Immunology Graduate Group

Mark I. Greene, M.D., Ph.D., F.R.C.P.
John Eckman Professor of Medical Science
Department of Pathology and Laboratory Medicine

Office Phone: (215) 898-2847
Email: greene@reo.med.upenn.edu

Education:
M.D., University of Manitoba, Canada
F.R.C.P., Internal Medicine, Fellow of the Royal College of Physicians
Ph.D., Immunology, University of Manitoba
Post Doctoral Fellow, Harvard Medical School

Research Interests

reovirus receptor, erbB receptors, T-cell receptors

Research Summary

Dr. Greene's research is concerned with defining the principles of receptor function. An area he has concentrated on for the last 20 years involves members of the erbB gene family.

A rationally designed inhibitor of the TNF receptor is shown bound to the receptor molecule. Development of a panel of small molecules which can penetrate into tissues and interfere with programmed cell death will help define the role of this process in lymphoid and neural development.

Greene's laboratory discovered that p185c-neu could associate with the EGFR to form a heteromeric assembly. This heteromeric complex possessed unique properties including increased kinase activity. The heteromers had a higher affinity for EGF than homomeric forms of the EGFR receptor and were found to represent the major signaling receptor form. Heteromer formation was found to be preferred over homomeric assembly and the ectodomains were found essential in stabilizing the oligomeric species.

Greene's laboratory developed an approach to down modulate oncoproteins which, when expressed were critical for abnormal growth. This simple approach developed in the neu system involved developing monoclonal antibodies specific for the ectodomain of p185. The approach was to take advantage of the formation of kinase active homomeric (p185-p185) or heteromeric p185c-neu-EGFR) assemblies found on malignant cells and which were active in mediating the transformed phenotype. Normal receptor species which are not down modulated,are in a kinase inactive configuration. Furthermore, down modulation of even normal receptors is not associated with cell injury. The approach was so successful that it is now approved for therapy of human breast tumors.

To develop this therapeutic modality Greene has developed an entirely new approach to reduce macromolecules such as antibodies to small synthetic forms. His laboratory was the first to develop organic synthetic antibody-like forms which retained biological activity. These small forms are designed with the aid of ray crystallography, structural analysis, computer modeling and peptide chemistry. The creation of small molecular forms modeled from the complementarity determining regions has now become widely practiced.

Finally, Greene's laboratory has been involved in the study of T cell tolerance for more than twenty years. The laboratory is now concerned with defining the affinity basis of escape from tolerance in transgenic models. The current studies are to analyze interactions with tolerogens and biochemical changes that occur after tolerogen induction. How isolated suppressor T cells mediate regulation is being studied at the cell and molecular level in a transgenic model.

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