Alan Levine, Ph.D.
Biomedical Research Building, 525
School of Medicine
2109 Adelbert Road.
Case Western Reserve University
Phone: (216) 368-0342
Fax: (216) 368-1674
Intestinal Host Defense: Immune tolerance, immune protection, and colon cancer
The intestinal mucosa is the largest lymphoid organ, as assessed by the quantity
of antibody produced, the number of resident leukocytes, and its surface area exposure
to the environment (greater than that of a tennis court). Confounding the situation,
the wall of the gut is continuously bathed by bacteria, parasites, fungi, amoebae,
viruses, mitogens, toxins, and immunogenic food proteins. Therefore, a complex multi-tiered
host defense system has evolved in the gut and can be divided into three areas:
(1) Barrier exclusion by an actively regenerating epithelial cell monolayer. (2)
Innate inflammatory responses mediated by local synthesis of pro- and anti-inflammatory
cytokines. (3) Acquired immune responses regulated by T lymphocytes.
Our laboratory focuses on the mechanisms that regulate these systems. (1) In murine
models of acute and chronic intestinal inflammation, we investigate the temporal
expression and regulation of pro-inflammatory and anti-inflammatory cytokines in
response to gut injury induced by ischemia or peritonitis, and in a transgenic mouse
that models human inflammatory bowel disease. (2) Using transgenic animal models,
we explore the mechanism by which co-stimulatory and accessory molecules direct
the development of immune tolerance as T cells migrate from the Peyer’s patch to
the gut wall. (3) We characterize the biochemical, spatial, temporal, and structural
organization of the signal transduction pathway initiating with the anti-specific
T cell receptor, and differentially regulated in naïve, helper, effector, and
mucosal T cells. (4) We research the regulation of integrin affinity/avidity, expression,
and activation in both naïve and memory T cells by the interstitial extracellular
matrix, and how matrix-induced T cell polarization modulates the partitioning of
the TCR/CD3 signaling complex in the plasma membrane.
With direct relevance to tumor immunology, (5) we study the overlap in the biochemical
signaling pathways emanating from integrin mediated adhesion of intestinal epithelial
cells to the basement membrane and a newly defined alternate pathway initiated by
transforming growth factor-beta, a cytokine that regulates both T cell function
and epithelial cell cycle and apoptosis in the intestine. Finally, (6) we are evaluating
a gene targeted murine model of colitis associated colorectal cancer (CAC). These
mutant mice develop initially epithelial hyperplasia and then adenomas at the sites
of intestinal inflammatory lesions. We are identifying those immune mediators that
mark the progression and initiate the transformation process.
Taddei, M.L., Parri, M., Zecchi, S., Raugei, G., Levine, A.D.,
Ramponi, G., Chiarugi. P. “Integrin-mediated cell adhesion and spreading engage
different sources of reactive oxygen species.” Antioxid Redox Signal.
Danese, S., Sans, M., Spencer, D., Beck, I., Doñate, F., Plunkett, M., de
la Motte, C., Redline, R., Shaw, D., Levine, A., Mazar, A., Fiocchi,
C. “Angiogenesis blockade as a new therapeutic approach to experimental colitis.”
Gut 56:855-862 (2007).
Winkelman, C., Higgins, P.A., Chen, Y.J.K., Levine, A.D. “Cytokines
in Long-term Ventilated ICU Patients after Activity and Rest.” Biol. Res.
Nursing 8(4):261-271 (2007).
Etling, M.R., Davies, S., Campbell, M., Redline, R.W., Pingfu Fu, P., Levine,
A.D. “Maturation of the mucosal immune system underlies colitis
susceptibility in interleukin-10 deficient (IL-10-/-) mice.” J. Leuko. Biol.
Kugathasan, S., Saubermann, L.J., Smith, L., Kou, D., Itoh, J., Binion, D.G.,
Levine, A.D., Blumberg, R.S., and Fiocchi, C. “Mucosal T-cell
immunoregulation varies in early and late inflammatory bowel disease.”
Gut 56:1696-1705 (2007).
Das, L., Levine, A.D. “TGF-b inhibits IL-2 Production and
Promotes Cell Cycle Arrest in T Cell Receptor-Activated Effector/Memory T Cells
in the presence of Sustained TCR Signal Transduction.” J. Immunol.
180(3): 1490-1498 (2008).
Stallion, A., Kou, T.D., Dudgeon, D.L., Levine A.D. “Endogenous
interleukin 6 production protects against histopathologic damage in a murine model
of ischemia/reperfusion injury.” Curr. Surg. 57 (6): 638-639 (2000).
Grossmann, J., Artinger, M., Grasso, A.W., Kung, H.-J., Scholmerich, J., Fiocchi,
C., Levine, A.D. “Hierarchical cleavage of focal
adhesion kinase (FAK) by caspases alters signal transduction during epithelial cell
apoptosis: Generation of two new kinases p94FAK and p84FAK.” Gastroenterology 120:
Robinson, J.K., Blanchard, T.G., Levine, A.D., Emancipator, S.N.,
Lamm, M.E. “A mucosal IgA-mediated excretory immune system in vivo.” J. Immunol.
166: 3688-3692 (2001).
Itoh, J., de la Motte, C., Strong, S.A., Levine, A.D.,
Fiocchi, C. “Decreased Bax expression by mucosal T-cells favours resistance to apoptosis
in Crohn’s disease.” Gut 49: 35-44 (2001).
Biedermann, T., Mailhammer, R., Mai, A., Sander, C., Ogilvie, A., Brombacher, F.,
Maier, K., Levine, A.D., Roecken, M. “Reversal
of established delayed type hypersensitivity reactions following therapy with IL-4
or antigen-specific Th2 cells.” Eur. J. Immunol., 31: 1582-1591 (2001).
Biedermann, T., S. Zimmermann, H. Himmelrich, A. Gumy, O. Egeter, A.K. Sakrauski,
I. Seegmuller, H. Voigt, P. Launois, A.D. Levine, H. Wagner, K.
Heeg, J.A. Louis, and M. Rocken. “IL-4 instructs TH1 responses and resistance to
Leishmania major in susceptible BALB/c mice.” Nature Immunology 2:1054-1060 (2001).
Spencer, D.M., Veldman, G.M., Banerjee S., Willis, J., Levine, A.D.
“Distinct inflammatory mechanisms mediate early versus late colitis in IL-10-deficient
mice.” Gastroenterology 122:94-105 (2002).
Schade, A.E., Levine, A.D. “Lipid raft heterogeneity
in human peripheral blood T lymphoblasts as a mechanism for regulating the initiation
of TCR signal transduction.” J. Immunology 168:2233-2239 (2002).
Jump, R.J., Levine, A.D. “Murine Peyer’s Patches
Favor Development of an IL-10-Secreting, Regulatory T Cell Population.” J. Immunology
168 (12): 6113-6119 (2002).
Latifi, S.Q., O’Riordan, M.A., Levine, A.D. “Interleukin
10 controls the onset of irreversible septic shock.” Infection and Immunity 70 (8):
Stallion, A., Kou, T.D., Miller, K.A., Dahms, B.B., Dudgeon, D.L., Levine A.D.
“Interleukin 10 is not protective in intestinal ischemic/reperfusion injury.”
J. Surgical Research 105: 145-152 (2002).
Schade, A., Levine, A.D. “Signal Transduction
through the T Cell Receptor Is Dynamically Regulated by Balancing Kinase and Phosphatase
Activity.” BBRC 296: 637-643 (2002).
Krivacic, K.A., Levine, A.D. “Extracellular matrix
preconditions T cells for adhesion to tissue epithelium” J. Immunol. 170: 5034-5044
Schade, A.E., Levine, A.D. “Phosphatases in concert
with kinases set the gain for signal transduction through the T cell receptor.”
Molecular Immunology (2003).
Krivacic, K.A., Levine, A.D. “Extracellular matrix
preconditions T cells for adhesion to tissue epithelium” J. Immunol.
170: 5034-5044 (2003).
Schade, A.E., Levine, A.D. “Phosphatases
in concert with kinases set the gain for signal transduction through the T cell
receptor.” Molecular Immunology 40 (8): 531-537 (2003).
Danese, S., de la Motte, C., Rivera Reyes, B.M., Sans, M., Levine, A.D.,
Fiocchi, C. “Cutting Edge: T Cells Trigger CD40-Dependent Platelet Activation
and Granular RANTES Release: A Novel Pathway for Immune Response Amplification.”
J. Immunology 172: 2011-2015 (2004).
Lin, F., Spencer, D., Hatala, D.A., Levine, A.D., Medof, M.E. “Decay-Accelerating
Factor Deficiency Increases Susceptibility to Dextran Sulfate Sodium-Induced Colitis:
Role for Complement in Inflammatory Bowel Disease.” J. Immunology
172: 3836-3841 (2004)
Schade, A.E, Levine, A.D. “Cutting Edge: Extracellular Regulated
Kinases 1/2 (ERK-1/2) function as integrators of T cell receptor signal strength.”
J Immunol. 172: 5828-5832 (2004).
Jump, R.L. and Levine, A.D. “Mechanisms of Natural Tolerance
in the Intestine: Implications for IBD.” IBD. 10:462-478
Sturm, A., Krivacic, K.A., Fiocchi, C., Levine, A.D. “Dual
Function of the Extracellular Matrix: Stimulatory for Cell Cycle Progression of
Naive T cells and Anti-Apoptotic for Memory T Cells.” J. Immunol.
173: 3889-3900 (2004).
Latifi, S.Q., O’Riordan, M.A., Levine, A.D., Stallion A.
“Persistent elevation of serum interleukin-6 in intra-abdominal sepsis identifies
those with prolonged length of stay.” J. Ped. Surgery. 39(10):1548-1552
Stallion, A., Kou, T.D., Miller, K.A., Dahms, B.B., Dudgeon, D.L., Levine, A.D.
“Ischemia / Reperfusion: A Clinically Relevant Model of Intestinal Injury.”
J. Ped. Surgery 40:470-477 (2005).
Manley, M. O, Levine, A.D., Latifi, S.Q. “Reversal of Immune
Paralysis and Return to Cytokine Homeostasis in Septic Shock Requires Infection
Control and IL-10 to Extend the Therapeutic Window.” Shock
Rivera Reyes, B.M., Danese, S., Sans, M., Fiocchi, C., Levine, A.D.
“Intracellular redox equilibrium in the intestinal lamina propria T cell (LPT)
tunes the T cell receptor (TCR) signaling cascade.” J. Immunology
175: 2158-2166 (2005).
Matsumoto, Y., Blanchard, T.G., Drakes, M.L., Basu, M., Redline, R.W., Levine,
A.D., Czinn, S.J. “Eradication of Helicobacter pylori and resolution
of gastritis in the gastric mucosa of IL-10 deficient mice.” Helicobacter
10(5): 407 (2005).