Andrew L. Mellor Ph.D.

email: amellor@georgiahealth.edu

Research Emphasis:

Our laboratory is interested in the role of tissue inflammation and the immune system in disease processes. Inflammation is a complex response and comes in many forms that can facilitate normal tissue functions or contribute to multiple diseases affecting human beings including cancer, infectious, autoimmune and allergic syndromes. We are interested in how inflammation in the innate immune system affects the adaptive immune system to promote beneficial responses that maintain health, or drive detrimental responses that cause disease. A major focus in our laboratory is the intracellular enzyme indoleamine 2,3-dioxygenase (IDO).  Some dendritic cells (DCs) – an innate immune cell type specialized to present antigens to T cells -  are capable of expressing IDO in physiologic settings of inflammation associated with tumor development, infections and autoimmunity. IDO expression confers potent T cell suppressor activity on DCs that can predominate over the T cell stimulatory functions of other DC subsets. Fundamental scientific research in our laboratory is focused on elucidating how IDO-expressing DCs promote T cell suppression to either promote (in cancer and chronic infections) or to attenuate (in autoimmunity and transplantation) disease syndromes.  To this end currently active (extramurally funded by the NIH and private Foundations) research projects are focused on (a) elucidating how IDO-expressing DCs regulate T cell responses; (b) the role of IDO in modulating or promoting disease processes in mouse models of human clinical disease syndromes. Our long term goal is to use knowledge gained from fundamental research on IDO to develop new immunotherapies for clinical applications. To this end, IDO inhibitors are currently under investigation as potential anti-tumor vaccine adjuvants in early phase oncology clinical trials in the US.

 

Laboratory members:
 

Phillip Chandler, PhD; Lei Huang, PhD; Baolin Kang, PhD; Lingquian Li; Burles Johnson III (MD/PhD Student); Diane Addis, Leisl Desevilla; Rachel Harbarger; Minghui Li.

Selected recent publications:

• Munn, D.H., Zhou M., Attwood J.T., Bondarev I., Conway S.J., Marshall B., Brown C. and Mellor A.L. (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191-1193. [PMID; 9712583]

• Mellor, A.L., Sivakumar, J, Chandler, P., Smith, K., Molina, H., Mao, D., and Munn, D.H. (2001) Prevention of T cell driven complement activation and inflammation by tryptophan catabolism during pregnancy.  Nature Immunology 2: 64-68. [PMID; 11135580]

• Munn, D.H., Sharma, M.D., Lee J.R., Jhaver, K.G., Johnson, T.S., Keskin, D.B., Marshall, B., Chandler, P., Antonia, S.J., Burgess, R., Slingluff, C.L., & Mellor, A.L. (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297: 1867-70.  [PMID; 12228717]

• Mellor, A.L., Babak, B., Chandler, P., Marshall, B., Jhaver, K., Hansen, A., Koni, P.A., Iwashima, M., Munn, D.H. (2003) Induced expression of indoleamine 2,3 dioxygenase in regulatory dendritic cells suppresses T cell responses. J. Immunol. (Cutting Edge), 171: 1652–1655. [PMID; 12902462]

• Mellor, A. L., Chandler, P. R., Baban, B. Hansen, A. M., Marshall, B., Pihkala, J., Waldmann, H., Cobbold, S. P., Adams, E., Munn, D. H. (2004). Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int. Immunol. 16: 1391. [PMID; 15351783]

• Baban B., Hansen A.M., Chandler P. R., Manlapat A., Bingaman A., Kahler D., Munn D. H. & Mellor A.L.  (2005). A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I interferon-signaling following B7 ligation. Int. Immunol. 17: 909-19. [PMID; 15967784]

• Munn D.H., Sharma M.D., Baban B., Harding H.P., Zhang Y., Ron D., & Mellor A.L.  (2005). GCN2 kinase in T cells mediates proliferative arrest and anergy induced by dendritic cells expressing indoleamine 2,3-dioxygenase.  Immunity, 22: 1-10. [PMID; 15894280]

• Mellor, A.L., Baban, B., Chandler, P.R., Manlapat, A., Kahler, D.J. and Munn, D.H.  (2005). CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3 dioxygenase-dependent T cell regulatory functions via interferon type 1 signaling. J. Immunol. (Cutting Edge), 175: 5601-5605.  [PMID; 16237046]

• Manlapat, AM, Kahler, DJ, Chandler, PR, Munn, DH & Mellor AL. (2007). Cell autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19+ dendritic cells Eur. J. Immunology. 37:1064-1071. [PMID; 17343295]

• Sharma, M, Baban, B, Chandler, PR, Hou, D-Y, Singh, N, Yagita, H, Azuma, M, Blazar, BR, Mellor, AL, & Munn, DH (2007). Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117: 1-13 [PMID; 17710230]

• Muller, AJ, Sharma, MD, Chandler PR, Everhart ME, Johnson BA, Kahler DJ, Pihkala J, DuHadaway J, Munn DH, Prendergast G, & Mellor, AL. (2008). Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc. Natl. Acad. Sci. 105:17073-17078. [PMID: 18952840]

• Sharma, MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler PR, Mellor AL, He Y, & Munn DH (2009). Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 113:6102-6111. [PMID: 19366986]

• Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D & Waldmann H (2009). Infectious tolerance via the consumption of essential amino acids and mTOR signaling Proc. Natl. Acad. Sci. 106:12055-12060. [PMID: 19567830]

• Baban B, Chandler PR, Sharma MD, Pihkala J, Munn DH, & Mellor AL (2009). IDO activates regulatory T cells and blocks their conversion into TH17-like T cells. J. Immunol. 183:2475-2483. [PMID: 19635913]

• Wang Y, Liu H, Keaney JF, Stasch JP, Wu BJ, Witting PK, McKenzie G, Ball HJ, Kapoor V, Thomas SR, Mellor AL, Hunt N & Stocker R. (2010). Kynurenine is a novel endothelium-derived vascular relaxing factor produced during inflammation Nat. Med. 16:279-285. [PMID: 20190767]

• Ding Z-C, Blazar BR, Mellor AL, Munn DH, and Zhou G (2010). Chemotherapy rescues tumor-driven aberrant CD4+ T cell differentiation and restores an activated polyfunctional helper phenotype. Blood, 115:2397-406. [PMID: 20118405] 

• Johnson BA, Kahler DJ, Baban B, Chandler PR, Kang, B, Shimoda M, Koni PA, Pihkala J, Busslinger M, Vilagos B, Munn DH & Mellor AL (2010). B-lymphoid cells with attributes of dendritic cells regulate T cells via IDO. Proc. Natl. Acad. Sci. 107:10644-8. [PMID: 20498068]

• Zhou Q, Xiao H, Liu Y, Peng Y, Hong Y, Chandler PR, Munn DH, Mellor AL, Fu N, and He Y. (2010). Blockade of programmed death receptor (PD1) pathway rescues the effector function of tumor infiltrating T cells and enhances the antitumor efficacy of lentivector immunization J. Immunol (in press).