department of pharmacology

Alan Levine, Ph.D.

levine

Professor

Biomedical Research Building, 525
School of Medicine
2109 Adelbert Road.
Case Western Reserve University


Phone: (216) 368-0342
Fax: (216) 368-1674
E-mail: adl4@case.edu

Research

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.

SELECTED REFERENCES:

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. 9(4):469-81 (2007).

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. 82:311-319 (2007)

 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: 79-88 (2001).

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): 4441-4446 (2002).

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 (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 (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 (2004).

 

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 (2004).

 

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 23(6):521-526 (2005).

 

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).