Contribution to Science
1) Industrial development of MSCs as a transfusion therapy was predicated on the notion that MSCs are intrinsically immune privileged and that they are not subjected to immune rejection. This assumption was the justification of use of random donor allogeneic MSCs for clinical trials. We rigorously tested this hypothesis in a series of animal models and found that the premise was flawed and that MSCs express MHC I and II and like any other somatic tissue can be immune rejected if transplanted across the MHC barrier. We further interrogated the immune plasticity of MSCs and discovered that MSCs are entirely capable of augmenting an immune response by behaving as antigen presenting cells. This was a highly controversial and disruptive finding for the field since it was felt that MSCs where solely immune suppressive. These data inform us that MSCs, like APCs can be activating or suppressive depending on the type of cytokine licensing.
- Nicoletta Eliopoulos, John Stagg, Laurence Lejeune, Sandra Pommey and Jacques Galipeau. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 2005 Dec 15, 106 (13): 4057-65. PMID: 16118325
- John Stagg, Sandra Pommey, Nicoletta Eliopoulos and Jacques Galipeau. Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood. 2006 Mar 15;107:2570-2577. PMID: 16293599
- Raphaëlle Romieu-Mourez, Moïra François, Marie-Noëlle Boivin, David E. Spaner and Jacques Galipeau. Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol. 2009 Jun 15;182(12):7963-73. PMID: 19494321.
- Moïra François, Raphaëlle Romieu-Mourez, Sophie Martineau, Marie-Noëlle Boivin, Jonathan L. Bramson, Jacques Galipeau. Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties. 2009 Sep 24;114(13):2632-8. Epub 2009 Aug 4. PMID: 19654411
2) Cognizant of the intriguing immune plasticity of MSC and their utility as immune modulators, we went on to fully define the cell physiological mechanisms by which MSCs can serve as immune suppressor in both pre-clinical models of autoimmune disease and translational analysis of primary human MSCs in vitro. Our further analysis of human MSCs defined the pivotal roles of IDO and PD-L1 in suppression as well. These data have informed the field on the paracrine effects of MSCs and further have informed clinical translation.
- Moïra François, Raphaëlle Romieu-Mourez, Mengyang Li, and Jacques Galipeau. Human MSC Suppression Correlates With Cytokine Induction of Indoleamine 2,3-Dioxygenase and Bystander M2 Macrophage Differentiation. Mol Ther. 2012 Jan;20(1):187-95. doi: 10.1038/mt.2011.189. Epub 2011 Sep 20. PMID: 21934657.
- Raghavan Chinnadurai, Ian B Copland, Marco A Garcia, Christopher Petersen, Christopher Lewis, Edmund K. Waller, Allan Kirk, Jacques Galipeau. Cryopreserved MSCs are susceptible to T-cell mediated apoptosis which is partly rescued by IFNγ licensing. Stem Cells. 2016 Sep;34(9):2429-42. doi: 10.1002/stem.2415. Epub 2016 Jul 4. PMID: 27299362
- Raghavan Chinnadurai, Devi Rajan, Spencer Ng, Kenneth McCullough, Dalia Arafat, Edmund K Waller, Larry J Anderson, Greg Gibson, Jacques Galipeau. Immune dysfunctionality of replicative senescent Mesenchymal Stromal Cells are corrected by IFNγ priming. Blood Adv. 2017 Apr 25;1(11):628-643. doi: 10.1182/bloodadvances.2017006205. PMID: 28713871
- Raghavan Chinnadurai, Devi Rajan, Muna Qayed, Dalia Arafat, Marco Garcia, Yifei Liu, Subra Kugathasan, Larry J Anderson, Greg Gibson, Jacques Galipeau. Potency Analysis of Mesenchymal Stromal Cells Using a Combinatorial Assay Matrix Approach. Cell Rep. 2018 Feb 27;22(9):2504-2517. doi: 10.1016/j.celrep.2018.02.013. PMID:29490284
3) Informed by our mechanistic work we sought to translate these finding in a manner which would address the promising utility of MSCs for treatment of human ailments as informed by cell biology of MSCs and shortcomings highlighted in published industrial clinical trials. These data have informed our launch of clinical trials based upon our scientific discoveries regarding effect of cryobanking on human MSCs testing the use of autologous mesenchymal stromal cells for treatment of Crohn’s disease (NCT01659762) and GVHD (NCT02359929).
- Moïra François, Ian B. Copland, Shala Yuan, Raphaëlle Romieu-Mourez, Edmund K. Waller and Jacques Galipeau. Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing. Cytotherapy. 2012 Feb;14(2):147-52. Epub 2011 Oct 27. PMID: 22029655
- Chinnadurai R, Garcia MA, Sakurai Y, Lam WA, Kirk AD, Galipeau J, Copland IB. Actin Cytoskeletal Disruption following Cryopreservation Alters the Biodistribution of Human Mesenchymal Stromal Cells In Vivo. Stem Cell Reports. 2014 Jun 6;3(1):60-72. PMID: 25068122
- Raghavan Chinnadurai, Ian B Copland, Spencer Ng, Marco Garcia, Mahadev Prasad, Dalia Arafat, Greg Gibson, Subra Kugathasan, Jacques Galipeau. Mesenchymal stromal cells derived from Crohn’s patients deploy indoleamine 2,3-dioxygenase mediated immune suppression, independent of autophagy. Mol Ther. 2015 Jul;23(7):1248-61. doi: 10.1038/mt.2015.67. Epub 2015 Apr 22 PMID: 25899824
- Tanvi Dhere, Ian Copland, Marco Garcia, KY Chiang, Raghavan Chinnadurai, Mahadev Prasad, Jacques Galipeau and Subra Kugathasan. Randomised clinical trial: safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn’s disease – a phase 1 trial with three doses. Aliment Pharmacol Ther. 2016 Sep;44(5):471-81. doi: 10.1111/apt.13717. Epub 2016 Jul 7. PMID: 27385373
4) Our group has developed of an entirely new class of synthetic cytokines we named fusokines. The GM-CSF and IL-15 fusokine (aka GIFT15) was the first ever agent demonstrated to cause expansion of B-regulatory cells which in turn can reverse autoimmune disorders such as multiple sclerosis in mice. This work was cited in science news https://www.sciencenews.org/article/novel-fused-protein-quells-inflammation. We have since derived an entire family of fusion cytokines, all of which deploy gain-of-function properties with substantial translational utility as highlighted by Emory’s Technology Transfer Office featured innovations.
- Moutih Rafei, Jeremy Hsieh, Simone Zehntner, MengYang Li, Kathy Forner, Elena Birman, and Jacques Galipeau. A granulocyte-macrophage colony-stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties. Nat Med. 2009 Sep;15(9):1038-1045. Epub 2009 Aug 9. PMID: 19668193
- Jiusheng Deng, Shala Yuan, Andrea Pennati, Jordan Murphy, Jian Hui Wu, David Lawson, Jacques Galipeau. Engineered fusokine GIFT4 licenses the ability of B cells to trigger a tumoricidal T cell response. Cancer Res. 2014 Aug 1;74(15):4133-44. doi: 10.1158/0008-5472.CAN-14-0708. Epub 2014 Jun 17. PMID: 24938765
- Spencer Ng, Jiusheng Deng, Raghavan Chinnadurai, Shala Yuan, Andrea Pennati, Jacques Galipeau. Stimulation of natural killer cell-mediated tumor immunity by an IL-15/TGF-ß neutralizing fusion protein. Cancer Res. 2016 Oct 1;76(19):5683-5695. PMID: 27488533
- Andrea Pennati, Spencer Ng, Yuanqiang Wu, Jordan R. Murphy, Jiusheng Deng, Jennifer L. Blanchfield, Brian Evavold and Jacques Galipeau. Regulatory B cells induce formation of IL-10 expressing T cells in mice with autoimmune neuroinflammation. J Neurosci. 2016 Dec 14;36(50):12598-12610. PMID: 27821578
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