21-217 Lineberger Comprehensive Cancer Center
Campus Box 7295
Chapel Hill, NC 27599-7295
The Serody laboratory is focused on the migration of dendritic cells and subpopulations of T lymphocytes during graft-versus-host disease (GVHD) after allogeneic stem cell transplantation and as a consequence of induction of an immune response to tumors using vaccine therapy. There are three predominant areas that we focus:
1. Migration of T cells that lead to GVHD during stem cell transplantation.
Our laboratory has been a pioneer in investigating how white cells migrate to cause GVHD. Recently we have focused on the site of induction of GVHD, and how regulatory T cells that block GVHD function to do this. We have shown that chemokines mitigate migration during GVHD as a bimodal process involving host production initially followed by donor T cell production eventually leading to GVHD (ref 9). Currently we are focused on the identification of specific proteins that mediate migration into specific GVHD target organs which could be used to generate therapeutic treatments. For this we are using novel in vivo imaging (ref 1) approaches to track T cells from transgenic mice that we generated that express eGFP. Our group is actively trying to understand the phenotype of T cell that mediates acute and GVHD in animal models and clinically.
2. Breaking of tolerance to self proteins using dendritic cells (DCs).
We are involved in research to determine the best means to activate DCs with tumor antigens to break tolerance both in animal models and in clinical trials. Our current work has involved characterizing the ability of alphavirus replicon particles to infect DCs and to use these to overcome tolerance (ref 11). We are also focused on the how B and T cell responses synergize in tumor vaccines and methods to deliver vaccines with chemotherapy.
3. Blocking migration of regulatory T cells to enhance tumor vaccination.
Our group was the first to show a specific role for the chemokine receptor CCR5 in the function of Treg cells (ref 9) and the first to show that loss of these receptors improves tumor vaccine therapy. We have exploited this finding to investigate if blocking the migration of Treg cells can enhance the ability of tumor vaccines to break tolerance.
4. Immune response during cancer and metastasis:
We are focusing on the role of immune cells in the growth of tumor locals locally and at distant sites. Additionally, we are looking at how immune cells modulate the tumor stroma to promote tumor growth.
Coghill, JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR, Serody JS. Effector CD4+ T cells, the cytokines they generate and graft-versus-host disease: Something Old, Something New. Blood . 2011 Jan 18 [Epub ahead of print].
Highfill SL, Rodriguez PC, Zhou Z, Goetz CA, Koehn BH, Veenstra RG, Taylor PA, Panoskaltsis-Mortari A, Serody JS, Munn DH, Tolar J, Ochoa AC, Blazar BR. Bone marrow myeloid-derived suppressor cells (MDSC) inhibit graft-versus-host disease (GVHD) via an arginase-1 dependent mechanism that is upregulated by IL-13. Blood 116(25): 5738-5747, 2010.
Carlson M, Fulton, L, Coghill JM, West MJ, Panoskaltsis-Mortari, A, Wan Y, Tedder T, Blazar BR, Serody JS. L-selectin is not absolutely required for regulatory T cell function in GVHD. 10(12): 2596-2603, 2010.
*Van Deventer H, *Burgents JE, Wu QP, Woodford RM, Brickey WJ, Allen IC, Tekippe EM, **Serody JS, **Ting JPY. The inflammasome component, NLRP3, impairs antitumor vaccination by enhancing accumulation of peritumoral myeloid derived suppressor cells. Cancer Research. 70(24): 10161-10169, 2010.* and ** equally contributed to work
Coghill JM, Carlson MJ, Panoskaltsis-Mortari A, West ML, Burgents JE, Blazar BR, Serody JS. Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting C-C chemokine receptor 7 on donor T cells. Blood 115(23): 4914-4922, 2010 (Inside Blood Comment).
Burgents, JE, Moran TM, Collier ML, West MJ, Davis NL, Johnston RE, Serody JS. The immunosuppressive tumor environment is the main impediment to successful vaccination in neu transgenic mice. J Immunotherapy 33(5): 482-491, 2010.
7. Wood, W, Garg, S, Adamus G, Gabriel D, Shea T, Serody, J. Alloimmune Retinopathy associated with antibodies to transducin-α as a complication of chronic GVHD. Biol of Blood and Marrow Transplantation DOI: 10:1016/j 06.012, 2009..
O’Shaunessey MJ, Vogtenhuber C, Sun K, Sitcheran R, Baldwin AS, Murphy WJ, Dang L, Jaffee B, Palmer E, Serody JS, Blazar BR..Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease. American Journal of Transplantation 9(3): 452-462, 2009.
Carlson, MJ, West M, Panoskaltsis-Mortari, A, Blazar BR. Serody JS. In vivo generated Th17 cells mediate lethal GVHD with severe cutaneous and pulmonary pathology. Blood113(6): 1365-1374, 2009.
Taylor PA, Ehrhardt MJ, Lees CJ, Panoskaltsis-Mortari A, Krieg AM, Sharpe AH, Murphy WJ, Serody JS, Hemmi H, Akira S, Levy RB, Blazar BR. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 112(8): 3508-3516, 2008.
Coghill, J, Carlson M, Moran TJ and Serody JS. The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting. Leukemia and Lymphoma July 25, 1-10, 2008.
van Deventer HW, Ping QW, Bergstralh DT, Davis BK, O'Connor BP, Ting JPY and Serody JS. C-C Chemokine Receptor 5 on Pulmonary Fibrocytes Facilitates Migration and Promotes Metastasis via Matrix Metalloproteinase 9. American Journal of Pathology, 173(1): 253-264, 2008.
Petermann KB, Rozenberg GI, Zedek D, Groben P, McKinnon KP, Buehler C, Kim W, Shields JM, Bear JE, Thomas NE, Serody JS, Sharpless NE. Erk activation induces CD200 expression and T cell suppression in melanoma. Journal of Clinical Investigation 117(12): 3922-3929, 2007.
Moran TP, Burgents JE, Long B, Ferrer I, Jaffee EM, Tisch R, Johnston RE, Serody JS. Alphaviral-vector transduced dendritic cells are successful therapeutic vaccines against Neu-expressing tumors. Vaccine 25(36):6604-6612, 2007.
Taylor PA, Ehrhardt MJ, Lees CJ, Tolar J, Weigel BJ, Panoskaltsis-Mortari A, Serody JS, Binkmann V, Blazar BR. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of GVHD. Blood 110(9): 3480-3488, 2007
Presentations regarding the function of chemokines in the biology of GVHD at scientific session of ASH 2003
Work presented at ASBMT meeting regarding role of regulatory T cells in GVHD 2004
Elizabeth Thomas Endowed Chair in Medicine 2006