Professor Andrew Mellor
Prof of Translational Immunology
- Email: email@example.com
- Telephone: +44 (0) 191 208 8503
- Address: Institute of Cellular Medicine
3rd Floor, Leech Building
Newcastle upon Tyne
I earned my PhD in the field of protein biosynthesis from Kings College, London while working on DNA tumor viruses at the Imperial Cancer Research Fund (1973-1976). During my postdoctoral training with Richard Flavell (1979-1984) at the National Institute for Medical Research (London) and Biogen Inc. (Boston) I cloned and sequenced mouse MHC class I genes,uncovered the genetic basis for MHC polymorphism and developed methods to transfect and express MHC genes into cells. In my first academic position (NIMR, 1984-1995) I continued to focus on MHC molecular genetics and developed new interests in studying peripheral tolerance mechanisms using MHC transgenic mice.
In 1995 I moved to the Medical College of Georgia (Augusta GA). In 1998, we reported the seminal discovery that fetal survival during pregnancy depends on regulation of maternal T cell immunity by the enzyme indoleamine 2,3 dioxygenase (IDO). This finding established a new paradigm in understanding how T cell regulation occurs at sites of inflammation by identifying tryptophan catabolism as a critical metabolic process regulating T cell immunity. My laboratory has worked on IDO ever since with major focus on identifying inflammatory pathways that stimulate IDO expression in dendritic cells and elucidating biochemical pathways that suppress T cell responses and activate regulatory T cells.
Another major goal is to develop new strategies and reagents to manipulate IDO activity for clinical benefit in a range of diseases that afflict many people, including cancer, chronic infections, autoimmune syndromes and transplant rejection. While IDO protects healthy tissues from immune attack, it also protects cancerous and infected tissues from attack, requiring IDO inducers and IDO inhibitors to manipulate inflammatory disease processes for clinical benefit. Based on our research, a proprietary IDO inhibitor (IndoximodTM) is under scrutiny in Phase II trials as a potential immune checkpoint blockade inhibitor in cancer patients. In addition, we have developed novel IDO-inducing reagents that prevent and alleviate autoimmune syndromes in mouse models of autoimmune diabetes, multiple sclerosis and rheumatoid arthritis.
In 2015 I moved to the Institute of Cellular Medicine at Newcastle University. Current research goals are to evaluate the role of nucleic acid sensing pathways in regulating autoimmunity and promoting tumourigenesis, developing novel immunotherapies by manipulating IDO, and elucidating how IDO enhances pain, a common co-morbidity associated with many chronic inflammatory syndromes of clinical importance
Tissue inflammation occurs during infections, cancer, autoimmune, allergic, cardiovascular and neurodegenerative syndromes, pregnancy, transplant rejection and following tissue wounding, burns and exposure to ionizing and ultra-violet radiation.
Inflammation is a complex physiologic phenomenon that can only be studied in whole organisms. Inflammation may initiate or inhibit immune responses contingent on many genetic, environmental and contextual factors.
Our research focuses on the role of the enzyme indoleamine 2,3 dioxygenase (IDO) in inflammatory disease and immunotherapies to treat them. We discovered that IDO protects foetal tissues during pregnancy. IDO also suppresses immunity that destroys healthy tissues but may cause morbidities associated with some chronic diseases such as pain and behavioural disorders.
IDO is induced by interferons type I (IFNalpha/beta) and II (IFNgamma). IDO catabolizes the amino acid tryptophan (Trp) to suppress T cell responses and protect tissues from immune-mediated damage. However some pathogens and tumours hijack the IDO pathway, allowing them to persist and cause chronic infections and cancer in immune competent individuals.
Our research objectives are to understand how altered Trp metabolism potentiates or regulates disease progression before clinical presentation and to apply this knowledge for clinical benefit by manipulating the IDO pathway using novel immunotherapies.
- Zhu H, Lemos H, Bhatt B, Islam BN, Singh A, Gurav A, Huang L, Browning DD, Mellor A, Fulzele S, Singh N. Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity. PLoS ONE 2017, 12(9), e0183484.
- Horvatinovich JM, Grogan EW, Norris M, Steinkasserer A, Lemos H, Mellor AL, Tcherepanova IY, Nicolette CA, DeBenedette MA. Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes. The Journal of Immunology 2017, 198(6), 2286-2301.
- Sivaprakasam S, Gurav A, Paschall AV, Coe GL, Chaudhary K, Cai Y, Kolhe R, Martin P, Browning D, Huang L, Shi H, Sifuentes H, Vijay-Kumar M, Thompson SA, Munn DH, Mellor A, McGaha TL, Shiao P, Cutler CW, Liu K, Ganapathy V, Li H, Singh N. An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 2016, 5, e238.
- Munn DH, Mellor AL. IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends in Immunology 2016, 37(3), 193-207.
- Lemos H, Mohamed E, Ou R, Pacholczyk G, Arbab AS, Munn D, Mellor A. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Research 2016, 76(8), 2076-2081.
- Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, Li L, Pacholczyk G, Randall J, Munn DH, Mellor AL. Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathogens 2016, 12(5).
- Lu X, Ding Z-C, Cao Y, Habtetsion T, Yu M, Lemos H, Mellor AL, Zhou G. Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells. Journal of Immunology 2015, 194(4), 2011-2021.
- Suryawanshi A, Manoharan I, Hong Y, Swafford D, Majumdar T, Taketo MM, Manicassamy B, Koni PA, Thangaraju M, Sun Z, Mellor AL, Munn DH, Manicassamy S. Canonical Wnt Signaling in Dendritic Cells Regulates Th1/Th17 Responses and Suppresses Autoimmune Neuroinflammation. Journal of Immunology 2015, 194(7), 3295-3304.
- Paschall AV, Zhang R, Bardhan K, Qi C-F, Peng L, Lu G, Yang J, Merad M, McGaha TL, Zhou G, Mellor AL, Abrams SI, Morse HC, Ozato K, Xiong H, Liu K. IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. Journal of Immunology 2015, 194(5), 2369-2379.
- Lemos H, Huang L, McGaha TL, Mellor AL. STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy?. Expert Review of Clinical Immunology 2015, 11(1), 155-165.
- Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Yagita H, Mellor AL, Blazar BR, Munn DH. The PTEN pathway in Tregs is a critical driver for the suppressive tumor microenvironment. Science Advances 2015, 1(10), e1500845.
- Hong Y, Manoharan I, Suryawanshi A, Majunder T, Angus-Hill A, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Research 2015, 75(4), 656-665.
- Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH, Mellor AL. Activation of the Stimulator of Interferon Genes (STING) adaptor attenuates experimental autoimmune encephalitis. Journal of Immunology 2014, 192(12), 5571-5578.
- Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH, Mellor AL. Activation of the STING Adaptor Attenuates Experimental Autoimmune Encephalitis. The Journal of Immunology 2014, 192(12), 5571-5578.
- Lemos H, Huang L, McGaha TL, Mellor AL. Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA. European Journal of Immunology 2014, 44(10), 2847-2853.
- Liu H, Huang L, Bradley J, Liu K, Bardhan K, Ron D, Mellor AL, Munn DH, McGaha TL. GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Molecular and Cellular Biology 2014, 34(3), 428-438.
- Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LMF, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. International Immunology 2014, 26(7), 357-367.
- Ding Z-C, Lu X, Yu M, Lemos H, Huang L, Chandler P, Liu K, Walters M, Krasinski A, Mack M, Blazer BR, Mellor AL, Munn DH, Zhou G. Immunosuppressive Myeloid Cells Induced by Chemotherapy Attenuate Antitumor CD4+ T-Cell Responses through the PD-1-PD-L1 Axis. Cancer Research 2014, 74(13), 3441-3353.
- Sage LK, Fox JM, Mellor AL, Tompkins SM, Tripp RA. Indoleamine 2,3-dioxygenase (IDO) activity during the primary immune response to influenza infection modifies the memory T cell response to influenza challenge. Viral Immunology 2014, 27(3), 112-123.
- Ravishankar B, Shinde R, Liu H, Chaudhary K, Bradley J, Lemos HP, Chandler P, Tanak M, Munn DH, Mellor AL, McGaha TL. Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proceedings of the National Academy of Sciences of the USA 2014, 111(11), 4215-4220.
- Huang L, Mellor AL. Metabolic control of tumour progression and antitumour immunity. Current Opinion in Oncology 2014, 26(1), 92-99.
- Bozec A, Zaiss MM, Kagwiria R, Voll R, Rauh M, Chen Z, Mueller-Schmucker S, Kroczek RA, Heinzerling L, Moser M, Mellor AL, David JP, Schett G. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Science Translational Medicine 2014, 6(235), 1-10.
- Li M, Bolduc AR, Hoda N, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Jojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. Journal for Immunotherapy of Cancer 2014, 2, 1-8.
- Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassany S. TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. Journal of Immunology 2014, 8(193), 4203-4213.
- Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, Shi H, Munn DH. An Inherently Bifunctional Subset of Foxp3+ T Helper Cells is Controlled by the Transcription Factor Eos. Immunity 2013, 38(5), 998-1012.
- Riella LV, Dada S, Chabtini L, Smith B, Huang L, Dakle P, Mfarraj B, D'Addio F, Adams LT, Kochupurakkal N, Vergani A, Fiorina P, Mellor AL, Sharpe AH, Yagita H, Guleria I. B7h (ICOS-L) maintains tolerance at the fetomaternal interface. American Journal of Pathology 2013, 182(6), 2204-2213.
- Koni PA, Bolduc A, Takezaki M, Ametani Y, Huang L, Lee JR, Nutt S, Kamanaka M, Flavell RA, Mellor AL, Tsubata T, Shimoda M. Constitutively CD40-activated B cells regulate CD8 T cell inflammatory response by IL-10 induction. Journal of Immunology 2013, 190(7), 3189-96.
- Huang L, Li L, Lemos H, Chandler PR, Pacholczyk G, Baban B, Barber GN, Hayakawa Y, McGaha TL, Ravishankar B, Munn DH, Mellor AL. Cutting Edge: DNA Sensing via the STING Adaptor in Myeloid Dendritic Cells Induces Potent Tolerogenic Responses. The Journal of Immunology 2013, 191(7), 3509-3513.
- Lucas R, Parikh S, Sridhar S, Guo D, Bhagatwala J, Dong Y, Caldwell R, Mellor A, Caldwell W, Zhu H, Dong Y. Cytokine profiling of young overweight and obese female African American adults with prediabetes. Cytokine 2013, 64(1), 310-5.
- Jrad-Lamine A, Henry-Berger J, Damon-Soubeyrand C, Saez F, Kocer A, Janny L, Pons-Rejraji H, Munn DH, Mellor AL, Gharbi N, Cadet R, Aitken RJ, Drevet JR. Indoleamine 2,3-Dioxygenase 1 (Ido1) Is Involved in the Control of Mouse Caput Epididymis Immune Environment. PLoS One 2013, 8(6).
- Huang L, Li L, Klonowski KD, Tompkins SM, Tripp RA, Mellor AL. Induction and role of indoleamine 2,3 dioxygenase in mouse models of influenza a virus infection. PLoS One 2013, 8(6).
- Fox JM, Sage LK, Huang L, Barber J, Klonowski KD, Mellor AL, Tompkins M, Tripp RA. Inhibition of indoleamine 2,3-dioxygenase enhances the T-cell response to influenza virus infection. Journal of General Virology 2013, 94(7), 1451-61.
- Xiao H, Peng Y, Hong Y, Huang L, Guo ZS, Bartlett DL, Fu N, Munn DH, Mellor AL, He Y. Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization. Journal of Immunology 2013, 190(11), 5866-73.
- Li L, Huang L, Lemos HP, Mautino M, Mellor AL. Altered tryptophan metabolism as a paradigm for good and bad aspects of immune privilege in chronic inflammatory diseases. Frontiers in Immunology 2012, 3(109).
- McGaha TL, Huang L, Lemos H, Metz R, Mautino M, Prendergast GC, Mellor AL. Amino acid catabolism: a pivotal regulator of innate and adaptive immunity. Immunological Reviews 2012, 249(1), 135-157.
- Huang L, Lemos H, Li L, Li M, Chandler PR, Baban B, McGaha TL, Ravishankar B, Lee J, Munn DH, Mellor AL. Engineering DNA Nanoparticles as Immunomodulatory Reagents that Activate Regulatory T Cells. The Journal of Immunology 2012, 188(10), 4913-4920.
- Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends in Immunology 2012, 34(3), 137-43.
- Ravishankar B, Liu H, Schinde R, chandler PR, Baban B, Tanaka M, Munn DH, Mellor AL, Karlsson MC, McGaha TL. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proceedings of the National Academy of Sciences of the United States of America 2012, 109(10), 3909-14.
- Makala LH, Baban B, Lemos H, El-Awady A, Chandler PR, Hou DY, Munn DH, Mellor AL. Leishmania major Attenuates Host Immunity by Stimulating Local Indoleamine 2,3-Dioxygenase Expression. Journal of Infectious Diseases 2011, 203(5), 715-725.
- Jrad-Lamine A, Henry-Berger J, Gourbeyre P, Damon-Soubeyrand C, Lenoir A, Combaret L, Saez F, Kocer A, Tone S, Fuchs D, Zhu W, Oefner PJ, Munn DH, Mellor AL, Gharbie N, Cadet R, Aitken RJ, Drevet JR. Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state. The Journal of Biological Chemistry 2011, 286(10), 8030-42.
- Medzhitov R, Shevach EM, Trinchieri G, Mellor AL, Munn DH, Gordon S, Libby P, Hansson GK, Shorman K, Dong C, Gabrilovich D, Gabrysova L, Howes A, O'Garra A. Highlights of 10 years of immunology in Nature Reviews Immunology. Nature Reviews Immunology 2011, 11, 693-702.
- Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, DuHadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL. Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. Journal of Infectious Diseases 2011, 205(1), 152-61.
- Baban B, Chandler PR, Huang L, Jonson BA, Li M, Sharpe ML, Francisco LM, Sharpe AH, Blazar BR, Munn DH, Mellor AL. Physiologic control of IDO competence in splenic dendritic cells. Journal of Immunology 2011, 187(5), 2329-35.
- Mellor AL, Munn DH. Physiologic control of the functional status of Foxp3+ regulatory T cells. Journal of Immunology 2011, 186(8), 4535-40.
- Diana J, Brezar V, Beaudoin L, Dalod M, Mellor AL, Tafuri A, vonHerrath M, Boitard C, Mallone R, Lehuen A. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. Journal of Experimental Medicine 2011, 208(4), 729-45.
- Johnson BA, Kahler DJ, Baban B, Chandler PR, Kang B, Shimoda M, Koni PA, Pihkala J, Vilagos B, Busslinger M, Munn DH, Mellor AL. B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proceedings of the National Academy of Sciences 2010, 107(23), 10644-10648.
- Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, Blazar BR, Mellor AL, Munn DH. Reprogrammed Foxp3+ Regulatory T Cells Provide Essential Help to Support Cross-presentation and CD8+ T Cell Priming in Naive Mice. Immunity 2010, 33(6), 942-954.
- Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. Journal of Immunology 2009, 183(4), 2475-2483.
- Muller AJ, Sharma MD, Chandler PR, DuHadaway J, Everhart ME, Johnson BA, Kahler DJ, Pihkala J, Peralta Soler A, Munn DH, Prendergast G, Mellor AL. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proceedings of the National Academy of Sciences 2008, 105(44), 17073-17078.
- HORUZSKO A, TOMLINSON PD, STRACHAN T, MELLOR AL. TRANSCRIPTION OF HLA-G TRANSGENES COMMENCES SHORTLY AFTER IMPLANTATION DURING EMBRYONIC-DEVELOPMENT IN MICE. IMMUNOLOGY 1994, 83(2), 324-328.