Michael G. Mage, D. D. S.
Building 37, Room 4C28
37 CONVENT DR MSC 4255
BETHESDA MD 20892-4255
Phone: 301-496-1249
Fax: 301-402-3095
xgm@cu.nih.gov
Biography:
Dr. Mage received his postdoctoral training at Columbia
University, studying affinity purification and properties of antihapten
antibodies with Stuart Tanenbaum and Sam Beiser. He came to the NIH. in
1962, where he has studied antibody structure, and pioneered what are now
standard affinity-based cell separation methods. With his immunology group,
he studies T cell immunity to recombinant MHC molecules. A holder of the
Public Health Service commendation medal, his NCI home since 1966 has been
the Laboratory of Biochemistry.
Research:
T cell responses to infections, neoplasms, and autoantigens require
degradation of antigenic proteins and display of antigenic peptides by
MHC molecules on the surface of antigen-presenting cells. For HIV infections,
there is evidence that certain T cell responses, of the TH1 type, in the
absence of antibody formation, may be highly protective, while others,
of the TH2 type, may interfere. In other infections, the reverse may be
true. Certain peptides, due to their effective concentration, relative
affinity for MHC molecules, or to the T cell repertoire, may dominate a
T cell response at the expense of other peptides. Whole organism, protein,
or peptide vaccines rely on the cellular machinery to cut out and bind
peptides to endogenous MHC molecules, so investigators have limited control
over which peptides will be presented by which MHC molecules to the T cells.
Our group seeks to circumvent such problems by development of peptide-MHC
molecular vaccines. We prepare recombinant genes that encode single chain
MHC molecules with covalently attached antigenic peptides (MHCP). Following
the engineering by Dr. Li Lee of a recombinant single chain human Class
I MHC (HLA-A2.1) molecule with a viral peptide from HTLV1 covalently attached,
Dr. Xiaojie Zhu has engineered recombinant single chain human class II
(HLA-DR1) MHCP with covalently attached peptides (from influenza HA or
from HIV gag). In these molecules the entire heterotrimer of peptide, beta
chain, and alpha chain is expressed as a single covalently linked polypeptide
chain. These recombinant MHCP are expressed on the surface of transfected
cells. They stimulate normal human lymphocytes and the appropriate T cell
clones.
Recombinant MHC molecules may also be useful for studying the cell
biology of T cell stimulation. Dr. Zhu has prepared covalently linked Class
II MHCP as "superdimers" and "supertrimers" to study
the role of valency in TCR signal transduction. We are also preparing such
molecules with antagonist, agonist, and mixed peptides to study peptide
antagonism at the level of the MHCP-TCR interaction. Such soluble molecules,
used in the absence of costimulators or Fc receptors may be useful as T
cell toleragens. They are being evaluated for use in ex-vivo T cell expansion
in collaboration with Carl June and Katya Schlienger of the Naval Medical
Research Institute. We are preparing variants of these molecules for collaborative
studies with Ettore
Appella, M.D.,of NCI, and Bill Biddison, Roland Martin, and Bernard
Hemmer of NINDS. In collaboration with David
Margulies, M.D., Ph.D., National
Institute of Allergy and Infectious Diseases,, we are also using single
chain MHC Class I molecules as transgenes to study selection and expansion
of the T cell repertoire. We are interested in collaborating with investigators
who wish to explore covalent MHCP as immunogens and tolerogens.
Recent Publications:
- Lee L, McHugh L, Ribaudo RK, Kozlowski S, Margulies DH and Mage MG.
Functional
cell surface expression by a recombinant single chain class I MHC molecule
with a cis active b2 microglobulin domain. Eur J Immunol 1994;
24: 2633-2639.
- Lee L, McHugh L, Sakuma S, Loftus D, Appella E, Margulies DH, Mage
M. Peptide loaded recombinant single chain HLA molecules as potential immunogens
for T cells. In Brown F, Chanock R, Ginsburg HS, Norrby E (Eds.):
Vaccines 95. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY
1995, pp. 243-247.
- Grohmann U, Puccetti P, Belladonna ML, Fallarino F, Bianchi R, Binaglia
L, Sagakuchi K, Mage MG, Appella E, Fioretti MC. Multiple
point mutations in an endogenous retroviral gene confer high immunogenicity
on a drug-treated murine tumor. J Immunol. 1995; 154:4630-4641.
- Lee L, Loftus D, Appella E, Margulies DH, Mage M. A
recombinant single chain HLA-A2.1 molecule, with a cis active beta-2-microglobulin
domain, is biologically active in peptide binding and antigen presentation.
Human Immunol 1996; 49: 28-37.
- Zhu X, Bavari S, Ulrich R, Sadegh-Nasseri S, Ferrone S, McHugh L, and
Mage M. A recombinant single chain human Class II MHC molecule (HLA-DR1)
as a covalently linked heterotrimer of alpha chain, beta chain, and antigenic
peptide, with immunogenicity in vitro and reduced affinity for bacterial
superantigens. Eur J Immunol 1997;27:1933-1997.
- Plaksin D, Polakova K, Mage MG, Margulies DH. Rigidification of the
Alpha 2 helix of an MHC Class I molecule by a valine to proline mutation
in position 165 does not prevent peptide specific antigen presentation.
J Immunol 1997;159:4408-4414.
Last revised on July 2, 1998, by Beverly
Miller
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