WeO-01


CHEMICAL COMMUNICATION BETWEEN CELLS TRYING TO OVERCOME A VIRAL INFECTION OR CANCER: DECIPHERING THE CODED MESSAGES BY MASS SPECTROMETRY

Donald F. Hunt

Departments of Chemistry and Pathology, University of Virginia, Charlottesville, Virginia 22901


A complex mixture of 10,000 fragments derived from cellular proteins is displayed on the surface of cells in association with class I glycoproteins of the major histocompatability complex (MHC). Cytotoxic T-lymphocytes (CTL) bind to the class I molecules, samples the peptides being presented, and lyse those cells that display new antigens as a result of viral infection, tissue transplantation, autoimmune disorders, or disease states such as cancer (1). Identification of these processed antigens is an important goal because it is a first step in the development of vaccines or other immunoregulators to control the above diseases (2,3). Peptides that cause CTL; (a) to kill melanoma cells (4), (b) to reject male tissues transplanted into females (5), (c) to eliminate leukemic cells prior to bone marrow transplantation (6) and (d) to lyse HIV infected cells have been identified recently. Each was identified and sequenced at the 0.2-50 femtomole level by combining microcapillary HPLC-tandem mass spectrometry with a sensitive immunological assay.

  1. How Cells Process Antigens, V.H. Engelhard, Scientific American, August, 1994, pp 54-61.
  2. Characterization of Peptides Associated with the Class I MHC Molecule, HLA-A2.1, D.F. Hunt, R. A. Henderson, J. Shabanowitz, K. Sakaguchi, H. Michel, N. Sevilir, A.L. Cox, E. Appella, and V. H. Engelhard, Science, 1992, 255, 1261-1263.
  3. Characteristics of Endogenous Peptides Eluted from the Class I MHC Molecule HLA B7 Determined by Mass Spectrometry and Computer Modeling, E. L. Huczko, W. M. Bodnar, D. Benjamin, K. Sakaguichi, N.Z. Zhu, J. Shabanowitz, R.A. Henderson, E. Appella, D.F. Hunt and V. H. Engelhard, J. Immunol. 1993, 151, 2572-2587
  4. Identification of a Peptide Recognized by Five Melanoma Specific Human Cytotoxic T-Cell Lines, A.L. Cox, J. Skipper, Y. Chen, R.A. Henderson, T.L. Darrow, J. Shabanowitz, V.H. Engelhard, D.F. Hunt, and C.L. Slingluff, Jr., Science, 1994, 264, 716-719.
  5. The Human Male Specific Histocompatibility Antigen H-Y is Derived from the SMCY Protein, W. Wang, L.R.Meadows, J.M.M. dan Haan, N.E. Sherman, Y. Chen, E. Blokland, J. Shabanowitz, A. I.Agulnik, C.E. Bishop, D.F. Hunt, E. Goulmy,and V.H. Engelhard, Science, 1995, 269, 1588-1590.
  6. Identification of a Graft-Versus-Host Disease Associated Human Minor Histocompatibility Antigen, J.M.M. den Haan, N.E. Sherman, E. Blokland, E. Huczko, F. Konig, J. W. Drijhout, J. Skipper, J. Shabanowitz, D.F. Hunt, V.H. Engelhard and E. Goulmy, Science, 1995, 268, 1476-1480.
  7. Posttranslational Modification of a Naturally Occurring Peptide Epitope in Melanoma Cells, J.C A. Skipper, R. Hendrickson, P. Gulden, V. Brichard, Y. Chen, J. Shabanowitz, C.J. Slingluff, Jr., T. Boon, D.F. Hunt, and V.H. Engelhard, J. Exp. Medicine, 1996, 183, 527-534.