7125 WMB, 101 Woodruff Circle
Atlanta, GA 30322
404 727-5929 Phone
Associate Professor, Emory University, School of Medicine, Dept. of Pathology and Laboratory Medicine
B.S. Chemistry, 1975 - 1975
M.S. Biochemistry, 1977 - 1977
Ph.D. Biochemistry, 1984 - 1984
Post Doc Immunology, 1984 - 1988
- Structure and function on Fc receptors
Fc receptors for IgG (FcgR) are involved in phagocytosis, antibody-dependent cellular cytotoxicity, and removal of immune complexes from blood circulation. FcgR III (CD16) is expressed in macrophages, granulocytes and NK cells. CD16 on granulocytes is phosphatidyl inositol glycan (GPI) anchored whereas the CD16 expressed on NK cells and macrophages is polypeptide anchored. These two membrane anchor isoforms of CD16 differ in triggering signals for tumor cell cytotoxicity and phagocytosis. Further structure-function studies will be carried out on membrane isoforms of CD16. We have also identified that the avidity state of FcgRII is regulated by cell activation. Future studies will focus on the defining the molecular mechanisms involved in regulation of affinity of FcgRII molecule expressed on human neutrophils.
- Development of 'artificial cancer cell vaccines' using protein transfer
Tumors modified by transfecting genes for immunostimulatory molecules such as B7 and cytokines are now considered as a potential therapeutic tumor vaccine. However, transfection is not always efficient and can be difficult with many cell types, especially freshly isolated tumor cells from patients. Moreover, transfection of genes requires the introduction of vectors of viral origin which is not desirable for human therapeutic purposes. Studies have shown that purified GPI-anchored cell surface proteins can be spontaneously incorporated into membranes by incubating the proteins with the cells or cell membranes (Protein Transfer). This unique property can be used to reconstitute cell surface expression receptors on cell membranes without the use of gene transfection. Using recombinant techniques, we have developed many immunostimulatory molecules including B7-1, IL-2, GM-CSF and IL-12 as GPI-anchored form. Currently we are using protein transfer to express these molecules to develop cancer vaccines for breast cancer and melanoma. In the long term the knowledge obtained from this study could be used to develop an 'artificial cell vaccine' to treat cancer.
Research Fellow, Harvard Medical School, 1988-1990
Instructor, Department of Pathology, Harvard Medical School, 1988-1990
Research Fellow, Wellcome Research Unit, Christian Medical College, 1979-1984
45. Fifadara NH, Tolentino TT, Shashidharamurthy R, Zarnitsina VI, Zhu C and Selvaraj P. Membrane cholesterol is critical for immune complex binding function for FcyRIIA. (Manuscript in preparation)
42. Selvaraj P, Yerra A, Tien L., Shashidharamurthy R. Custom designing therapeutic cancer vaccines: Delivery of immunostimulatory molecule adjuvants by protein transfer. Hum. Vaccin. 4: (5).
41. Shashidharamurthy R, Hennigar RA, Fuchs A, Palaniswami P and Selvaraj P. Extravasation and emigration of neutrophils tothe inflammatory site depend on the interaction of imjmune-complex with Fcy receptors and can be effectively blocked by decoy Fcy receptors. Blood 111: 894-904.
44. Bumgarner GW, Shashidharamurthy R, Nagarajan S, D'Souza MJ and Selvaraj P. Surface engineering of microparticles using a novel protein transfer technique: Potential applications in targeted drug delivery and vaccine adjuvant development J. Conrl. Release. (Under revision).
37. SkountzouI, Quan FS, Gangadhara S, Ye L, Vzorov A, Selvaraj P, Jacob J, Compans RW, Kang SM. Incorporation of glycoslphosphatidylinositol-anchored granulocyte-macrophage colony-stimulating factor or CD40 ligad enhances immunogenicity of chimeric simian imunodeficiency virus-like particles. J. Virol. 81:1083-94.
40. Shashidharamurthy R, Amaro A, Ezekwudo E and Selvaraj P. Analysis of competitive interaction of H and R allelic forms of CD32A with rabbit IgG immune-complex. Proc. Intl. Cong. Immunol. p 513-522.
38. LiP, Jiang N, Nagarajan S, Wohlhueter R, Selvaraj P and zhu C. Affinity and Kinetic Analysis of Fcy Receptor IIIa (CD16a) Binding to IgG Ligands. J. Biol. Chem. 282:6210-21.
35. Long M, Chen J, Jiang N, Selvaraj P, McEver RP and Zhu, C. Probabilistic modeling of rosette formation mediated by CD16B-hIgG and selectin-ligand interactions. Biophys J. 91:352-363
36. Wang YC, Sashidharamurthy R, Nagarajan S and Selvaraj P. B7-1-HSA (CD80-CD24), a recombiant hybrid costimulatory molecule retains ligand binding and costimulatory functions. Immunol Lett. 105:185-192
34. Nagarajan S and Selvaraj P. Human tumor membrane vesicles modified to express glycolipid-anchored IL-12 by protein transfer induce T cell proliferation in vitro: a protential approach for local delivery of cytokines during vaccination. Vaccine 14:2264-74.
30. Bumgarner GW, Zampell JC, Nagarajan S, Poloso NJ, Dorn AS, D'Souza MJ, Selvaraj P. Modified cell ELISA to determine the solubilization of cell surface proteins:Applications in GPI-anchored protein purification. J Biochem Biophys Methods. 64:99-109.
31. Nagarajan S, Fifadara NH, Selvaraj P. Signal-specific activation and regulation of human neutrophil Fc gamma receptors. J Immunol.174:5423-32.
32. Bumgarner, GW, Nagarajan, S, Poloso, N.J., Dorn, AS, D'Souza MJ, and P. Selvaraj. Modified cell ELISA to determine the solubilization of cell surface proteins: Applications in GPI-anchored protein purification. J. Biochem. Biophs. Methods 65:99-109.
33. Zhang F, Marcus WD, Goyal NH, Selvaraj P, Spring TA and Zhu C. Two-dimensional kinetics regulation of &alphaL&Beta2-ICAM-1 interaction by conformational changes of the &alphaL insterted domain. J. Biol. Chem. 280:42207-18.
28. Nagarajan, S, Li, P., C. Zhu and P. Selvaraj. Recombinant CD16A-Ig forms a homodimer and cross-blocks the ligand binding functions of neutrophil and monocyte Fcg Receptors. Mol. Immunol. 38:527-38.
29. Poloso NJ, Nagarajan S, Meji-Oneta JM and Selvaraj P. GPI-anchoring of GM-CSF results in active membrane-bound and partially shed cytokine. Mol Immunol. 38:803-16.
27. Poloso, N., S. Nagarajan, G. W. Bumgarner, J. Zampell, and P. Selvaraj. Designer Cancer Vaccines Made Easy: Protein Transfer of Immunostimulatory Molecules for Use in Therapeutic Tumor Vaccines. Frontiers in Biosci. 6:760-765.
26. Williams, T.E., S. Nagarajan, P. Selvaraj J, and C. Zhu. Quantifying the impact of microtopology on effective two-dimensional affinity. J. Biol. Chem. 276: 13283-13288.
25. Reaves, T.A., S.P. Colgan, P. Selvaraj, M.M. Pochet, S. Walsh, A. Nusrat, T.W. Liang, J.L. Madara and C.A. Parkos. Neutrophil transepithelial migration: regulation at the apical epithelial surface by Fc-mediated events. Am. J. Physiol 2001; 280:746-54.
21. Williams, T.E., P. Selvaraj, and C. Zhu. Concurrent binding to multiple ligands: Kinetic rates of CD16b for membrane-bound IgG1 and IgG2. Biophys. J. 2000; 79: 1858-1866
20. Chesla,S.E., P. Li, P. Selvaraj and C. Zhu. The membrane anchor influences ligand binding and 2D kinetic rates and 3D affinity of Fcg RIII (CD16). J. Biol. Chem. 275: 10235-10246
22. Williams, T.E., S. Nagarajan, P. Selvaraj, and C. Zhu. Concurrent and independent binding of Fcg receptors IIa and IIIb to surface-bound IgG. Biophys. J. 79: 1867-1875.
23. Nagarajan, S., K. Venkiteswaran, M. Anderson, U. Sayed, C. Zhu and P. Selvaraj. Cell specific, activation dependent regulation of neutrophil CD32A ligand binding function. Blood , 95: 1069-1077
23. Nagarajan, S., K. Venkiteswaran, M. Anderson, U. Sayed, C. Zhu and P. Selvaraj. Cell specific, activation dependent regulation of neutrophil CD32A ligand binding function. Blood , 2000; 95: 1069-1077
17. McHugh, R.S., S. Nagarajan, Y-C Wang, K.W. Sell and P. Selvaraj. Protein Transfer of GPI-B7-1 into Tumor Cell Membranes: A novel approach to tumor immunotherapy. Cancer Res. 59:2433-2437
19. Li, P., P. Selvaraj, P. and C. Zhu. Analysis of competition binding between soluble and surface-linked ligands for the same cell surface receptor. Biophys. J. 77: 3394-3406.
18. Nagarajan, S.and P. Selvaraj Protein transfer on tumor cells of functionally active glycolipid anchored B7-1 (CD80) expressed in recombinant baculovirus infected insect cells. Protein Expression and Purification 17: 273-281
15. McHugh, RS, Gilmartin., R, Sell, K.W. and P. Selvaraj. Detection of soluble form of B7-1 in synovial fluids using monoclonal antibodies against distinct epitopes of human B7-1. Clin. Immunol Immunopathol. 87: 50-59
16. Chesla S. E., P. Selvaraj and C. Zhu Measuring two-dimensional CD16 receptor-ligand binding kinetics with micropipette. Biophys J. 75: 1553-1572
14. Wang YC, L. Zhu, R. McHugh, S. D. Graham Jr., C. D. Hillyer, D. Dillehay, K. W. Sell and P. Selvaraj. Induction of autologous tumor specific cytotoxic T lymphocyte activity against a human renal carcinoma cell line by B7-1 (CD80) costimulation in vitro. J. Immunotherapy 19:1-8.
10. Wang, Y-C., L. Zhu, R. McHugh, K. W. Sell and P. Selvaraj. Heat stable antigen/CD24 provides a costimulatory signal for the tumor specific T cell proliferation and cytotoxicity in mice. Eur. J. Immunol. 25:1163-1167
11. Nagarajan, S., M. Anderson S. N. Ahmed, K. W. Sell.and P. Selvaraj. Purification and optimization of functional reconstitution on the surface of leukemic cell lines of GPI-anchored Fcg receptor III. J. Immunol. Methods 184: 241-251
12. Nagarajan, S., S. Chelsa, L. Cobern, P. Anderson, C. Zhu and P. Selvaraj. Ligand binding and phagocytic properties of CD16 isoforms: Phagocytic signaling by associated g and z subunits. J. Biol. Chem. 270:25762-25770
13. McHugh, R., S. N. Ahmed, Y-C. Wang K. W. Sell and P. Selvaraj. Construction, purification and functional reconstitution of a glycolipid anchored form of B7.1 on tumor cell membranes. Proc. Natl. Acad. Sci. (USA) 92:8059-8063
9. 16.Hibbs, M.L., P. Selvaraj., O. Carpen, T. A. Springer, H. Kuster, M. H. Jouvin, and J. P. Kinet. Mechanism regulating expression of membrane isoforms of Fcg R III (CD16). Science 246: 1608-1611
8. Selvaraj, P., O. Carpen, M. Hibbs, and T.A. Springer. Natural Killer cell and granulocytes Fcg receptor III (CD16) differ in membrane anchor and signal transduction. J. Immunol. 143: 3283 - 3288.
7. Selvaraj, P., W.F. Rosse, R. Silber, and T.A. Springer. The major Fc receptor in blood has a phosphatidylinositol anchor and is deficient in Paroxysmal Nocturnal Hemoglobinuria. Nature 333: 565 - 567
6. Dustin M.L., P. Selvaraj, R. Mattaliano, and T.A. Springer. Anchoring mechanisms for LFA-3 cell adhesion glycoprotein at membrane surface. Nature 329: 846 - 848.
5. Plunkett M.L., M.E. Sanders, P. Selvaraj, M.L. Dustin, S. Shaw and T.A. Springer. Rosetting of activated T-lymphocytes with autologous erythrocytes: Definition of the receptor and ligand molecules as CD2 and lymphocyte function associated antigen-3 (LFA-3). J. Exp. Med. 165: 664 - 676
4. Selvaraj, P., M.L. Dustin, R. Silber, M.G. Low and T.A. Springer. Deficiency of lymphocyte function associated antigen- 3 (LFA-3) in Paroxysmal Nocturnal Hemoglobinuria: Functional correlates and evidence for a phosphatidylinositol membrane anchor. J. Exp. Med.; 166: 1011 - 1025.
3. Selvaraj, P., M.L. Dustin, R. Mitnacht, T. Hunig, T.A. Springer and M.L. Plunkett. Rosetting of human T-lymphocytes with sheep and human erythrocytes: Comparison of human and sheep ligands binding using purified E receptor. J. Immunol. 138: 2690 - 2695
2. Selvaraj, P., M.L. Plunkett, M.L. Dustin, M.E. Sanders, S. Shaw and T.A. Springer. The T-lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3. Nature. 326: 400 - 403
1. Selvaraj, P., K.A. Balasubramanian. Comparative structural and lectin binding studies on gamma-glutamyltransferase from human adult liver, fetal liver and primary hepatomaEur. J. Biochem. 153: 485 - 490.
39. Selvaraj P. T cell Response. Encyclopedia of Cancer (Edited by Dr. Manfred Schwab, Springer-Verlag Berlin and Heidelberg GmbH & Co).
43. Ezekwudo D, Shashidharamurthy R, Devineni D, Bozeman E, Palaniappan R and Selvaraj P. Inhibition of expression of anti-apoptotic protein Bcl-1 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. Cancer Letters (In Press).