, Strom AD, O'Neil TE, Broadway MM, Stephenson GL, Morris KR Muralitharan M, Sandrin MS, Ierino FL, Bean AG (2007) Development of an anti-porcine CD34 monoclonal antibody that identifies hematopoietic stem cells. Exp Hematol. 35: 171-8. Wilson, T.J., Truman, D., Giudice, A., and Hertzog, P. (2007). Rapid generation of gene-targeting constructs. Chapter 11 In: PCR Methods Express. Edited by S. Hughes and A. Moody. Scion Publishing Ltd. Book chapters Fletcher, A.L., and Boyd, R.L., (2008) Immunology, In Scientifica, - The comprehensive guide to the world of science, Sydney: Millenium, pp.344-345 Dudakov, J.A., and Boyd, R.L., (2008) Stem Cells, In Scientifica, - The comprehensive guide to the world of science, Sydney: Millenium. pp. 286-287 Fletcher, A.L., Reiseger, J.J., Vlahos, K., Seach, N.L., Dudakov, J.A., Chidgey, A.P., and Boyd, R.L. (2008) Thymic regeneration in mice and humans following sex steroid ablation. In Fulop, T., Hirokawa, K., Franceschi, C., and Pawelec, G. (Eds) Handbook on Immunosenescence, Springer. In press. Soh, C., Lim, J.M.C., Boyd, R.L., and Chidgey, A.P., (2008) Epithelial stem cells and the development of the thymus, parathyroid and skin. In, Dr V.K. Rajasekhar and Dr M. Vemuri (Eds) Regulatory Networks in Stem Cells, Humana Press Incorporated. In press. Selected pre-2007 publicationsChidgey, A.P., & Boyd, R.L. (2006) Stemming the tide of thymic ageing. Nat Immunol. 7(10):1013-6. Gray, D.H.D, Seach, N., Ueno, T., Milton, M., Liston, A., Lew, A.M., Goodnow, C. H., Boyd, R.L. (2006) Developmental kinetics, turnover and stimulatory capacity of thymic epithelial cells. Blood 108(12):3777-85 Ann P. Chidgey and Richard L. Boyd Stemming the tide of thymic ageing. Nature Immunology. 7(10):1013-6, 2006 Jeremy Millar, Jayne Sutherland, & Richard Boyd Alternative explanations for T-cell response to in-situ gene therapy for prostate cancer: In reply to Fugita et al (Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 1, pp. 84-90, 2006). International Journal of Radiation Oncology, Biology, Physics, 66 (5): 1599. Nijhof JG. Braun KM. Giangreco A. van Pelt C. Kawamoto H. Boyd RL. Willemze R. Mullenders LH. Watt FM. de Gruijl FR. van Ewijk W. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development. 133(15):3027-37, 2006 Uldrich, A.P., Berzins, S.P., Malin, M.A., Bouillet, P., Strasser, A., Smyth, M.J., Boyd, R.L.* and Godfrey, D.I.* (2006). Antigen challenge inhibits thymic emigration. J. Immunol. 176: 4553-4561 (* equal contribution) Kurobe, H., Liu, C., Ueno, T., Saito, F., Ohigashi, I.,Seach, N.,Arakaki, R.,Hayashi, Y.,Kitagawa, T., Lipp, M., Boyd, R.L., and Takahama,Y. (2006) CCR7-dependent cortex to medulla migration of positively selected thymocytes is dispensable for T-cell maturation and thymic export but is essential for establishing central tolerance. Immunity. 24(2):165-77. Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu SX, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Muriglan SJ, Suh D, Boyd RL, van den Brink MR. (2006) Keratinocyte Growth Factor (KGF) Is Required For Post-Natal Thymic Regeneration. Blood, 107(6):2453-60. Goldberg, G.L., Sutherland, J.S., Hammet, M.V., Milton, M.K., Heng, T.S.P, Chidgey, A.P., Boyd, R.L.. (2005) Sex Steroid Ablation Enhances Lymphoid Recovery Following Autologous Haematopoietic Stem Cell Transplantation. Transplantation. 80(11):1604-1613 Heng, T.S.P., Goldberg, G.L., Gray, D.H.D., Sutherland, J.S., Chidgey, A.P. and Boyd, R.L.. (2005) Effects of castration on thymocyte development in two different models of thymic involution. Journal of Immunology, 175: 2982-2993 Sutherland, J.S., Goldberg, G.L., Hammett, M.V., Uldrich,, A.P., Berzins, S.P.,Heng, T.S., Blazar, B.R., Millar, J.L., Malin, M.A., Chidgey, A.P., and Boyd, R.L. (2005). Activation of thymic regeneration in mice and humans following androgen blockade. Journal of Immunology, 175(4):2741-53 Goldberg, G.L., Sutherland, J.S., Hammett, M.V., Milton, M.K., Heng, T.S.P., Chidgey, A., and Boyd, R.L., (2005) Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation,80: 1604-1613. Heng, T.S.P., Goldberg, G.L., Gray, D.H.D., Sutherland, J.S., Chidgey, A.P., and Boyd, R.L. (2005) Effects of castration on thymocyte development in two different models of thymic involution. Journal of Immunology, 175: 2982-2993. Sutherland, J.S., Goldberg, G.L., Hammett, M.V., Uldrich, A.P, Berzins, S.P., Heng, T.S.P., Blazar, B.R., Millar, J.L., Malin, M.A., Chidgey, A.P., and Boyd, R.L., (2005) Activation of thymic regeneration in mice and humans following androgen blockade. Journal of Immunology. 175: 2741-2753. Liston, A., Lesage, S., Gray, D.H.D., Boyd, R.L. and Goodnow, C.H. (2005).Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunological Reviews, 204: 87 – 101 Gray, D.H.D., Ueno,T., Chidgey,A., Goldberg,G., Takahama, Y. and Boyd, R.L. (2005). Controlling the thymic microenvironment. Current Opinion in Immunology 17: 137-143 Van den Brink, M., Alpdogan, O. and Boyd, R. (2004). Strategies to enhance T cell reconstitution in immunocompromised patients. Nature Reviews. Immunology, 4(11): 856- 867. Gill, J., Malin,M., Sutherland,J., Gray,D., Goldberg,G., Hollander,G., and Boyd, R.L. (2003) Thymic generation and regeneration. Immunological Reviews. 195: 28-50. Berzins SP, Uldrich AP, Sutherland JS, Gill J, Miller JF, Godfrey DI, Boyd RL. (2002). Thymic regeneration: teaching an old immune system new tricks. Trends Mol Med. 10: 469-76. Gill, J., Malin,M., Holländer, G.A., and Boyd, R.L. (2002).Generation of a complete thymic microenvironment by MTS 24+ thymic epithelial cells. Nature Immunol. 3: 635 – 642. Grant awardsAustralian Stem Cell Centre2006-2007 NH&MRC Program grant2007-2011 NH&MRC Project grant2007-2009 Monash University Strategic (collaborative) Grant2007 |
