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Andrew
L. Mellor, Ph.D.
E-mail:
Research Emphasis: The immune system plays a critical role in many disease processes, including infectious and autoimmune diseases, allergic reactions and cancer, which all have inflammatory components that drive disease. In my laboratory we seek to understand how immune responses are regulated using genetically-manipulated mouse model systems. In 1998, through a continuing collaboration with Dr. David Munn's laboratory, we discovered a new molecular mechanism that protects the developing mouse fetus from attack by maternal T cells (Munn et al., 1998 Science 281:1191 and Mellor et al., 2001 Nature Immunology 2:64). We found that fetal survival depends on expression of indoleamine 2,3 dioxygenase (IDO), an enzyme that degrades the essential amino acid tryptophan. This seminal discovery helps explain the perplexing immunological paradox of fetal survival during mammalian pregnancy. Based on these studies, we proposed that cells expressing IDO regulate T cell responses by removing tryptophan. Current research is focused on distinct novel subsets of dendritic cells (DCs) that inhibit T cell responses when induced to express IDO by specific stimuli and the molecular mechanisms in DCs and in T cells involved in IDO-dependent regulation of T cell responses. To address these issues we use genetically manipulated (transgenic and knockout) mice, and a variety of experimental systems and approaches, including recombinant DNA technology, cell culture and transfection, flow cytometry and imaging techniques. Our goal is to understand how the immune system functions normally and under circumstances leading to disease. Potential clinical applications of our research include, improved control of infectious and autoimmune diseases, cancer, tissue transplant rejection, and spontaneous fetal miscarriage. Research activities in my laboratory are funded through multiple grant awards from the National Institutes of Health (NIH).
Selected Publications: (from a total of 114)
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
Marshall, B., Schulz, R., Zhou, M., and Mellor, A. (1999). Alternative splicing and hypermutation of a nonproductively rearranged TCRa chain in a T cell hybridoma. Journal of Immunology, 162:871-877.
Munn D.H., Shafizadeh, E. Attwood J.T., Bondarev, I., Pashine A., and Mellor A.L. (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. Journal of Experimental Medicine 189:1363-1372.
Jhaver, K.G., Chandler, P., Simpson, E. and Mellor A.L. (1999) Thymocyte antigens do not induce tolerance in the CD4+ T cell compartment. Journal of Immunology 163:4851-4858.
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.
Marshall, B., Keskin, D.B., Mellor, A.L. (2001) Regulation of protaglandin synthesis and cell adhesion by a tryptophan catabolizing enzyme. BMC Biochem 2:5.
Mellor, A.L. and Munn, D.H. (2001). Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. Journal of Reproductive Immunology 52:5-13.
A.L. Mellor, Chandler, P., Lee, G.K., Johnson, T., Keskin, D.B., Lee, J., & Munn, D.H. (2002) Indoleamine 2,3 dioxygenase, immunosuppression and pregnancy, Journal of Reproductive Immunology 57:143-150.
Fallarino, F., Vacca, C., Orabona, C.,Belladonna, M.L., Bianchi, R., Marshall, B., Keskin, D.B., Mellor, A.L., Fioretti, M.C., Grohmann, U., & Puccetti, P. (2002) Functional expression of indoleamine 2,3-dioxygenase by murine CD8a+ dendritic cells. International Immunology 14:65-68.
Mellor, A.L., Keskin, D.B., Johnson, T., Chandler, P., & Munn, D.H. (2002) Cells expressing indoleamine 2,3 dioxygenase inhibit T cell responses. Journal of Immunology 168:3771-6.
Friberg, M., Jennings, R., Alsarrag, M., Dessureault, S., Cantor, A., Extermann, M., Mellor, A.L., Munn, D. H., & Antonia, S. J. (2002) Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell mediated rejection. International Journal of Cancer 101:151-155.
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.
Lee, G.K., Park, H.J., Macleod, M., Chandler, P., Munn, D.H. & Mellor, A.L. (2002) Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107:1-9.
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.
Lee, J.R., Dalton, R.R., Messina, J.L., Sharma, M., Smith, D.M., Burgess, R.E., Mazzella, F., Antonia, S.J., Mellor, A.L., Munn, D.H., (2003) Pattern of recruitment of immunoregulatory antigen presenting cells in malignant melanoma. Lab. Invest. 83:1457-1466.
Baban, B., Chandler, P., McCool, D., Munn, D.H., Mellor, A.L. (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells and is maternal genome specific. J. Reproductive. Immunol. 61:67.
Munn, D.H., Sharma, M.D., Mellor, A.L. (2004) Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells J. Immunol. 172:4100-4110.
Munn D.H., Sharma M.D., Hou D., Baban B., Lee J.R., Antonia S.J., Messina J.L., Chandler P., Koni P.A., Mellor, A.L. (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin. Invest. 114:280.
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. 16:1391-6.
Invited Reviews:
Mellor, A.L. & Munn, D. (1999) Tryptophan catabolism and T cell tolerance: immunosuppression by starvation? Immunology Today 20:469-473.
Mellor, A.L. & Munn. D.H. (2000). Immunology at the maternal-fetal interface: Lessons for T cell tolerance and suppression. Annual Review of Immunology 18:367-391.
Mellor, A.L. & Munn D.H. (2001). Extinguishing maternal immune responses during pregnancy: Implications for immunosuppression. Seminars in Immunology 13:213-218
Mellor, A.L., & Munn, David H., (2003) Tryptophan catabolism and regulation of adaptive immunity. J. Immunol. 170:5809-5813.
Munn, D.H., & Mellor, A.L., (2003) Macrophages and the regulation of self-reactive T cells. Curr. Pharm. Design 9:257-264.
Munn, D.H., & Mellor, A.L. (2004) IDO and tolerance to tumors. Trends in Mol. Med. 10:15-18.
Mellor, A. L., & Munn, D. H. (2004). Policing Pregnancy: Regulatory T cells help keep the peace. Trends in Immunology. 25:563-5.
Mellor, A. L., & Munn, D. H. (2004). Indoleamine 2,3 dioxygenase expression in dendritic cells: Tolerance and tryptophan catabolism. Nature Rev. Immunol. 4:762-774.