| | Principal Investigators
| David Neville, M.D. |
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Dr.
Neville received his M.D degree from the University of
Rochester School of Medicine in 1959 after completing
the four-year program plus an additional year within the
Department of Pathology as a student fellow. During this
time Dr. Neville developed the first method for isolating
a cell membrane fraction from a nucleated cell. Dr. Neville's
interest in cell surface membranes and receptors has been
the principle guide for his research career. After completing
an internship in internal medicine at Grace New Haven
Hospital, he moved to NIMH in 1960 where he was introduced
to macromolecular chemistry under the tutelage of Drs.
Bernhard, Bradley and Davies. Dr. Neville is currently
a Senior Investigator in NIMH. His laboratory is working
on the development of highly efficient recombinant anti-T
cell immunotoxins and their use to induce transplantation
tolerance. |
| Research Interests |
The
goal of Dr. Neville's work is to develop
an anti-T cell immunotoxin that can induce tolerance to
organ allografts and tolerance to various T cell driven
autoimmune diseases in a clinical setting. The working
hypothesis being tested is that a transient but profound
T cell depletion can reset the immune system to a tolerized
state in the presence of non-self antigen presentation.
With Dr. Judith Thomas at the University of Alabama in
Birmingham Dr. Neville's laboratory developed a protocol using a 2 day
course of immunotoxin and 14 days of deoxyspergualin (DSG),
an NFkB inhibitor. The immunotoxin plus DSG protocol has
been found to produce true tolerance in monkeys to mismatched
kidney allografts. These grafts are in place after 2-4
years without any evidence of chronic rejection as judged
by biopsy and normal serum creatinine values. The tolerant
state, which depends on the unique synergy between DSG
and immunotoxin, is characterized by: T cell hyporesponsiveness
to allograft antigens; absence of antibody to allograft
antigens; an immune deviation toward a TH2 state consisting
of 10-fold elevations in serum IL-4 and IL-10 levels lasting
over 2 years. Chimerism and micro-chimerism are not present.
No long-term untoward effects have been noted in these
monkeys. The same immunotoxin plus DSG protocol reverses
experimental diabetes in streptozotocin treated juvenile
monkeys given portal vein pancreatic islet allografts.
Current work centers on the development of recombinant
high affinity divalent anti-T cell immunotoxins using
the techniques of protein engineering. Affinity maturation
of mutated single chain antibody domains is being performed
by yeast display methodology coupled with fluorescent
activated cell sorting. Novel eukaryotic expression systems
are being investigated for immunotoxin production with
a focus on the yeast Pichia pastoris. GMP grade recombinant
immunotoxin is under production for an anticipated clinical
trial. |
| Representative Selected Recent Publications: |
- Thompson, J., Stavrou, S., Weetall, M., Hexam, M., Digan, M.E.,
Wang, Z., Woo, J.H. Yu, Y., Mathias, A., Liu, Y.Y., Ma, S., Gordienko, I., Lake, P. and
Neville DM Jr.: Improved Binding of a Bivalent Single-Chain Immunotoxin Results in
Increased Efficacy for In Vivo T-cell Depletion. Protein Engineering, 14, 1035-1041.
- Contreras, J.L., Jenkins, S., Eckhoff, D.E., Hubbard, W.J., Lobashevsky, A., Bilbao, G., Thomas,
F.T., Neville, D.M., Jr., Thomas, J.M.: Stable α- and β- Islet Cell Function After Tolerance Induction to Pancreatic Islet Allografts in Diabetic Primates.
American Journal of Transplantation, 3, 128-138.
- Liu, Y. Y., Woo, J.H. and Neville, D.M. Jr.:
Targeted Introduction of a Diphtheria Toxin Resistant Mutation into the Chromosomal EF-2 Locus of Pichia pastoris and Expression of Immunotoxin in the EF-2 Mutants.,
Protein Expression and Purification., 30, 262-274.
- Zhirui Wang and David M. Neville, Jr.:
Expression and Characterization of Recombinant Soluble Monkey CD3 Molecules: Mapping the FN18 Polymorphic Epitope.,
Molecular Immunology, 40(16), 1179-1188.
- Woo, J.H., Stavrou, S. and Neville, D.M. Jr.:
Increasing Secretion of a Bivalent Anti-T Cell Immunotoxin by Pichia pastoris.,
Applied and Experimental Microbiology, 70(6), 3370-3376.
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| Address: |
Dr.
David M. Neville
Section on Biophysical Chemistry
Laboratory of Molecular Biology, NIMH
Building 10, Room 3D46
10 Center Drive, MSC 1216
Bethesda, MD 20892-1216 |
| Phone: |
301-496-6807 |
| Email Dr. Neville |
| Fax: |
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| Lab Web Site: |
No website available |
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